Bundelan Ko2 Kelas C Dan D 2021

Praktikum Kimia Organik II
Tahun Akademik 2020/2021

BUNDELAN
PRAKTIKUM KIMIA ORGANIK II
TAHUN AJARAN 2020/2021
KELAS : C DAN D
SHIFT : SIANG
JAM : 13.30 - 16.00
KOORDINATOR HARIAN : ANNISA RAHMI Z.J, S.Si
KOODINATOR UMUM : RAHMI VIKA ULIA, S.Si
JURUSAN KIMIA
FAKULTAS MATEMATIKA DAN ILMU PENGETAHUAN ALAM
UNIVERSITAS ANDALAS
PADANG
2021
i
HALAMAN PENGESAHAN
Bundelan ini dibuat oleh kelas C dan D sebagai salah satu syarat untuk mengikuti Ujian
Akhir Praktikum Kimia Organik II dan disahkan pada tanggal…….
Disetujui oleh :
Koordinator Harian Koordinator Umum
Annisa Rahmi Z.J, S.Si Rahmi Vika Ulia, S.Si
2020412018 2020412006
Mengetahui
Dosen Pengampu Praktikum
Emil Salim, M.Sc.,M.Si
NIP. 198508142015041001
i
HALAMAN PERSETUJUAN
Bundelan ini telah diperiksa dan disetujui oleh Asisten Praktikum Kimia Organik II
Kelas C dan D.
Diperiksa oleh :
Objek I Objek II Objek III
Annisa Rahmi Z.J, S.Si Annisa Rahmi Z.J, S.Si Rahmi Vika Ulia, S.Si
2020412018 2020412018 2020412006
Objek IV Objek V Objek VI
Martania Anggriany, S.Si Rifki Rinaldi, S.Si Rifki Rinaldi, S.Si

2020412010 1610413007 1610413007
ii
KATA PENGANTAR
Puji syukur kehadirat Allah SWT yang telah hingga saat ini masih memberikan kita
nikmat iman dan kesehatan, sehingga masih diberi kesempatan untuk menyelesaikan
Bundelan Praktikum Kimia Organik II dengan tepat waktu. Shalawat serta salam tidak
lupa selalu kita haturkan untuk junjungan nabi kita, yaitu Nabi Muhammad SAW yang
telah menyampaikan petunjuk dari Allah SWT untuk kita semua, yang merupakan
sebuah petunjuk yang paling benar yakni Syariah Agama Islam yang sempurna dan
merupakan satu-satunya karunia paling besar bagi seluruh alam semesta.
Bundelan Praktikum Kimia Organik II disusun dengan maksud untuk

melengkapi tugas akhir praktikum dan syarat untuk mengikuti Ujian Akhir Praktikum
(UAP) Kimia Organik II. Dalam melakukan praktikum dan penysunan Bundelan
Praktikum Kimia Organik II ini, tentunya banyak sekali hambatan yang dialami, oleh
karena itu kami berterimakasih kepada dosen pengampu praktikum dan asisten
praktikum yang telah membantu dan mengawasi kami selama proses ini. Selain itu
kami sadar bahwa pada Bundekan Praktikum kimia Organik II ini dapat ditemukan
banyak sekalii kekurangan serta jauh dari kesempurnaan. Oleh sebab itu, kami
mengharapkan saran serta masukan dari pada pembaca demi tersusunnya Bundelan
Praktikum Kimia Organik II lain yang lebih baik lagi. Akhir kata, kami berharap agar
Bundelan Praktikum Kimia Organik II ini dapat memberikan banyak manfaat dalam
berlangsungnya Praktkum Kimia Organik II berikutnya.
Padang,28 Mei 2021
Penyusun
iii
DAFTAR ISI
HALAMAN SAMPUL
HALAMAN PENGESAHAN ................................................................................. i
HALAMAN PERSETUJUAN .............................................................................. ii
KATA PENGANTAR ........................................................................................... iii
DAFTAR ISI ......................................................................................................... iv
OBJEK I : SINTESIS ETIL ASETAT .................................................................. 1
I. TUJUAN .................................................................................................. 2
II. LANDASAN TEORI ................................................................................ 2
2.1 Etil Asetat ......................................................................................... 2
2.2 Sifat-Sifat Etil Asetat ......................................................................... 3
2.3 Proses Pembuatan Etil Asetat .......................................................... 3
III. PROSEDUR PERCOBAAN ................................................................... 5
3.1 Alat dan Bahan .................................................................................. 5
3.1.1 Alat dan Fungsi ........................................................................ 5
3.1.2 Bahan dan Fungsi .................................................................... 5
3.2 Cara Kerja ........................................................................................ 6
3.3 Skema Kerja ...................................................................................... 7
3.4 Skema Alat ........................................................................................ 8
3.4.1 Alat Refluks ............................................................................. 8
3.4.2 Alat Destilasi ........................................................................... 9
IV. DATA DAN PERHITUNGAN ................................................................... 10
4.1 Data dan Perhitungan ....................................................................... 10
4.1.1 Data ......................................................................................... 10
4.1.2 Perhitungan ............................................................................. 10
4.2 Hasil Karakterisasi ............................................................................ 12
4.3 Pembahasan ................................................................................... 13
iv
V. KESIMPULAN DAN SARAN ................................................................. 15
5.1 Kesimpulan ...................................................................................... 15
5.2 Saran ............................................................................................... 15
DAFTAR PUSTAKA ...................................................................................... 16
Lampiran I. Tugas Sebelum Praktikum ..................................................... 17
Lampiran II. Struktur Senyawa yang Digunakan ....................................... 19
Lampiran III. Analisis Artikel Ilmiah ........................................................... 20
Artikel yang Dianalisis
OBJEK II : SINTESIS METIL SALISILAT ........................................................... 25

I. TUJUAN .................................................................................................. 26
2.1 Ester ................................................................................................ 26
2.2 Asam Salisilat ................................................................................... 26
2.3 Metil Salisilat .................................................................................... 27
3.1 Alat dan Bahan ................................................................................. 29
3.1.1 Alat dan Fungsi ........................................................................ 29
3.1.2 Bahan dan Fungsi .................................................................... 29
3.2 Cara Kerja ........................................................................................ 30
3.3 Skema Kerja ...................................................................................... 31
3.4 Skema Alat ........................................................................................ 32
3.4.1 Alat Refluks ............................................................................. 32
3.4.2 Alat Destilasi ........................................................................... 33
IV. HASIL DAN PEMBAHASAN .................................................................. 34
4.1.1 Data ......................................................................................... 34
4.1.2 Perhitungan ............................................................................. 34
4.2 Pembahasan .................................................................................... 36
V. KESIMPULAN ........................................................................................ 38
5.1 Kesimpulan ...................................................................................... 38
5.2 Saran ............................................................................................... 38
DAFTAR PUSTAKA ...................................................................................... 39
v
OBJEK III : ASETON ........................................................................................... 55

I. TUJUAN .................................................................................................. 56
2.1 Keton ............................................................................................... 56
2.2 Aseton .............................................................................................. 57
2.3 Pembuatan Aseton ............................................................................ 58
3.1 Alat dan Bahan ................................................................................. 60
3.1.1 Alat dan Fungsi ........................................................................ 60
3.1.2 Bahan dan Fungsi .................................................................... 60
3.2 Cara Kerja ........................................................................................ 61
3.3 Skema Kerja ...................................................................................... 62
3.3.1 Pembuatan larutan oksidator K2Cr2O7 ..................................... 62
3.3.2 Pembuatan Aseton .................................................................. 62
3.4 Skema Alat ........................................................................................ 63
4.1.1 Data ......................................................................................... 64
4.1.2 Perhitungan ............................................................................. 64
4.2.1 Hasil Spektrum FT-IR ............................................................... 66
4.2.2 Tabel Hasil Spektrum Beserta Gugus Fungsi ........................... 66
4.3 Pembahasan .................................................................................... 67
V. KESIMPULAN ........................................................................................ 70
5.3 Kesimpulan ...................................................................................... 70
5.4 Saran ............................................................................................... 70
DAFTAR PUSTAKA ...................................................................................... 71
vi
OBJEK IV : SINTESIS KLOROFORM ................................................................. 87
I. TUJUAN .................................................................................................. 88
2.1 Kloroform ......................................................................................... 88
2.2 Aseton .............................................................................................. 90
3.1 Alat dan Bahan ................................................................................. 92
3.1.1 Alat dan Fungsi ........................................................................ 92
3.1.2 Bahan dan Fungsi .................................................................... 92
3.2 Cara Kerja ........................................................................................ 93
3.3 Skema Kerja ...................................................................................... 94
3.4 Skema Alat ........................................................................................ 95
IV. DATA DAN PERHITUNGAN ................................................................... 96
4.1 Data dan Perhitungan ...................................................................... 96
4.1.1 Data ......................................................................................... 96
4.1.2 Perhitungan ............................................................................. 96
4.2 Pembahasan .................................................................................... 98
V. KESIMPULAN ........................................................................................ 100
5.1 Kesimpulan ...................................................................................... 100
5.2 Saran ............................................................................................... 100
DAFTAR PUSTAKA ...................................................................................... 101
OBJEK V : SINTESIS ASETANILIDA ................................................................. 116

I. TUJUAN .................................................................................................. 117
2.1 Asam Karboksilat ............................................................................. 117
2.2 Amida ............................................................................................... 117
2.3 Asetanilida ........................................................................................ 117
2.4 Sintesis Asetanilida .......................................................................... 118
2.5 Pembentukan Kristal ........................................................................ 119
vii
3.1 Alat dan Bahan ................................................................................. 121
3.1.1 Alat dan Fungsi ........................................................................ 121
3.1.2 Bahan dan Fungsi .................................................................... 121
3.2 Cara Kerja ........................................................................................ 122
3.3 Skema Kerja ...................................................................................... 123
3.4 Skema Alat ........................................................................................ 124
4.1.1 Data ......................................................................................... 125
4.1.2 Perhitungan ............................................................................. 125
4.3 Pembahasan .................................................................................... 128
V. KESIMPULAN ........................................................................................ 130
5.1 Kesimpulan ...................................................................................... 130
5.2 Saran ............................................................................................... 130
DAFTAR PUSTAKA ...................................................................................... 131
OBJEK VI : SINTESIS ASPIRIN.......................................................................... 144

I. TUJUAN ................................................................................................. 145
II. LANDASAN TEORI ............................................................................... 145
2.1 Asam Salisilat ( C6H4(OH)COOH ) ................................................... 145
2.2 Asal Asam Salisilat ........................................................................... 145
2.3 Reaksi Esterifikasi ............................................................................ 146
2.4 Reaksi Asetilasi Friedel-Craft ........................................................... 147
2.5 Proses Pembuatan Aspirin ............................................................... 147
2.6 Rekristalisasi .................................................................................... 148
3.1 Alat dan Bahan ................................................................................. 149
3.1.1 Alat dan Fungsi ........................................................................ 149
3.1.2 Bahan dan Fungsi .................................................................... 149
3.2 Cara Kerja ........................................................................................ 150
viii
3.3 Skema Kerja ...................................................................................... 151
3.4 Skema Alat ........................................................................................ 152
4.1.1 Data ......................................................................................... 153
4.1.2 Perhitungan ............................................................................. 153
4.3 Pembahasan .................................................................................... 156
V. KESIMPULAN DAN SARAN .................................................................. 159
5.1 Kesimpulan ...................................................................................... 159
5.2 Saran ............................................................................................... 159
DAFTAR PUSTAKA ...................................................................................... 160
ix
OBJEK I
SINTESIS ETIL ASETAT
ANNISA RAHMI Z.J, S.Si

“ A negative mind will never give you a positive life”
SINTESIS ETIL ASETAT
I. TUJUAN
1. Mensintesis etil asetat dari etanol dan asam asetat dengan menggunakan
katalis asam sulfat
2. Memahami mekanisme reaksi pembuatan etil asetat
II. LANDASAN TEORI
2.1 Etil Asetat
Etil asetat adalah cairan jernih, tidak berwarna, berbau khas yang digunakan
sebagai pelarut tinta, perekat dan resin. Jika dibandingkan dengan etanol, etil asetat
memiliki koefisien distribusi yang lebih tinggi dibanding etanol termasuk kelarutannya
dalam gasoline. Selain dari penggunaannya sebagai pelarut, etil asetat dapat
berfungsi sebagai bahan aditif untuk meningkatkan bilangan oktan pada bensin serta
dapat berguna sebagai bahan baku kimia serba guna. Pembuatan etil asetat
biasanya dilakukan dengan esterifikasi.
Reaksi asam karboksilat dengan alkohol menghasilkan senyawa ester melalui
reaksi yang dikenal dengan nama esterifikasi dan biasanya menggunakan katalis
asam. Reaksi akan berlangsung dengan baik jika direfluks bersama sedikit asam
sulfat atau asam klorida. Di industri dan di laboratorium etil asetat dibuat dengan
memanaskan etanol dengan asam asetat glasial dengan penambahan asam sulfat.
Reaksi antara asam asetat dan etanol dengan katalis asam sulfat akan
menghasilkan etil ester dan air seperti pada reaksi dibawah ini1.
CH3 COOH + CH3CH2 OH ↔ CH3 COOC2 H5 + H2 O
Asam Asetat Etanol Etil Asetat Air
Proses ini membutuhkan katalis asam seperti asam sulfat, asam klorida, asam
ptoluena sulfonat. Campuran ini diubah menjadi ester sekitar 65% rendemen pada
suhu kamar. Reaksi dapat dipercepat dengan katalisis asam dan kesetimbangan
dapat digeser ke kanan dengan menghilangkan air. Titik didih normal etil asetat,
etanol, air dan asam asetat masing-masing adalah 77,1; 78,4; 100 dan 118,1°C.
Urutan volatilitas adalah etil asetat, etanol, air dan asam asetat. Etanol dan air tidak
berbeda jauh dalam volatilitas, sehingga sulit untuk memisahkannya. Aezotrop
homogen biner titik didih minimum antara etanol-air dibentuk pada suhu 78,2°C,
untuk etil aseta-etanol dibentuk pada suhu 71,8°C serta etanol-etil asetat-air dibentuk
pada suhu 70,3 C2.
2
Sintesis Etil Asetat
2.2 Sifat-Sifat Etil Asetat
Sifat fisika dan kimia etil asetat dapat dilihat pada tabel 1 berikut.
Tabel 1. Sifat Fisika Etil Asetat
Sifat Fisika Keterangan
Wujud Cairan bening
Berat molekul 88,105 gr/mol
Densitas 0,897 gr/ml
Titik leleh -83,6 ͦC
Titik didih 77,1 ͦC
Titik nyala -4 ͦC
(Data diambil pada keadaan standar 25°C dan 100 Kpa)
Etil asetat mempunyai ciri-ciri sebagai berikut:
1. Tidak beracun dan tidak terhigroskopis.
2. Merupakan pelarut polar menengah yang volatil (mudah menguap).
3. Dapat melarutkan air hingga 3%, dan larut dalam air hingga kelarutan 8%
pada suhu kamar.
4. Merupakan penerima ikatan hidrogen yang lemah dan bukan suatu donor
ikatan hidrogen.
5. Kelarutannya meningkat pada suhu yang lebih tinggi. Namun demikian
senyawa ini tidak stabil dalam air yang mengandung basa atau asam3.
2.3 Proses Pembuatan Etil Asetat
Etil ester dapat disintesis melalui reaksi esterifikasi. Esterifikasi merupakan reaksi
pembentukan ester dengan reaksi langsung antara suatu asam karboksilat dengan
suatu alkohol. Reaksi esterifikasi dipengaruhi beberapa variabel, salah satunya yaitu
katalis. Katalis meyebabkan laju reaksi kimia menjadi lebih cepat pada suhu tertentu.
Katalis H2SO4 lebih dipilih dibanding HCl karena katalis H2SO4 memiliki konsentrasi
ion H+ lebih besar dibanding HCl4. Etil asetat dapat dibuat dengan berbagai proses,
berikut ini beberapa proses pembuatan etil asetat, diantaranya adalah:
1. Proses Esterifikasi
Proses esterifikasi dalam industri dapat dilakukan secara kontinyu maupun
batch. Pemilihan kedua macam proses tersebut tergantung pada kapasitas
produksinya. Untuk kapasitas produksi yang relatif kecil sebaiknya jenis yang
digunakan adalah proses batch. Pada proses ini reaktan yang digunakan merupakan
etanol dan asam asetat dengan menggunakan katalis asam sulfat. Proses ini
3
berlangsung pada temperatur 100°C dengan yield etil asetat yang dihasilkan yaitu
67%.
Reaksi yang berlangsung:
CH3COOH(l) + CH3CH2OH(l)  CH3COOCH2CH3(l) + H2O(l)
2. Proses Reaksi Tischenko
Proses pembuatan etil asetat dengan reaksi Tischenco, menghasilkan yield
60% ester dengan penambahan aluminum ethoxide dalam asetaldehid terjadi pada
suhu -20ºC. Pengembangan produk pada skala industri berada di Eropa selama awal
pertengahan abad, lalu asetaldehid menjadi produk intermediat penting dalam bahan
dasar pembuatan asetilen.
2CH3CHO(l)  CH3COOCH2CH3(l)
3. Proses Theodore
Bahan baku yang digunakan adalah etanol dan asam asetat dengan katalis
zirconium dioxide pada suhu 70oC. Proses ini berlangsung secara batch dengan
konversi mencapai 64%.
CH3COOH(l) + C2H5OH(l)  CH3COOCH2CH3(l)
4. Proses Hidrogenasi
Bahan baku yang digunakan adalah asam asetat dari distilasi pertama pada
kolom distilasi kedua dipisahkan dan dikembalikan ke mixing point. Distilasi dari
kolom pertama akan diekstraksi pada kolom ekstraksi dengan top product berupa etil
asetat. Sedangkan residu kolom ekstraksi akan dipisahkan pada kolom distilasi
ketiga sehingga dihasilkan etanol sebagai distilat dan air sebagai residunya.
5. Proses Dehidrogenasi dan Dimerisasi
Proses ini dijelaskan pada US Pat. No. 9447018 dimana bahan baku yang
digunakan adalah etanol. Produksi etil asetat terjadi pada suhu 211°C dengan
tekanan 20 bar di dalam Reactive Distillation Coloumn (RDC) menggunakan katalis
CuO/ZnO/Al2O3. Pada proses dehidrogenasi akan terbentuk esetaldehid dan
hidrogen. Sedangkan pada proses dimerisasi, etanol akan bereaksi dengan
asetaldehid membentuk etil asetat dan hidrogen. Kemurnian etil asetat dalam proses
ini sebesar 98,5%5.
C2H5OH(l)  CH3CHO(l) + H2(g)
CH3CHO(l) + C2H5OH(l)  CH3COOC2H5(l) + H2(g)
4
III. PROSEDUR PERCOBAAN
3.1 Alat dan Bahan
3.1.1 Alat dan Fungsi
No Alat Fungsi
1 Gelas piala Sebagai wadah melarutkan zat
2 Kondensor Sebagai pendingin
3 Gelas ukur Sebagai wadah untuk penakar volume zat cair
4 Labu destilasi Sebagai tempat mendistilasi
5 Batang pengaduk Sebagai alat untuk mengaduk larutan
6 Erlenmeyer Sebagai wadah hasil distilasi
3.1.2 Bahan dan Fungsi

No Bahan Fungsi
1 Asam asetat Sebagai bahan dasar
2 Kalium klorida anhidrat Sebagai penarik air
3 Etanol Sebagai bahan dasar
4 Asam sulfat pekat Sebagai katalis
5 Natrium karbonat Sebagai bahan penetral asam
6 Batu es Sebagai bahan pendingin larutan
7 Kalsium klorida 5% Sebagai bahan penarik air
8 Kerta lakmus Sebagai penguji pH
5
3.2 Cara Kerja
1. Dalam labu destilasi, dicampurkan dengan hati-hati 30 gram etanol, 30 gram
asam asetat dan 8 gram asam sulfat pekat. Dilakukan refluks selama 90
menit.
2. Destilasi dilakukan
3. Diuji etil asetat yang terbentuk dengan cara dituangkan 10 tetes distilat ke
dalam 1 mL air. Jika terbentuk 2 lapisan, berarti sudah terbentuk senyawa
esternya. Kemudian dilanjutkan distilasinya. Disamping itu dapat juga
dengan mendeteksi baunya.
4. Setelah distilasi selesai, terhadap distilat ditambahkan natrium karbonat 2
gram, dicek dengan kertas lakmus.
5. Dipisahkan ester dari lapisan air kemudian dicuci ester yang terbentuk
dengan 15 mL air es. Lapisan air dibuang.
6. Ditambahkan kalsium klorida 5% sebanyak 25 mL, dipisahkan ester yang
terbentuk dan dikeringkan dengan kalsium klorida anhidrat.
7. Rendemen etil asetat yang terbentuk dihitung,
8. Dikarakterisasi dengan spektrofotometer UV-Vis, FT-IR dan HPLC.
6
3.3 Skema Kerja
30 g asam asetat
- dimasukkan ke dalam labu distilasi

- ditambahkan 30 gram etanol
- ditambahkan 8 gram asam sulfat pekat
- dicampurkan dengan hati-hati
Campuran
- direfluks selama 90 menit

- didistilasi
- diuji sudah terbentuk etil asetat atau belum
Distilat
- ditambahkan 2 gram natrium karbonat

- dicek dengan kertas lakmus
- dipisahkan ester yang terbentuk
Ester
- dicuci dengan 15 mL air dingin

- dibuang lapisan air
- ditambahkan kalsium klorida 5% 25 mL
- dipisahkan lapisan air
- dikeringkan dengan kalsium klorida anhidrat
- dihitung rendemen
Hasil
7
3.4 Skema Alat
3.4.1 Alat Refluks
1 3
2
4
6
7
Keterangan:
1. Standar
2. Klem
3. Air keluar
4. Kondensor
5. Air masuk
6. Labu didih
7. Batu didih
8. Pemanas
8
3.4.2 Alat Destilasi
1
8
9
2
4 7
5 10
11
Keterangan:
1. Standar
2. Klem
3. Termometer
4. Labu didih
5. Batu didih
6. Pemanas
7. Kondensor
8. Air keluar
9. Air masuk
10. Adaptor
11. Erlenmeyer
9
IV. HASIL DAN PEMBAHASAN
4.1 Data dan Perhitungan
4.1.1 Data
Massa etanol = 30 gram
Massa asam asetat = 30 gram
Massa asam sulfat = 8 gram
Berat jenis etanol = 0,08 g/mol
Berat jenis asam asetat = 1,05 g/mol
Berat jenis asam sulfat = 1,03 g/mol
4.1.2 Perhitungan
a) Volume Etanol
V etanol = 30 g × 0,1 80
ml
g
= 37,5 ml
b) Volume asam asetat

1 ml
V asam asetat = 30 g × 1,05 g
= 28,57 ml
c) Volume asam sulfat

1 ml
V asam sulfat = 8 g × 1,03 g = 4,37 ml
d) Mol etanol
1 mol
Mol etanol = 30 g × 46 g = 0,65 ml
e) Mol asam asetat
Mol asam asetat = 30 g × 160molg = 0,5 mol
f) Mol asam sulfat

1 mol
Mol asam sulfat =8g × 98 g
= 0,08 mol
Reaksi
CH3COOH + C2H5OH → CH3COOC2H5 + H2O
M: 0,5 mol 0,65 mol - -
B: 0,5 mol 0,5 mol 0,5 mol 0,5 mol
S: - 0,15 mol 0,5 mol 0,5 mol
g) Massa etil asetat teori
88 gram
g CH3COOC2H5 = 0,5 mol × 1 mol
= 44 gram
h) Massa etil asetat praktikum

0,9 gram
g CH3COOC2H5 = 30,5 mol × 1 mol
= 24,45 gram
10
i) Rendemen
massa praktikum
Rendemen = × 100%
massa teori
24,45 gram
= 44 gram × 100%
= 62,39%
11
4.2 Hasil Karakterisasi
Gambar 1. Spektrum FTIR Etil Asetat (CH3COOC2H5)
No. Bilangan Gelombang Gugus Fungsi
1 441,71 C-H
2 845,8 C-H
3 1046,4 C-N
4 1260,5 C-O
5 1373,34 C-H
6 1440,85 C-H
7 1646,27 C=C
8 1729,21 C=O
9 3382,24 O-H
Tabel 1. Hasil Karakterisasi FTIR Etil Asetat (CH3COOC2H5)
12
4.3 Pembahasan
Pada percobaan kali ini yakni mengenai sintesis etil asetat, bahan yang digunakan
ialah asam asetat dan etanol serta ditambahkan katalis asam sulfat. Prinsip kerja dari
percobaan ini ialah refluks dan distilasi, sedangkan prinsip reaksinya ialah
esterifikasi.
Dalam melakukan sintesis etil asetat, hal pertama yang perlu dilakukan ialah
mereaksikan asam asetat dengan katalis asam sulfat terlebih dahulu, karena atom H
pada asam sulfat akan bereaksi dengan atom O pada gugus karbonil, selain itu hal
ini bertujuan untuk mencegah terjadinya percikan, selanjutnya baru ditambahkan
etanol. Larutan kemudian dihomogenkan dan ditambahkan batu didih untuk
meratakan pemanasan dan mencegah terjadinya bumping. Reaksi sintesis etil
asetat termasuk kedalam reaksi setimbang, sehingga untuk mendapatkan hasil yang
maksimal kesetimbangan harus bergeser ke kanan (produk). Hal itu dapat dilakukan
dengan cara memperbesar konsentrasi salah satu reaktannya atau molnya,
sehingga terbentuk reaksi pembatas.
Larutan asam asetat, asam sulfat, dan etanol yang telah bercampur dalam
labu distilasi selanjutnya dilakukan proses refluks (pemanasan berulang-ulang) hal ini
bertujuan agar semua campuran menjadi homogen dan proses terbentuknya etil
asetat menjadi lebih cepat. Selain itu refluks juga bertujuan untuk menyempurnakan
proses sintesis etil asetat. Kira-kira waktu yang dibutuhkan untuk merefluks sekitar
90 menit, yang merupakan waktu optimum dalam pembentukan etil asetat.
Setelah direfluks, larutan didistilasi untuk memisahkan etil asetat dengan
akuades. Proses ini dilakukan hingga suhu mencapai 77°C yang merupakan titik
didih dari etil asetat, sedangkan akuades titik didihnya 100°C sehingga etil asetat
akan menguap terlebih dahulu dan terbentuk sebagai distilat pada erlenmeyer.
Selama proses distilasi, akan tercium aroma khas, yang mana berasal dari ester
yang sifatnya memiliki aroma khas. Setelah proses distilasi selesai, dilakukan
pengujian terbentuknya ester dengan mencampurkan distilat dengan akuades,
dimana terbentuknya ester ditandai dengan adanya dua lapisan yang terbentuk yaitu
lapisan air dan juga lapisan ester. Pada lapisan bawah merupakan ester dan di
lapisan atasnya merupakan akuades, sebab massa relatif dari ester lebih besar
daripada akuades.
Setelah itu, lapisan ester dipisahkan dan ditambahkan dengan natrium
karbonat. Hal ini bertujuan untuk menetralkan larutan dari sifat asam. Natrium
karbonat merupakan garam bersifat basa yang akan mengikat ion asam dari katalis.
13
pH larutan kemudian diuji dengan kertas lakmus hingga kertas lakmus biru tidak
berubah lagi menjadi merah yang menandakan kandungan asam yang telah
dinetralkan oleh natrium karbonat.
Adapun hasil karakterisasi menggunakan FTIR dalam spektrum hasil
karakterisasi, selain menandai keberadaan etil asetat, didapat puncak lain yang
terdeteksi yakni 1046,4 cm-1, 1260,5 cm-1 serta 3382,24 cm-1 menandakan kehadiran
senyawa lainnya, sebab pada nilai tersebut kemungkinan gugus fungsinya ialah C-N,
C-O dan O-H. Sedangkan spektrum yang menandai adanya etil asetat ialah pada
daerah ikatan ganda (1600 cm-1 sampai 2000 cm-1) terdeteksi pada bilangan
gelombang 1729,21 cm-1 yang biasanya mengindikasikan adanya gugus C=O,
kemudian pada daerah sidik jari (600 cm-1-1000 cm-1), yang mana dari grafik
terdeteksi 845,8 cm-1 mengindikasikan adanya gugus C-H.
Dari hasil karakterisasi menggunakan FTIR, dari spektrum yang muncul
adanya gugus fungsi C-N pada bilangan gelombang 1046,4 cm-1 dan O-H dengan
bilangan gelombang 3382,24 cm-1, yang mana bukan merupakan gugus fungsi yang
terdapat dalam struktur etil asetat. Hal ini kemungkinan besar menunjukkan larutan
yang diperoleh masih mengandung etanol atau air, selain itu gugus fungsi yang
terdeteksi ini dapat disebabkan oleh kontaminasi yang terdapat pada bahan yang
digunakan. Proses reaksi dan pemanasan yang mungkin tidak sempurna turut andil
menghasilkan sintesis etil asetat yang tidak maksimal. Karena banyaknya terdapat
puncak serapan yang terbaca pada analisis karakterisasi, menandakan dengan jelas
adanya senyawa lain yang tidak diinginkan.
Hasil volume etil asetat yang didapatkan dari praktikum yang sudah dilakukan
ialah 30,5 mL (27,45 gram) namun secara teori etil asetat yang diperoleh ialah 44
gram. Larutan etil asetat yang diperoleh berupa cairan bening dan memiliki aroma
yang khas. Hasil yang diperoleh belum akurat karena ada beberapa kemungkinan
kesalahan saat melakukan praktikum, diantaranya ialah waktu refluks yang sebentar,
suhu yang sulit di konstankan dan proses destilasi yang tidak sempurna.
14
V. KESIMPULAN DAN SARAN
5.1 Kesimpulan
Dari percobaan yang telah dilakukan dapat ditarik kesimpulan sebagai berikut:
1. Prinsip kerja dari percobaan ini adalah destilasi dan refluks.
2. Prinsip reaksi dari sintesis etil asetat adalah esterifikasi.
3. Volume etil asetat yang diperoleh adalah sebesar 30,5 mL
4. Rendemen yang diperoleh sebesar 62,39%.
5. Hasil karakterisasi menggunakan FTIR selain mendapati etil asetat,
didapatkan juga hasil zat lain diantaranya ditandai dengan terdeteksinya
gugus fungsi C-N dan O-H, yang mana bukan merupakan gugus fungsi yang
terdapat dalam struktur etil asetat.
5.2 Saran
Untuk praktikum berikutnya yang lebih baik disarankan beberapa hal berikut:
1. Pastikan labu tertutup agar tidak ada bahan yang menguap.
2. Perhatikan waktu optimum percobaan agar hasil yang didapatkan maksimal.
3. Jangan lupa untuk memasukkan batu didih ke dalam labu destilasi.
15
DAFTAR PUSTAKA
[1] S. L. dkk Azura, “Pembuatan Etil Asetat Dari Hasil Hidrolisis, Fermentasi Dan
Esterifikasi Kulit Pisang Raja (Musa paradisiaca L),” J. Tek. Kim. USU, vol. 4,
no. 1, pp. 1–6, 2015.
[2] B. N. Pattanaik and H. C. Mandalia, Ethyl Acetate: Properties, Production
Processes And Applications - A Review. Bharuch: Research & Development
Centre, Gujarat Narmada Valley Fertilizer Company Ltd., 2011.
[3] S. . Pine, Kimia Organik II. Bandung: ITB, 1998.
[4] M. J. dkk Jaya, “Sintesis Senyawa Etil Laurat Menggunakan Variasi Volume
Katalis Asam Sulfat Pekat,” J. Labora Med., vol. 3, no. 1, pp. 1–9, 2019.
[5] E. T. dkk Putri, Pra Rencana Pabrik Pembuatan Etil Asetat dari Etanol dengan
Kapasitas 77.000 Ton/Tahun. Malang: Universitas Brawijaya, 2018.
16
Lampiran I. Tugas Sebelum Praktikum
1. Tuliskan mekanisme reaksi dari percobaan ini !
O O
H3C C O H + H O S O H + H3C CH2 O H
O H O
H3C C O H + O S O H + H3C CH2 O H
O H
O
H3C C O H
+ O S O H
O
O
H3C H2C H
O H O
H3C C O H + H O S O H
H3C H2C O O
O O
H3C C O CH2 CH3 + H O H + H O S O H
17
2. Bagaimana cara mengoptimalkan produk dalam siatu reaksi setimbang
Jawab :
- Melebihkan jumlah salah satu reaktan
- Mengurangi jumlah salah satu produk
- Menambah katalis
- Memperbesar konsentrasi asam asetat atau alkohol
3. Bagaimana cara menguji telah terbentuk senyawa ester atau belum dalam
suatu reaksi esterifikasi ?
Jawab :
Cara menguji telah terbentuknya senyawa ester atau belumnya dalam suatu
reaksi esterfikasi yaitu dengan menuangkan 10 tetes distilat kedalam 1 ml air.
Jika terbentuk dua lapisan berarti sudah terbentuk senyawa esternya.
18
Lampiran II. Struktur Senyawa Utama
No. Nama Senyawa Struktur Senyawa

1. Asam asetat
(CH3COOH)
2. Etil alkohol (Etanol) H
(C2H5OH)
CH3 C OH
H
3. Asam sulfat
(H2SO4)
4. Kalsium klorida
(CaCl2)
5. Natrium karbonat
(Na2CO3)
6. Etil asetat O
H
(CH3COOC2H5) CH3 C
O C CH3
19
Lampiran III. Analisis Artikel Ilmiah
I. JUDUL
Kinetics and mecaniscm of ethyl acetate productionusing Eco-Benign solid
catalyst
II. TUJUAN
Untuk mengetahui nilai kinetic dan mekanisme dari tanah liat ramah lingkungan
dalam produksi etil asetat
III. SKEMA KERJA
Asam Asetat
- ditambahkan tanah liat yang telah di

keringkan selama 2 hari sebagai katalis
- ditambahkan etanol yang telah dipanaskan
terpisah
- direfluks larutan hingga suhu 367 K
- dihitung perhitungan kinetic yang terjadi
- diambil 2 mL larutan lalu dititrasi dengan
NaOH 0,1 mL dengan indikator PP
- dihitung rasio mol alcohol dengan asam
Hasil
IV. HASIL
Kinetika dan mekanisme esterifikasi telah menunjukan asam asetat dan etanol
mengikuti dua persamaan reaksi orde dua dan mekanisme Eley-Rideal (ER).
Pekerjaan ini telah menunjukan hal itu katalis tanah liat ini memiliki potensi untuk
esterifikasi dan trans-esterifikasi asam karboksilat menjadi produk penting.
V. PERBANDINGAN DENGAN PRAKTIKUM
Pada praktikum menggunakan metode refluks (pemanasan berulang-ulang)
dan distilasi (pemisahan berdasarkan perbedaan titik didih), sedangkan pada artikel
menggunakan metode ER untuk menganalisis etil asetat.
20
Journal of Physical Chemistry &
l Chemist
ys
ica ry Chidi and Peter, J Phys Chem Biophys 2016, 6:3
DOI: 10.4172/2161-0398.1000219
urnal of Ph
&
Biophysics
Biophysics
Jo
ISSN: 2161-0398
Research Article OpenAccess

Open Access
Kinetics and Mechanism of Ethyl Acetate Production Using Eco-Benign

Solid Catalyst
Obi Chidi* and Okoye Ifedi Peter
Physical Chemistry Unit, Department of Pure and Industrial Chemistry, Faculty of Science, University of Port Harcourt, Rivers State, Nigeria
Abstract
The kinetics and mechanism of an eco-benign clay catalyst employed in the production of ethyl acetate was evaluated.
The results obtained revealed that the conversion of acetic acid was dependent on the catalyst weight, reaction time
and mole ratio. The maximum conversion of acetic acid was obtained for mole ratio (acid: alcohol) of 2:1 with optimum
catalyst weight of 2.0g at a reaction temperature of 363K and 150 minutes time on-stream. Kinetic studies revealed that the
esterification reaction was second-order and followed the single step Eley-Rideal reaction mechanism.
Keywords: Al-Pillaring; Clay catalyst; Esterification; Kinetics and Eastern (Black cotton soil) part of Nigeria. These areas comprise of
mechanism Borno, Yola, Adamawa and Taraba states [7]. There are also commercial
quantity deposits of bentonite in the Southern part of Nigeria. This
Introduction large bentonite reserve awaits commercial exploration for its various
Esterification reaction generally refers to the formation of esters applications. Pillared interlayer clays (PILCs) are an interesting class
by the interaction of alcohols and carboxylic acids. Alternatively, of two-dimensional micro-porous and meso-porous materials [8]. The
it refers to as the process of formation of an ester by the reaction need to transform natural clay to pillared forms is to improve on its
between an alkanol and an acid. It is a reversible process and does surface area and porosity. The pillared clays are very attractive solids
not proceed to any appreciable extent in the absence of catalysts for adsorption and catalysis purposes [9]. Therefore, this work looks at
or supercritical condition [1]. This process is described as an acid- the kinetics and mechanism of the application of an eco-benign solid
catalyzed equilibrium synthesis developed by Emil Fischer. It is the catalyst (Al-PILC) in the synthesis of ethylacetate (ester).
simplest pathway among several pathways used in synthesis of esters.
When catalysed by a strong acid usually tetraoxosulphate (VI) acid, the
Materials and Methods
reaction is called Fisher esterification [2]. This important process is one Natural clay sample was collected from the open clay deposit in
of the most organic reactions in chemical and allied industries visa vis Ezinachi, Okigwe Local Government Area, Imo state, Nigeria. The clay
its applications as intermediate in the synthesis of fine chemicals, drugs, sample was washed and sun-dried for two days. Aluminum pillared
perfumes, food preservatives, and also in the production of biodiesels material was produced by ion exchange and calcinations at 473 K.
via transesterification. It is widely applied from the preparation of Esterification reactions were carried out in a batch mode using a
highly specialized esters in the chemical laboratory to the production of three-necked round bottom glass flask of 250 ml capacity fitted with
millions of tons of commercial ester products [3]. Esterification process a reflux condenser and mercury in glass thermometer to monitor the
can be carried out either as a batch or a continuous process. The batch temperature. Heating and stirring was achieved using a magnetic hot
procedure involves a single pot reactor that is filled with the acid and plate with a stirrer. Acetic acid and the clay catalyst (for 1:1, 2:1, 3:1, 4:1
alcohol reactants. The acid catalyst is added and the water removed as acid: alcohol mole ratio) were charged into the reactor and heated to
the reaction proceeds. This method is most often used in the chemical 363 K. After the desired temperature has been reached, a known amount
laboratories, but in a few cases, it is used by industry to make large of ethanol preheated separately using heating mantle was added into
quantities of esters [4]. Ethyl acetate is a colorless liquid with a the reactor. The kinetic measurement was done by varying the time of
characteristic smell. It has wide applications especially as solvents used the process from 0-150 mins. The reaction mixture (2 ml) was taken
by many industrial, beverage and pharmaceutical outlets [3]. In order immediately using Pasteur pipette and titrated against 0.1 M NaOH
to eliminate the corrosiveness and deterioration of the reaction plants solution using phenolphthalein indicator. All the experimental runs
and environment by mineral acids used as catalyst, the esterification were designed by varying the amount of the catalyst, the acid to alcohol
of carboxylic acids with alcohols in the presence of solid acid catalysts mole ratios, and the reaction period while keeping the temperature
that are eco-friendly has gained the attention of many researchers in constant for all the runs. The concentration of acetic acid consumed
recent times. From academic standpoint, the mechanism proposed for during the reaction was calculated by the following formula below [10].
the esterification reaction involving an alcohol and carboxylic acid is
an acid promoted acyl substitution, which results in the substitution
of an alkoxy group for the hydroxyl portion of the carboxyl group. In
*Corresponding author: Obi Chidi, Physical Chemistry Unit, Department of
this reaction, a carboxylic acid does not react with an alcohol unless Pure and Industrial Chemistry, Faculty of Science, University of Port Harcourt,
an acid catalyst is used; protonation makes the carbonyl group more Rivers State, Nigeria, E-mail: zarasexcom@yahoo.com
electrophilic and enables it to react with the alcohol, which is a weak Received May 26, 2016; Accepted June 04, 2016; Published June 11, 2016
nucleophile [5]. Clays and clay minerals are solid acid green chemical
catalysts according to Kurian and Kavitha, [6] which can function as Citation: Chidi O, Peter OI (2016) Kinetics and Mechanism of Ethyl Acetate
Production Using Eco-Benign Solid Catalyst. J Phys Chem Biophys 6: 219.
both Bronsted and Lewis acids in their natural and modified states. The doi:10.4172/2161-0398.1000219
clay mineral used in this study is “Bentonite”. Bentonite clay is one
Copyright: © 2016 Chidi O, et al. This is an open-access article distributed under
of the most abundant smectitic clays in nature. In Nigeria, bentonite
the terms of the Creative Commons Attribution License, which permits unrestricted
deposits had been found in different parts of the country. An estimated use, distribution, and reproduction in any medium, provided the original author and
reserve of about 700 million tones had been indicated in the North source are credited.
J Phys Chem Biophys

ISSN: 2161-0398 JPCB, an open access journal Volume 6 • Issue 3 • 1000219
Citation: Chidi O, Peter OI (2016) Kinetics and Mechanism of Ethyl Acetate Production Using Eco-Benign Solid Catalyst. J Phys Chem Biophys 6:
219. doi:10.4172/2161-0398.1000219
Page 2 of 4
C NaOH ×VNaOH 0.4

catalyst loading
Concentration of acetic acid (M)= 1
VCH3COOH 0.3 0.5g catalyst
1.0g catalyst
Where CNaOH=Concentration of sodium hydroxide in molarity, 0.2 1.5g catalyst
2.0g catalyst
VNaOH=Volume of sodium hydroxide used in titration in dm3 and 0.1
In[A]
VCH COOH =Volume of reaction mixture sample titrated measured in 0
3
dm3. -0.1
0 20 40 60 80 100 120 140 160
However, the percentage conversion of acetic acid was equally -0.2

calculated by the formula below [11]: -0.3
[Ac]o − [Ac] -0.4
Conversion of acetic acid (%)= ×100 2 Time (mins)
[Ac]o
Figure 1: Plot of In [A] against time for catalyst loading for Al-pillared clay.
Where [Ac]o=initial concentration of acetic acid (M) and
[Ac]=measured concentration of acetic acid at time of sampling (M).
1.6
catalyst loading
Results and Discussion 1.4 0.5g catalyst
1.0g catalyst
Kinetics of esterification of acetic acid and ethanol 1.2 1.5g catalyst
2.0g catalyst
The reaction kinetics for the esterification of acetic acid and ethanol 1
1/[A]mol-1 dm3
using pillared clay catalysts was analysed by using the integral method of 0.8
analysis of rate data to determine the order of the esterification reaction 0.6
[12]. In order to determine the order of the esterification reaction, the 0.4
equations 3 and 4 below were used to plot a graph of In[CH3COOH]t
0.2
against time t and 1/[CH3COOH]t against time t.
0
In [CH3COOH]t=In [CH3COOH]0 - Kt 3 0 20 40 60 80 100 120 140 160
Time (mins)
1 1
= Kt + 4 Figure 2: Plot of 1/[A] against time for catalyst loading for Al-pillared clay.
[CH 3COOH]t [CH 3COOH]0
Table 1: Reaction rate constants for formation of ethyl acetate for various acid:
Where [CH3COOH]o and [CH3COOH]t are the concentration of alcohol mole ratios using 2.0 g of Al-pillared clay catalyst at 363 K.
acetic acid at zero time and at a particular time t respectively. Equations
Acid to alcohol mole ratio Rate constant K (dm3mol-1s-1)
3 and 4 are for first and second-order reactions. The plots of first-order 1:1 0.0059
reaction for Al-pillared clay as regards to loading and mole ratio are 2:1 0.0040
represented in Figures 1 and 2 while plots of second-order reaction for 3:1 0.0013
Al-pillared clay are represented in Figures 3 and 4. From the plots, it 4:1 0.0006
was observed that the correlation coefficient (R2) of the second-order
reaction gave best fit compared to the first-order reaction, hence it can Table 2: Reaction rate constants for formation of ethyl acetate for various catalyst
weights of Al-pillared clay at 363 K and acid: alcohol mole ratio of 2:1.
be concluded that the esterification of acetic acid and ethanol using Al-
pillared clay catalyst obey the second-order reaction equation. The rate Catalyst weights (g) Rate constant K (dm3mol-1s-1)
0.5 0.0019
constants obtained are presented in Tables 1-3.
1.0 0.0025
Reaction mechanism 1.5 0.0034
2.0 0.0040
In this study, the reaction mechanism according to Fogler [13] can
be written as follows: Table 3: Initial reaction rate values for the mechanistic pathway.
k1 (CA, o) (M) 1/CA, o (1/M) (Ro) (M/min) 1/Ro (min/M)
CH3COOH + H + CH3COOH2+ (5) 1.05 0.95 0.01 85.71
(A) (PC) k-1 (AS) 0.96 1.05 0.003 315.76
k2 0.87 1.16 0.003 333.33
CH3COOH2 + C2H5OH
+
CH3COOC2H6 + H2O (6) 0.79 1.27 0.0025 400.00
(AS) (B) k-2 (EH) (W) 0.75 1.34 0.0015 666.67
k3 The rate equation for the first step of the mechanism (equation 5),
CH3COOC2H6 CH3COOC2H5 + H+ (7) can be written as:
(EH) k-3 (E) (PC) -dCA
-R A = = K1CA CS – K -1CAS (8)
The above mechanism, equations 5-6 depicts the activation of dt
carbonyl oxygen of acetic acid by the pillared clay catalysts, followed Under steady-state conditions, the rate of production of
by the nucleophilic attack of protonated acetic acid by ethanol forming intermediates (AS, EH) can be equated to zero. Thus, rates for (AH)
ester and water, and the deprotonation of ethyl acetate respectively. and (EH) becomes:
J Phys Chem Biophys

219. doi:10.4172/2161-0398.1000219
Page 3 of 4
acid:alcohole mole ratio K1ρCA CC

mole ratio 1:1 R= (12)
1.5 mole ratio 2:1 1+ K B CB
mole ratio 3:1
1 mole ratio 4:1 If, on the other hand, the opposite is true with the adsorption and
desorption process being faster than surface reaction, k2CB « k1, k-1,
0.5 then equation (11) reduces to:
0 k1k 2 ρC A C B CC
In[A]
R=
0 20 40 60 80 100 120 140 160  k  (13)
-0.5 k −1 1 + k B C B + 1 CA 
 k −1 
-1
Defining kA=k1/k-1 as the adsorption equilibrium constant of the
-1.5 acetic acid, we have
Time (mins) (K1K 2 ρ)CA CB CC KCA CB CC
R= = (14)
Figure 3: Plot of In[A] against time for acid: alcohol mole ratio for Al-Pillared clay. 1+ K B CB + K A CA 1+ K B CB + K A CA
Where k is equivalent to kAk2ρ. Using equation (14) and initial reaction
3
acid:alcohole mole ratio rate (Ro) measured at various initial acid concentrations; a mathematical
mole ratio 1:1 model was developed to predict esterification mechanism.
2.5 mole ratio 2:1
mole ratio 3:1 1 KA 1+ K BC B,0 1
2 mole ratio 4:1 = + ( ) (15)
R 0 KC B,0CC KC B,0CC C A,0
1/[A]dm3mol-1
1.5 For a plot of 1/Ro against concentration of acid at fixed alcohol

concentration, if the plot pass through a maximum then it means that
1
the esterification reaction proceeds through a Langmuir-Hinshelwood
0.5
(LH) mechanism, but if there is no such maximum encountered, it
means that the esterification reaction follows an Eley-Rideal (ER)
0 mechanism [14]. From the plots of 1/Ro against 1/CA,O for Al-pillared
0 20 40 60 80 100 120 140 160 catalyst represented Figures 5 and 6, it showed that the initial reaction
Time (mins)
Figure 4: Plot of 1/[A] against time for acid: alcohol mole ratio for Al-Pillared clay. 800
700
dCAS 600
= K1C A CS - K -1C AS - K 2 C ASC B + K -2 C EH C W = 0 (9)
dt
1/Ro (min/M)
500
dC EH 400
= K1CASC B - K -2 C EH CW - K 3C EH + K -3C E CS = 0 (10)
300
dt
200
Since ethanol is a strong nucleophile, it competes for the catalyst
100
acid sites with acetic acid as does water once it is produced from
0
reaction.
0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6
Considering the initial reaction period when reverse hydrolysis is 1/CA,o (M)
not important. Using the pseudo-steady state approximation equation
for the intermediates (AS, EH) and solving for CAS with the site balance Figure 5: Plot of 1/Ro against 1/CA,o for Al-pillared clay catalyst.
(ρ.CC=CAS+CBS+CS) gives the rate expression as:
K1K 2 ρC A C B CC
R= o
K1 (11) H+
CH3CH2OH
(K -1 + K 2 C B )(1+ K B C B + CA ) H3C
C
OH Pillared clay CH3
C
OH
K -1 + K 2 CB OH+
Where CC, CB, CA, and CS are the concentrations of catalyst, ethanol, CH3 CH2
o
CH3 CH2
CH3 CH2 + H
o
acetic acid and vacant acid site on the catalyst surface, respectively; o
CCH3
ρ denotes the site density of the catalyst, CBS is the concentration of -H2O H3CC
+
OH2
H3CC OH
o o
ethanol adsorbed on the catalytic acid sites, kB represents the adsorption o
H
equilibrium constant for ethanol on the acid sites; k1 and k−1 are the H H
acetic acid adsorption and desorption constants, respectively; and k2 is
o
the surface reaction constant.
CH3 CH2 o C CH3 H+
If the surface reaction (k2) is favoured over the adsorption and
desorption of the acid (k1 and k−1), K C >> K , K , then equation Figure 6: Possible reaction mechanism for the esterification of acetic acid with
2 B 1 −1 ethanol over Al-pillared catalyst.
(11) can be approximated as:
J Phys Chem Biophys

219. doi:10.4172/2161-0398.1000219
Page 4 of 4
rate increases linearly with acid concentration, thus suggesting that the 5. Trost BM, Fleming I (1991) Comprehensive Organic Chemistry Synthesis:
esterification of acetic acid and ethanol follow ER mechanism [3]. Selectivity, Strategy and Efficiency in Modern Organic Chemistry. Pergamon
Press, New York, USA.
Conclusion 6. Kurian M, Kavitha S (2016) A Review on the Importance of Pillared Interlayered
Clays in Green Chemicals Catalysis. ISOR - Journal of Applied Chemistry, pp:
The kinetics and mechanism has shown that the esterification 47-54.
of acetic acid and ethanol followed second-order reaction equation
and Eley-Rideal (ER) mechanism. This work has demonstrated that 7. James OO, Mesubi MA, Adekola FA, Odebunmi EO, Adekeye JID (2008)
Bleaching performance of a Nigerian bentonite. Latin American Applied
Al-pillared clay catalyst has potential for esterification and trans-
Research 38: 45-49.
esterification of carboxylic acids into important products.
8. Miguel AV, Carolina B, Mikhail S, Roman PK, Antonio G (2009) Relationship
Acknowledgements between the surface properties and the catalytic performances of Al-, Ga-, and
AlGa-Pillared saponites. In Eng Chem Les 48: 406-414.
The Authors are grateful to Cardiff Catalysis Institute, School of Chemistry and
University of Cardiff, United Kingdom. 9. Gill A, Korili SA, Raquel T, Miguel AV (2010) Pillared clays and related catalysts.
1st edn. Springer-Verlag, New York, USA, pp: 1-522.
Competing Interests
Authors have declared that no competing interests exist. 10. Bhimashankar RP, Hanumant G, Vijay VB (2010) Ethyl acetate synthesis by
esterification of acetic acid with ethanol over a heteropolyacid on montmorillonite
References K10. Catalysis Division, National Chemical Laboratory, India 1: 227-231.
1. Tewari KS, Mehrotra SN, Vishnoi NK (1980) Organic Chemistry. Vikas 11. Fatimah I, Narsito S, Wijaya K (2011) Effect of Aluminium Pillared Montmorillonite
Publishing House Pvt Ltd., New Delhi, India, pp: 677-681. on Its Surface Acidity Properties. ITB J Sci 43A: 123-138.
2. Patai S, Rappoport Z (1991) Synthesis of carboxylic acids, esters and their 12. Teo HTR, Saha B (2004) Heterogeneously catalyzed esterification of acetic
derivatives. John Wiley and Sons Inc., New York, USA.
acid with Iso-amyl alcohol: kinetic studies. Journal of Catalysis 228: 174-182.
3. Kiran DP, Bhaskar DK (2014) Kinetics Studies on Esterification Reaction
of Acetic acid with Iso-amyl Alcohol over Ion Exchange Resin as Catalysts. 13. Fogler HS (1991) Elements of Chemical Reaction Engineering. 3rd edn.
International Journal of Engineering Research 3: 488-493. Prentice-Hall Inc., New Jersey, USA.
4. Ming C, Qingshi T, Jeffrey YY, Mingming L (2014) Esterification pretreatment 14. Robert GM (2008) Physical Chemistry. 3rd edn. Elsevier Academic Press,
of free fatty acid in biodiesel production, from laboratory to industry. Fuel Theobald’s Road, London, UK, pp: 484-574.
Processing Technology 125: 106-113.
J Phys Chem Biophys

OBJEK II
SINTESIS METIL SALISILAT
ANNISA RAHMI Z.J, S.Si

“ A negative mind will never give you a positive life”
SINTESIS METIL SALISILAT
I. TUJUAN
1. Mensintesis metilsalisilat dari asam salisilat
2. Memahami mekanisme reaksi pembuatan metil salisilat
II. TEORI
2.1 Ester
Ester, RCO2R', dinamai sebagai garam, yang mana gugus R' dinamai terlebih
dahulu, diikuti dengan nama gugus karboksilat (misalnya, CH3CO2CH2CH3 adalah
etil asetat). Ester dapat dibuat dari asam dan alkohol, dengan katalis asam mineral
(esterifikasi Fischer). Langkah dari mekanisme ini adalah serangan nukleofilik oleh
alkohol pada gugus karbonil terprotonasi dari asam. Ester banyak digunakan sebagai
pemberi rasa dan parfum 1.
Ester merupakan salah satu senyawa derivat asam karboksilat (asam
organik) dimana gugus hidroksilnya (-OH) digantikan oleh gugus alkoksi (-OR) dari
alkohol. Pada penelitian ini senyawa asam karboksilat yang digunakan adalah asam
vanilat sedangkan alkohol yang digunakan adalah monosakarida dari jenis arabinosa
yang mempunyai satu gugus aldehid dan empat gugus alkohol (tetra-ol). Senyawa
yang dikategorikan sebagai derivat asam karboksilat adalah senyawa- senyawa yang
apabila dihidrolisis akan menghasilkan asam karboksilat. Contoh derivat asam
karboksilat selain ester adalah halida asam, anhidrida asam, amida serta nitril.
Halida asam merupakan derivat yang paling reaktif karena mempunyai gugus pergi
yang baik2.
Produksi ester secara industri dilakukan dengan mereaksikan anhidrida asam
dengan alkohol. Ester penting yang dibuat dengan cara ini ialah asam asetil salisilat,
atau aspirin. Asam asetil salisilat dibuat dari anhidrida asetat dan asam salisilat3.
2.2 Asam Salisilat
Asam salisilat dikenal juga dengan Asam 2,hidroksi-benzoat merupakan senyawa
golongan fenol. Pemerian hablur, biasanya berbentuk jarum halus atau serbuk halus;
putih; rasa agak manis, tajam dan stabil di udara. Bentuk sintetis warna putih dan
tidak berbau. Kelarutannya sukar larut dalam air dan dalam benzena. Mudah larut
dalam etanol dan dalam eter. Larut dalam air mendidih dan agak sukar larut dalam
kloroform. Khasiat dan penggunaan sebagai keratolitikum (menipiskan selaput
kulit/meratakan kulit) dan anti fungi. Asam salisilat merupakan senyawa yang
berkhasiat sebagai fungisidal dan bakteriostatis lemah. Asam salisilat bekerja
Sintesis Metil Salisilat 26

keratolitis sehingga digunakan dalam sediaan obat luar terhadap infeksi jamur yang
ringan 4.
Asam salisilat adalah salah satu bahan kimia penting di dalam kehidupan
sehari-hari dan mempunyai suatu nilai ekonomis yang lumayan tinggi karena asam
salisilat bisa digunakan untuk bahan intermediet dari pembuatan obat-obatan
contohnya obat analgesik dan antiseptik serta untuk keperluan bahan baku farmasi.
Asam salisilat dengan rumus molekul C6H4COOHOH memiliki bentuk kristal kecil
berwarna merah muda terang, hingga kecokelatan dengan berat molekul sebesar
138,123 g/mol dengan titik leleh sebesar 156ºC dan densitas pada 25ºC sebesar
1,443 g/mL. Turunanturunan dari asam salisilat telah banyak digunakan di berbagai
bidang salah satunya adalah metil salisilat 5.
Asam salisilat sebagai zat aktif utama maupun tambahan tersedia dalam
berbagai produk dengan beragam vehikulum. Penggunaan asam salisilat harus tetap
berhati-hati dan tidak boleh diberikan pada area yang luas dalam jangka panjang.
Asam salisilat merupakan zat yang sering ditambahkan pada produk perawatan kulit
untuk jerawat dan psoriasis.Asam salisilat adalah obat topikal murah yang digunakan
sebagai bahan penting dalam banyak produk perawatan kulit yaitu untuk pengobatan
jerawat, psoriasis, kapalan, kutil, ketombe, dan masalah kulit lainnya 4.
Asam salisilat bekerja sebagai keratolitik, komedolitik dan sebagai
bakteriostatik,membuka pori-pori yang tersumbat, juga digunakan dalam beberapa
produk sampo untuk mengobati ketombe 4.
2.3 Metil Salisilat

Metil salisilat merupakan bahan yang mempunyai berbagai kegunaan. Sebagai
bahan obat metil salisilat merupakan salah satu obat anti inflamasi non steroid
(NSAID) golongan salisilat. Bahan ini dapat dibuat dalam sediaan berupa linimentum
atau salep yang berfungsi untuk menghilangkan nyeri pada pinggang, panggul dan
rematik. Manfaat lain dari metil salisilat adalah dapat digunakan sebagai bahan untuk
formula keratolitik, anti plak (pada obat kumur), bahan perasa dengan kadar tidak
lebih dari 0,04% dan bahan pewangi pada pestisida golongan organofosfat. Selain
itu juga dapat digunakan untuk memperjelas warna dari jaringan tanaman atau
binatang untuk keperluan imunohistokimia 5.
Senyawa metil salisilat merupakan turunan dari ester asam salisilat.

Senyawa ester dihasilkan dari reaksi asam karboksilat dengan alkohol atau yang
lebih dikenal dengan istilah esterifikasi dan biasanya reaksi ini menggunakan suatu

katalis asam. Reaksi ini akan berlangsung dengan baik jika direfluks bersamaan
dengan adanya sedikit asam klorida atau asam sulfat. Reaksi asam karboksilat
dengan alkohol yang disertai adanya katalis asam merupakan salah satu cara baku
untuk membuat ester. Reaksinya yang dikenal sebagai esterifikasi Fischer,
merupakan jalan sederhana untuk membentuk ester dari bahan mula yang mudah
diperoleh.
Berdasarkan dari uraian di atas metil salisilat banyak memberikan manfaat

terutama dibidang kesehatan. Oleh karena itu, perlu dilakukannya penelitian lebih
lanjut terhadap pembuatan metil salisilat dengan menggunakan katalis asam dengan
menggunakan metode tanpa pelarut. Metil Salisilat yang dihasilkan dari reaksi
esterifikasi antara metil salisilat dengan metanol dengan menggunakan katalis asam
sulfat yaitu memiliki karakteristik larutan kuning jernih (seperti minyak) dan memiliki
bau yang khas 4.
Secara natural metil salisilat diperoleh dari tanaman yang termasuk famili
Pyrolaceaeterutaa genus Pyrola, beberapa species dari genus Gaultheria famili
Ericaceae, beberapa spesies genus Betula famili Betulaceae terutama genus
Betulenta dan pada semua spesies famili Spiraes. Produksi komersial metil salisilat
adalah merupakan hasil esterifikasi asam salisilat dan metanol. Pada sintesis metil
salisilat dari asam salisilat dan metanol dengan menggunakan katalis asam sulfat ini
dibutuhkan lama pemanasan sekurang- kurangnya lima jam pada suhu sekitar
1000°C, tetapi ada prosedur lain yang menyatakan bahwa untuk sintesis metil
salisilat ini hanya diperlukan pemanasan selama tiga jam saja. Lama pemanasan ini
akan mempengaruhi hasil siintesis metil salisilat dan diduga dengan pemanasan
yang lebih lama akan memberikan persentase hasil yang lebih tinggi sampai
kemudian pada lama pemanasan tertentu sudah tidak meningkatkan persentase
hasil sintesis metil salisilat 3.

3.1 Alat dan Bahan
3.1.1 Alat dan Fungsinya
No Alat Fungsi
1 Labu destilasi sebagai wadah larutan
2 Kondensor sebagai alat untuk mendinginkan suhu uap
3 Erlenmeyer sebagai wadah penampung destilat
4 Corong sebagai alat untuk memindahkan zat
5 Batang pengaduk sebagai alat untuk mengaduk larutan
6 Corong pisah sebagai alat untuk memisahkan campuran
3.1.2 Bahan dan Kegunaannya
No Bahan Fungsi
1 Asam salisilat sebagai bahan dasar sumber salisilat
2 Metanol sebagai bahan dasar sumber metil
3 H2SO4 pekat sebagai katalis
4 Akuades sebagai pelarut
5 MgSO4 anhidrat sebagai penarik sisa air
6 Na2CO3 pekat sebagai penarik sisa asam

3.2. Cara Kerja
1. Sebanyak 7 gram asam salisilat dan 18 gram metanol dimasukkan ke dalam
labu didih.
2. Dengan hati-hati ditambahkan sambil diaduk 2 mL asam sulfat pekat, kemudian
dimasukkan batu didih.
3. Larutan direfluks pada penangas selama ± 1,5 jam.
4. Dilakukan distilasi kelebihan metanol pada penagas air dan dibiarkan dingin.
5. Residu dituangkan ke dalam 250 mL air di dalam corong pisah.
6. Campuran dikocok dan kemudian dibiarkan sampai terbentuk 2 lapisan.
7. Lapisan esternya dicuci dengan 25 mL air dan larutan natrium karbonat pekat.
8. Larutan dikeringkan dengan magnesium sulfat anhidrat.
9. Lapisan metil salisilatnya dipisahkan dan rendemen dihitung.
10. Produk dikarakterisasi dengan spektrofotometer UV-Vis, FT-IR, dan HPLC.

3.3 Skema Kerja
Asam salisilat Metanol
- ditimbang 7 gram - ditimbang 18 gram

- dimasukkan kedalam - dimasukkan kedalam
labu didih labu didih
Campuran
- ditambahkan 2 mL asam sulfat pekat

dengan hati-hati
- dimasukkan batu didih
- direfluks pada penangas air selama 1,5
jam
- didestilasi kelebihan metanol pada
penangas air
- dibiarkan dingin
Destilat Residu
- dituangkan ke dalam corong pisah yang

berisi 250 mL air
- dikocok dan dibiarkan hingga terbentuk 2
lapisan
- dipisahkan kedua lapisan
Lapisan air Lapisan ester

(Bagian atas) (Bagian bawah)
- dicuci dengan 25 mL air dan larutan

(bagian atas)
Na2CO3
- dikeringkan dengan MgSO4
- dipisahkan lapisan ester
- dihitung rendemen
Hasil

3.4 Skema Alat
3.4.1 Refluks
1
4
Keterangan:
1. Standar
2. Klem
3. Kondensor
4. Air keluar
5. Air masuk
6. Labu destilasi
7. Penangas

3.4.2 Alat Destilasi
2 4
1
8
11
9
3
10
5
7
Keterangan:
1. Standar
2. Klem
3. Labu didih
4. Termometer
5. Penangas
6. Erlenmeyer
7. Kondensor
8. Air keluar
9. Air masuk
10. Alonga
11. Cabang tiga

4.1.1 Data
Mr metil salisilat = 152 gram/mol
Mr asam salisilat = 138,12 gram/mol
Massa asam salisilat = 7 gram
Berat jenis asam salisilat = 1,181 gram/mL
Mr metanol = 32,04 gram/mol
Massa metanol = 18 gram
Berat jenis metanol = 0,792 gram/mL
Massa metil salisilat = 6,12 gram
4.1.2 Perhitungan
7 gram
n asam salisilat = 138,12 gram/mol
= 0,05 mol
18 gram
n metanol = 32,04 gram/mol
= 0,56 mol
Reaksi :
C7H6O3 + CH3OH C8H8O3 + H2O
Mula-mula 0,05 mol 0,56 mol - -
Bereaksi 0,05 mol -0,05 +0,05 mol +0,05mol
Sisa - 0,51 mol 0,05 mol 0,05mol
Massa metil salisilat = mol metil salisiat x Mr metil salisilat
= 0,05 mol x 152 gram/mol
= 7,6 gram
34
Sintesis Metil Salisilat
massa praktikum
Rendemen = x 100%
massa teori
6,12 gram
= x 100%
7,6 gram
= 80,5 %
35
4.2 Pembahasan
Percobaan kali ini yaitu melakukan sintesis metil salisilat yang bertujuan memahami
mekanisme reaksi pembuatan metil salisilat dan mensintesis metil salisilat dari asam
salisilat. Prinsip percobaan yang dilakukan adalah refluks dan distilasi sedangkan
prinsip reaksi yaitu reaksi esterifikasi atau reaksi pembuatan ester. Refluks
merupakan pemanasan berulang untuk mempercepat reaksi dan distilasi merupakan
adalah pemisahan senyawa berdasarkan perbedaan titik didih. Prinsip esterifikasi
yang digunakan karena metil salisilat merupakan senyawa ester atau derivat dari
senyawa asam karboksilat. Esterifikasi yaitu pembentukan ester dari asam
karboksilat dan alkohol. Pada percobaan ini digunakan asam salisilat dan metanol
serta asam sulfat sebagai katalis untuk mempercepat reaksi.
Dalam melakukan sintesis metil salisilat, larutan asam salisilat, metanol dan
katalis asam sulfat dimasukkan ke dalam labu didih, selanjutnya campuran direfluks
selama 90 menit, dimana ini adalah waktu optimum untuk mereaksikan larutan.
Refluks ini bertujuan untuk menghomogenkan larutan dan mempercepat terjadinya
reaksi dengan cara dilakukan pemanasan. Saat direfluks tidak lupa ditambahkan
batu didih. Adapun fungsi dari batu didih ini yaitu untuk mencegah terjadinya ledakan
atau bumping serta meratakan pemanasan. Larutan kemudian didistilasi kelebihan
metanol pada penangas air dan kemudian didinginkan. Distilasi digunakan untuk
memisahkan metil salisilat dengan metanol. Metil salisilat berada pada residu, hal ini
dikarenakan metanol memiliki titik didih yang lebih rendah dari pada metil salisilat,
sehingga saat distilasi metanol akan menguap terlebih dahulu dan mengalir ke
wadah destilat dan yang tertinggal adalah metil salisilat sebagai residu. Titik didih
dari metil salisilat yaitu 220 0C dan titik didih metanol 64,7 0C.
Metil salisilat yang terbentuk bisa berupa minyak maupun berupa gel. Pemisahan
akan mudah dilakukan saat metil salisilat berbentuk minyak. Selama proses distilasi
suhu perlu dijaga agar tidak melebihi titik didih metanol, karena apabila melebihi titik
didih metanol tersebut maka kemungkinan larutan akan bercampur dengan zat lain
sehingga tidak hanya metanol saja yang dihasilkan. Selanjutnya setelah proses
distilasi selesai, metil salisilat yang terbentuk pada residu dituangkan ke dalam
corong pisah dan ditambahkan dengan 250 ml air, larutan kemudian dikocok
sehingga membentuk dua lapisan, metil salisilat akan berada pada bagian bawah
dan air berada pada bagian atas karena berat jenis metil salisilat yang lebih besar
dibandingkan air yaitu 1,176 – 1,89 gram/mol. Selanjutnya kedua larutan dipisahkan
dan diambil lapisan ester atau yang mengandung metil salisilat.
36
Terbentuknya metil salisilat ditandai dengan adanya aroma yang dikeluarkan
berupa bau wangi seperti balsem yang cukup menyengat. Hal ini dikarenakan metil
salisilat merupakan senyawa turunan dari ester yang mempunyai aroma khas seperti
balsem atau buah-buahan. Metil salisilat yang diperoleh dicuci terlebih dahulu
dengan air dan Na2CO3 untuk mengikat sisa asam sulfat yang masih ada dalam
senyawa sehingga larutan menjadi netral. Dari hasil percobaan pada praktikum kali
ini berat metil salisilat yang didapatkan yaitu sebesar 6,12 gram dan rendemen yang
didapatkan sebesar 79.415%. Hasil yang didapatkan hampir mendekati teori, yaitu
7.6 gram. Semakin tinggi rendemen maka hasil yang didapatkan semakin baik.
37
5.1 Kesimpulan
Berdasarkan percobaan yang telah dilakukan, dapat disimpulkan bahwa:
1. Metil Salisilat dapat diperoleh dari asam salisilat dan ,etanol dengan bantuan
katalis asam sulfat pekat
2. Prinsip kerja pada percobaan ini adalah refluks dan distilasi
3. Prinsip reaksi pada percobaan ini yaitu esterifikasi
4. Massa C8H8O3 yang didapatkan adalah 6,12 gram
5. Rendemen yang didapatkan sebesar 80,5 %
5.2 Saran
Beberapa saran untuk percobaan selanjutnya adalah:
1. Pastikan pemanasan berlangsung sempurna
2. Berhati-hati dalam mencampurkan zat
3. Saat melakukan refluks dan distilasi dipastikan tidak ada uap yang keluar
38
DAFTAR PUSTAKA
1Hart, H., Hadad, C. M., Craine, L. E., & Hart, D. J. 2013. Organic Chemistry Study
Guide and Solutions Manual: A Short Course. Boston.Brooks/Cole Publishing
Company
2Ali, R. 2008. Sintesis Ester Arabinovanilat dengan Metode Fischer Menggunakan

Pelarut Aseton.Skripsi.
3Chasanah, U. (2012). Pengaruh Lama Pemanasan Terhadap Hasil Reaksi Sintesis

Metil Salisilat Dari Asam Salisilat Dan Metanol Dengan Katalis Asam Sulfat
Pekat. In Saintika Medika (Vol. 5, Issue 1).
4 Fatmawati, F., & Herlina, L. 2017. Validasi Metode dan Penentuan Kadar Asam
Salisilat Bedak Tabur dari Pasar Majalaya. EduChemia (Jurnal Kimia Dan
Pendidikan), 2(2), 141.
5Priambodo, W. S., Saleh, C., Kimia, J., & Mulawarman, U. 2019. Pembuatan Metil
Salisilat Menggunakan Katalis Asam Dengan Metode Tanpa Pelarut. Atomik,
04(1), 41–44.
39
1. Tulis mekanisme reaksi pembuatan metilsalisilat pada percobaan ini!

Jawab :
+
+
+ H2 SO4
+ +
40
2. Bagaimana mengetahui adanya senyawa ester?

Jawab :
 Dari aromanya
Jika telah terbentuk dua lapisan, maka telah terbentuk ester, dengan ester
berada pada lapisan atas.
41
Lampiran II. Struktur Senyawa yang Digunakan
No Nama Senyawa Struktur Senyawa

1. Asam Salisilat
(C6 H4 OHCOOH)
2. Metanol
(CH3 OH)
3. Asam Sulfat
(H2 SO4 )
4. Metil salisilat
(C6 H4 OHCOOCH3 )
42
Lampiran III. Analisis Artikel Ilmiah
I. Judul
Penjeratan Stretomyces sp.Lipase dalam Cupric-beads untuk sintesis Metil Salisilat
II. Tujuan
Mengetahui penjeratan yang optimal dari Streptomyces sp.Lipase dalam Cupric-
beads dan aplikasinya dalam sintesis metil salisilat
III. Skema Kerja
Lipase steptomyces ekstraseluler

(24,3 + 1,3 U/ml ; 2,297 mg protein/ml
- disekresikan oleh Stretopmyces sp dalam kaldu nutrisi

(500 ml)
- dimasukkan (0-50%) presipitasi ammonium sulfat
- dipertahankan protein yang diendapkan
- dibentuk kembali dalam volume minimum Tris HCl (pH
7,5)
- didialisis secara ekstensif selama 12 jam terhadap Tris
HCl (pH 7,5)
- dicatat aktivitas enzim 58,9 U/ml ± 1,3 dengan
pemurnian 5,6 kali lipat
Hasil
IV. Hasil dan Pembahasan

1. Percobaan lipase yang terikat alginat menunjukkan aktivitas yang maksimal
terhadap p.nitrofenilpalmitat pasa pH 8,5 dan suhu 55◦ C setelah diinkubasi
selama 10 menit.
2. Konstanta Michaelis yang rendah (k,2,0 mM) dan energi aktivitas yang kecil (2,61
kJ/mol) menunjukkan hubungan afinitas antara enzim dan substrat.
3. Alginat-lipase amobil juga mempertahankan hampir 50% dari aktivitas hidrolitik
aslinya setelah 2 jam inkubasi pada suhu 55◦ C.
4. Sintesis metil salisilat yang berhasil dalam koktail reaksi dengan esterifikasi
reaksi menggunakan lipase amobil alginat dikonfirmasi dengan HPLC dan
diperoleh produk metil salisilat sebesar 309,46 mg.
43
V. Perbandingkan dengan Praktikum

1. Praktikum dan jurnal sama-sama membahas mengenai metil salisilat.
Perbedaannya, pada artikel ini bertujuan mengetahui aktivitas suatu enzim dan
pengaplikasiannya pada sintesis metil salisilat sedangkan pada praktikum
bertujuan mesintesis metil salisilat dari asam sulfat.
44
See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/327954074
Entrapment of Streptomyces sp. Lipase in Cupric-beads for Methyl Salicylate

Synthesis
Article in Trends in Carbohydrate Research · September 2018
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OBJEK III
SINTESIS ASETON
RAHMI VIKA ULIA, S. Si

“ Hasbunallah Wanikmal Wakil”
SINTESIS ASETON
I. TUJUAN
1. Mensintesis aseton dari isopropil alkohol
2. Memahami mekanisme reaksi pembuatan aseton
II. LANDASAN TEORI

2.1 Keton
Keton merupakan suatu senyawa organik yang mempunyai sebuah gugus karbonil
terikat pada dua buah gugus alkil, dua gugus aril, atau sebuah gugus alkil dan sebuah
gugus aril. Berbeda dengan aldehida, keton tidak mempunyai atom hidrogen yang
terikat pada gugus karbonil. Gugus karbonil merupakan gugus yang bersifat polar dan
mengalami beragam reaksi seperti reaksi adisi nukleofilik, substitusi, oksidasi, dan
reduksi. Sifat polar gugus karbonil disebabkan oleh oksigen yang lebih elektronegatif
daripada karbon. Ikatan rangkap karbon-oksigen dalam gugus karbonil (mengandung
ikatan sigma dan ikatan π) elektronnya lebih polar daripada ikatan tunggal karbon-
oksigen dalam alkohol. Elektron π yang berasal dari ikatan π karbonil, letaknya lebih
jauh dari inti sehingga ikatannya lebih lemah dan lebih mudah dipolarisasikan. Atom
oksigen pada gugus karbonil mempunyai sepasang elektron valensi yang dapat
bereaksi dengan sebuah proton untuk menambah muatan positif dari karbon karbonil
(C)1.
Gugus keton
Keton merupakan salah satu senyawa organik yang sering dijumpai dalam
kehidupan sehari-hari, baik dalam kosmetik, makanan, maupun pembersih. Senyawa
keton juga bisa ditemukan secara alamiah. Pada umumnya, keton mempunyai titik
didih yang lebih tinggi daripada alkana karena keton lebih polar dan gaya tarik dipol-
dipol antara molekul-molekulnya besar. Namun, titik didih keton lebih rendah daripada
alkohol karena dua gugus karbonil tidak dapat mengadakan ikatan hidrogen1.
Meskipun keton murni tidak dapat membentuk ikatan hidrogen antarmolekulnya,
namun senyawa ini dapat membentuk ikatan hidrogen dengan molekul lain. Atom
oksigen dalam gugus karbonil keton dapat mengikat molekul lain sehingga terbentuk
ikatan hidrogen. Keton larut dalam pelarut organik, karena keton mempunyai sebuah
56
Sintesis Aseton
atom oksigen dengan pasangan elektron bebas, sehingga dapat mengalami ikatan
hidrogen dalam molekul air. Semakin panjang rantai karbon, kelarutan dalam air
semakin menurun1.
2.2 Aseton
Aseton merupakan senyawa karbonil yang memiliki gugus fungsi keton (-CO). Aseton,
juga dikenal sebagai propanon, dimetil keton, 2-propanon, propan-2-on,
dimetilformaldehida, dan β-ketopropana. Aseton dapat dibuat dari alkohol sekunder
dengan cara oksidasi. Aseton adalah senyawa organik yang berupa cairan tidak
berwarna dan mudah terbakar. Aseton merupakan senyawa keton yang paling
sederhana. Aseton larut dalam berbagai perbandingan air, etanol, dietil eter, dan lain-
lain. Aseton sendiri juga merupakan pelarut penting2.
Aseton dibuat secara langsung maupun tidak langsung dari propena. Secara
umum, melalui proses kumena, benzene dialkilasi dengan propena dan produk proses
kumena (isopropilbenzena) dioksidasi untuk menghasilkan fenol dan aseton :
Konversi di atas terjadi melaui zat antara kumena hidroperoksida,

C6H5C(OOH)(CH3)2. Aseton juga diproduksi melalui propena yang dioksidasi langsung
dengan menggunakan ktalis Pd(II)/Cu(II), mirip seperti ‘proses wacker’. Aseton adalah
zat yang tidak berwarna dengan berat jenis 0.812 g/mL pada suhu 0˚C. Aseton juga
merupakan senyawa yang memiliki bau khas. Aseton juga merupakan suatu pelarut
yang baik bagi zat-zat organik. Salah satu ciri-ciri dari cairan aseton ini ialah mudah
sekali menguap. Ciri-ciri dari aseton lainnya adalah mudah terbakar, dan biasanya
dihasilkan tanpa ada warna. Kandungan dari aseton ini mempunyai bau2.
Pada saat ini aseton banyak digunakan untuk pelarut, di samping untuk bahan
baku dalam pembuatan senyawa kimia petroleum seperti metal isobutyl keton (MIBK,
metal meta akrilat, metal isobutil karbinol, bisfenol A, dan lain-lain). Konsumen bahan
kimia ini adalah industri cat, pernis, karet, acetic acid, plastik, dan kosmetik3.
57
Sintesis Aseton
2.3 Pembuatan Aseton
Ada beberapa macam proses pembuatan Aseton secara komersial, antara lain :
1. Proses Cumene Hidroperoksida
Mula-mula Cumene dioksidasi menjadi Cumene Hidroperoksida dengan udara
atmosfir atau udara kaya oksigen dalam satu atau beberapa oksidasinya. Temperatur
yang digunakan adalah antara 80˚C–130˚C dengan 6 atm, serta dengan penambahan
Na2CO3. Pada umumnya proses oksidasi ini dijalankan dalam 3 atau 4 reaktor yang
dipasang seri. Reaksi :
Hasil dari oksidasi pada reaktor pertama mengandung 9-12% Cumene

Hidroperoksida, 15-20% pada reaktor kedua, 24-29% pada reaktor ketiga, dan 32-39%
pada reaktor selanjutnya. Kemudian produk reaktor keempat dievaporasi sampai
konsentrasi Cumene Hidroperoksida menjadi 75-85%3.
Ketika penambahan asam akan terjadi reaksi pembelahan Cumene
Hidroperoksida menjadi suatu campuran yang terdiri dari fenol, aseton dan berbagai
produk lain seperti cumilfenol, asetofenon, dimetil fenilkarbinol, α-metilstirene, dan
hidroksi aseton. Campuran ini kemudian dinetralkan dengan penambahan sodium
fenoksida atau basa lain atau dengan ion exchanger yang lain3.
Campuran dipisahkan dan crude aseton diperoleh dengan cara distilasi. Untuk
mendapatkan kemurnian yang diinginkan perlu dilakukan penambahan satu atau
kolom distilasi. Jika digunakan dua kolom, kolom pertama untuk memisahkan
impuritas seperti asetaldehid atau propionaldehid. Sedangkan kolom kedua berfungsi
untuk memisahkan fraksi-fraksi berat yang sebagian besar terdiri dari air. Aseton
diperoleh sebagai hasil atas menara kedua3.
2. Proses Oksidasi Propilen
Proses oksidasi propilen menjadi aseton dapat berlangsung pada suhu 145˚C
dan tekanan 10 atm dengan bantuan katalis bismut phaspomolibdat pada alumina.
Pada proses ini hasil reaksi terdiri dari aseton dan propanoldehid. Reaksi :
3. Proses Oksidasi Isopropil Alkohol

Pada pembuatan aseton dengan proses ini, isopropil alkohol dicampur dengan
udara dan digunakan sebagai umpan reaktor yang beroperasi pada suhu 200˚C –
800˚C. Reaksi dapat berjalan dengan baik menggunakan katalis seperti yang
digunakan pada proses dehidrogenasi isopropil alkohol. Reaksi :
58
Sintesis Aseton
Reaksi ini sangat eksotermis (43 kkal/mol) pada 25˚C dan untuk itu diperlukan
pengontrolan suhu yang sangat cermat untuk mencegah turunnya yield yang
dihasilkan. Untuk mendapatkan konversi yang baik reaktor dirancang agar hasil dapat
langsung diinginkan. Proses jarang digunakan bila dibandingkan dengan proses
dehidrogenasi3.
4. Proses Dehidrogenasasi Isopropil Alkohol
Proses lain yang sangat penting untuk memproduksi aseton adalah
dehidrogenasi katalitik dimana reaksinya adalah endotermis. Reaksi :
Pada proses ini isopropil alkohol diuapkan dengan vaporizer dan dipanaskan dalam
HE dengan menggunakan steam kemudian dimasukkan ke dalam multi turbular fixed
bed reactor. Ada sejumlah katalis yang dapat digunakan dalam proses ini yaitu
kombinasi zinc oksida - zirkonium oksida, kombinasi tembaga-kromium oksida,
tembaga, silikon dioksida. Kondisi operasi reaktor ini adalah 1.5-3 atm dan suhu
400˚C-600˚C. Dengan proses ini konversi dapat mencapai 75-98% dan yield dapat
mencapai 85-90%. Gas panas keluar dari reaktor yang terdiri dari isopropil alkohol,
aseton, dan hidrogen dilewatkan scrubber, untuk dipisahkan antara gas insoluble (H2)
dengan aseton, isopropil alkohol, dan air. Hasil dari scrubber ini didistilasi, aseton
diambil sebagai hasil atas sedangkan campuran isopropil alkohol dan air sebagai hasil
bawah. Hasil bawah ini didistilasi lagi untuk recovery isopropil alkohol yang diambil
sebagai hasil atas yang kemudian di recycle ke reaktor3.
59
Sintesis Aseton
3.1 Alat dan Bahan
No Alat Fungsi
1 Labu Distilasi Untuk wadah distilasi
2 Gelas Ukur Untuk alat ukur volume tertentu
3 Corong Untuk alat bantu pemindahan larutan
4 Gelas Piala Untuk tempat membuat larutan
5 Termometer Untuk pengukur suhu
6 Corong Pisah Untuk tempat pemisah 2 larutan
7 Erlenmeyer Untuk alat penampung distilat
3.1.2 Bahan dan Fungsinya

No Bahan Fungsi
1 Isopropil Alkohol ( C3H7OH ) Sebagai bahan dasar pembuat aseton
2 Asam Sulfat Pekat ( H2SO4 ) Sebagai katalis
3 Aquadest ( H2O ) Sebagai pelarut
4 Kalium Bikromat ( K2Cr2O7 ) Sebagai oksidator
60
Sintesis Aseton
3.2 Cara Kerja
1. Alat distilasi disiapkan dan dipasang sebagaimana mestinya.
2. Campuran asam sulfat encer dengan isopropil alkohol dibuat sebagai berikut :
 Air sebanyak 50 mL diambil dan dimasukkan ke dalam gelas piala 300 mL.
 Asam sulfat pekat sebanyak 27,5 mL ditambahkan secara perlahan-lahan (tetes
demi tetes sambil diaduk).
 Larutan tersebut didinginkan dan dengan hati-hati ditambahkan 29,2 mL
isopropil akohol sambil diaduk perlahan.
 Suhu larutan dijaga tidak boleh lebih dari 50 oC.
3. Larutan dituangkan kedalam labu suling melalui labu corong pisah dan diusahakan
tangkai corong pisah selalu dipenuhi larutan ini.
4. Kalium bikromat sebanyak 100 gr dilarutkan dalam 100 mL air dan dimasukkan
ke dalam corong pisah.
5. Labu suling dipanaskan perlahan-lahan sampai larutan mendidih.
6. Sumber pemanas dipindahkan, Larutan kalium bikromat ditambahkan secara
perlahan-lahan (tetes demi tetes) dan sangat hati-hati larutan ke dalam labu
suling.
7. Waktu yang diperlukan untuk menambahkan larutan kalium bikromat kira-kira
setengah jam.
8. Panas yang ditimbulkan sewaktu terjadi reaksi akan membuat larutan dalam labu
suling tetap mendidih dan suhu dijaga agar tidak melebihi 65oC.
9. Setelah semua larutan kalium bikromat dialirkan ke dalam labu suling dan suhu
dinaikkan sampai 75oC.
10. Setelah distilasi selesai, diukur volume atau berat dari aseton yang didapat dan
dihitung rendemennya.
11. Produk dikarakterisasi dengan spektrofotometer, UV-Vis, FT-IR dan HPLC.
61
Sintesis Aseton
3.3 Skema Kerja
3.3.1 Pembuatan larutan oksidator K2Cr2O7
Serbuk K2Cr2O7
- dimasukkan 10 gram kedalam gelas piala

- ditambahkan 100 mL akuades
- diaduk hingga larut
- dimasukkan kedalam corong pisah
Larutan K2Cr2O7
3.3.2 Pembuatan Aseton
Asam sulfat pekat
- dipipet 27,5 mL
- dimasukkan kedalam gelas piala yang telah berisi dengan
50 ml akuades sambil diaduk dan ditambah 29,2 mL
isopropil alkohol.
- dijaga suhu larutan tidak lebih dari 50°C
Campuran
- dipindahkan ke dalam labu distilasi

- dipanaskan perlahan – lahan sampai larutan mulai mendidih
- dipindahkan pemanas
- ditambahkan larutan kalium bikromat setetes demi setetes ke
dalam larutan. Dijaga suhunya tidak boleh lebih dari 65°C
- setelah semua kalium bikromat habis ditambahkan, distilasi
dilanjutkan kembali dipanaskan hingga suhu 75°C
Aseton
- diukur volume
- dihitung rendemen
- dikarakterisasi dengan spektrofotometer, UV-Vis, FT-IR dan
HPLC
Hasil
62
Sintesis Aseton
3.4 Skema Alat
Keterangan :
1. Standar
2. Klem
3. Termometer
4. Corong pisah
5. Labu distilasi
6. Batu didih
7. Pemanas
8. Air keluar
9. Air masuk
10. Kondensor
11. Alonga
12. Erlenmeyer
63
Sintesis Aseton
4.1.1 Data
Volume isopropil alkohol = 29.2 mL
Bj isopropil alkohol = 0.786 g/mL
Massa isopropil alkohol
Mol isopropil alkohol =
Mr isopropil alkohol
22.95 gram
=
60 g/mol
= 0.38 mol
Massa isopropil alkohol = massa jenis x volume
= 0.786 g/mL x 29.2 mL
= 22.95 gram
Mr Aseton = 60 g/mol
Bj Aseton = 0.784 g/mL
4.1.2 Perhitungan
C3H7OH + HCrO4 → CH6O + HCrO-
Awal 0.38 mol - - -
Bereaksi 0.38 mol 0.38 mol 0.38 mol 0.38 mol
Setimbang - 0.38 mol 0.38 mol 0.38 mol
Mol aseton = 0.38 mol

Massa aseton teori = mol x Mr
= 0.38 mol x 58 g/mol
= 22.04 gram
Volume aseton percobaan = 18.5 mL
massa aseton
Volume aseton =
Bj Aseton
22.04 gram
=
0.784 g/mL
= 28.11 mL
64
Sintesis Aseton
Volume percobaan
% Randemen = x 100%
Volume teori
18.5 mL
= x 100%
28.11 mL
= 65.81%
65
Sintesis Aseton
4.2.1 Hasil Spektrum FT-IR
4.2.2 Tabel Hasil Spektrum Beserta Gugus Fungsi
No Bilangan Gelombang Gugus Fungsi
1. 1354.05 ; 1464.96 ; 2964.64 C−H
2. 1635.66 – 1726;32 C=O
3. 3367.77 O−H
4. 1635.66 C=C
5. 1191.06 C−N
6. 1068.58 C−O
66
Sintesis Aseton
4.3 Pembahasan
Pada praktikum kali ini, dilakukan percobaan mengenai sintesis aseton dengan
tujuan mensintesis aseton dari isopropil alkohol dan memahami mekanisme reaksi
pembentukan aseton. Prinsip kerja dari sintesis aseton adalah destilasi. Destilasi
merupakan pemisahan suatu senyawa berdasarkan perbedaan titik didih yang
cukup jauh. Prinsip reaksi yang digunakan yaitu reaksi redoks (oksidasi reduksi).
Reaksi redoks merupakan proses bertambahnya atom O dengan pelepasan gugus
H. Aseton yang dihasilkan terbentuk dari proses sintesis melalui reaksi oksidasi
isopropil alkohol dengan oksidator kuat dan bantuan katalis asam. Isopropil alkohol
digunakan karena tergolong alkohol sekunder dan dapat dioksidasi melalui keton.
Oksidator yang digunakan adalah kalium bikromat dan katalis yang digunakan adalah
asam sulfat.
Pada saat pembuatan campuran asam sulfat dengan isopropil alkohol, asam
sulfat tersebut dicampurkan terlebih dahulu dengan air agar suhu tidak naik secara
drastis. Penambahan asam sulfat pekat dan air dengan isopropil alkohol dilakukan
tetes per tetes ke gelas piala yang diletakkan dalam wadah berisi air es. Hal ini
dilakukan untuk menjaga suhu agar tetap stabil saat penambahan asam sulfat
pekat karena reaksi terhadap asam sulfat pekat bersifat eksoterm . Reaksi ini akan
melepaskan kalor dari sistem ke lingkungan sehingga energi sistem akan berkurang.
Larutan dipindahkan ke dalam labu didih dan ditambahkan batu didih. Saat
menuangkan larutan ke dalam labu, corong pisah dipasang menyatu dengan labu
agar larutan tidak menguap. Batu didih berfungsi untuk meratakan pemanasan
dan mencegah terjadinya bumping. Ketika proses destilasi berlangsung, labu
destilasi ditutup dengan aluminium voil. Hal ini juga bertujuan untuk menghindari
terjadinya penguapan tersebut nantinya.
Pada pencampuran asam sulfat dengan isopropil alkohol, suhu larutan dijaga
dan tidak boleh lewat dari 50 ֯ C. Hal ini dikarenakan jika suhu lebih dari 50 ֯C, maka
akan menyebabkan suhu menjadi naik secara drastis. Suhu dapat naik secara drastis
karena asam sulfat yang digunakan bersifat panas. Pemanasan dilakukan sampai
larutan mulai mendidih untuk mereaksikan produk agar produk yang dihasilkan lebih
optimum. Suhu larutan diukur menggunakan termometer. Pengukuran suhu larutan
tidak boleh menyentuh dinding gelas atau permukaannya, tetapi hanya menyentuh
larutan tersebut. Hal ini dilakukan agar suhu yang terukur adalah suhu larutan, bukan
67
Sintesis Aseton
suhu dari air es.
Setelah labu destilasi dipanaskan, maka sumber pemanas dipindahkan. Jika
sumber pemanas tidak dipindahkan, maka ketika mengompres labu didih akan
menjadi sulit. Kalium bikromat ditambahkan secara perlahan-lahan ke dalam labu
didih agar suhu tidak naik drastis. Saat penambahan kalium bikromat secara
perlahan-lahan tersebut , labu destilasi harus selalu dikompres supaya labu tidak
terlalu panas. Kalium bikromat dididihkan agar terjadi reaksi antara katalis dengan
bahan dasar yang digunakan. Panas yang ditimbulkan sewaktu terjadi reaksi akan
membuat larutan dalam labu destilasi tetap mendidih dan suhu dijaga agar tidak
lebih dari 65 ֯ C. Apabila suhunya tidak dijaga, maka hasil yang terbentuk tidak
sempurna dan akan mencapai suhu isopropil alkohol yaitu 82 ֯ C. Dengan demikian,
maka yang disintesis nantinya yaitu isopropil alkohol, bukan aseton.
Pada saat semua larutan kalium bikromat dialirkan dalam labu destilasi, suhu
dinaikkan menjadi 75 ֯C. Pada suhu ini, K2Cr2O7 tereduksi menjadi Cr3+ dan akan
bereaksi dengan isopropil alkohol membentuk reaksi yang sempurna. Suhu yang
rendah menyebabkan larutan tidak bereaksi secara maksimum. Ketika
penambahan kalium bikromat, warna larutan awalnya adalah oranye. Setelah
bercampur dengan isopropil alkohol, ditambahkan H2SO4 ke dalam labu didih
sehingga warna larutan menjadi hijau. Warna larutan dapat berubah karena
disebabkan oleh adanya reaksi oksidasi-reduksi yaitu perubahan bilangan oksidasi
dari Cr7+ menjadi Cr3+. Selain itu, perubahan warna terjadi karena disebabkan oleh
adanya reaksi kompleks.
Berdasarkan percobaan yang telah dilakukan, didapatkan volume aseton
sebanyak 4,5 mL dan rendemen sebesar 66,07 %. Percobaan yang dilakukan
masih kurang sempurna dan aseton yang didapatkan belum murni karena masih
terdapat pengotor di dalamnya. Hal ini juga dapat disebabkan pada saat percobaan,
mulut labu tidak ditutup secara sempurna sehingga banyak isopropanol yang
menguap. Kesalahan dapat juga terjadi karena kurang teliti dalam melihat perubahan
titik didih sehingga proses destilasi tidak berjalan dengan baik. Selain itu pemanasan
yang dilakukan kurang optimal sehingga hasil rendemen yang didapatkan belum
terlalu maksimal.
Dari sampel yang telah dikarakterisasi oleh spektrofotometer FTIR, didapatkan
hasil berupa spektrum. Pada daerah 1600-1820 cm-1 terdapat gugus karbonil
(C=O) yakni pada spektrum 1641,45 dan 1749,57 cm-1 dengan intensitas yang kuat.
68
Sintesis Aseton
Pada serapan 3300-3500 cm-1 yaitu tepatnya pada spektrum 3379,34 cm-1 terdapat
gugus (O-H) atau alkohol. Untuk gugus (C-O) terdapat pada sekitaran 1000-1300
cm-1 tepanya pada spektum 1011,68 dan 1069,58 cm-1 adanya senyawa tipe
alkohol, eter, asam karboksilat, dan ester dengan intensitas yang kuat. Pada
spektrum 2879,77 dan 2966,57 cm-1 adanya gugus (C-H) dengan intensitas yang
kuat. Dalam karakterisasi tersebut, juga terdapat gugus fungsi yang bukan
pembentuk aseton. Hal ini disebabkan karena dalam mensintesis aseton terbentuk
juga senyawa lain yang terdeteksi oleh FTIR. Selain itu, hal tersebut juga
disebabkan oleh adanya pengotor lain yang dapat menyebabkan adanya gugus
fungsi ini masuk dalam hasil karakterisasi tersebut.
Berdasarkan karakterisasi yang telah dilakukan, dapat disimpulkan bahwa di dalam
aseton terdapat gugus fungsi C-H (alkana, alkena, alkuna, dan aromatik), C-O ( alkohol,
eter, asam karboksilat, dan ester ) dan gugus fungsi C=O ( karbonil ). Aseton
susah didapat karena aseton memiliki gugus O yang masih dapat berikatan
dengan hidrogen sehingga akan membentuk senyawa ketoetanol dan akan sulit
untuk dipisahkan. Dari karakterisasi sintesis aseton melalui spektrofotometer FT-IR
yang didapatkan bukan aseton melainkan alkohol karena terdapat gugus (O-H) di
dalamnya. Hal ini disebabkan karena isopropil yang digunakan menguap.
69
Sintesis Aseton
5.1 Kesimpulan
Berdasarkan percobaan yang telah dilakukan, dapat disimpulkan bahwa :
1. Prinsip percobaan yaitu reaksi redoks (oksidasi reduksi) dan prinsip kerjanya
adalah destilasi.
2. Volume aseton yang diperoleh yaitu sebanyak 4,5 mL
3. Rendemen yang didapatkkan adalah sebesar 16,01 %.
4. Di dalam aseton terdapat gugus fungsi C-H (alkana, alkena, alkuna, dan
aromatik) , C-O ( alkohol, eter, asam karboksilat, dan ester ) dan gugus fungsi
C=O ( karbonil ).
6 Dari karakterisasi sintesis aseton melalui spektrofotometer FT-IR yang
didapatkan bukan aseton melainkan alkohol karena terdapat gugus (O-H) di
dalamnya. Hal ini disebabkan karena isopropil yang digunakan menguap.
5.2 Saran
Agar percobaan selanjutnya lebih baik lagi, maka disarankan untuk :
1. Pahami skema kerja dengan baik.
2. Pahami sifat fisika dan sifat kimia yang digunakan dalam percobaan.
3. Berhati-hati dalam mengambil dan mencampurkan bahan-bahan kimia
yang digunakan.
4. Gunakan safety lab saat melakukan percobaan.
70
Sintesis Aseton
DAFTAR PUSTAKA
1. Damayanti, Latifah Adelina dan Jaslin Ikhsan. 2016. Augmented Chemistry

Aldehida & Keton (Aplikasi Augmented Reality pada Pembelajaran Kimia).
Yogyakarta : UNY.
2. Gigih, Lintang P, dkk. “Potensi Kandungan Aseton dari Limbah Puntung Rokok.”
Jurnal Teknik Kimia, Fakultas Teknologi Industri, Universitas Islam Indonesia,
Yogyakarta.
3. Alfia, Sinta Intani. 2009. ”Prarancangan Pabrik Aseton Proses Dehidrogenasi
Isopropil Alkohol Kapasitas 19.500 Ton/Tahun.” Surakarta: Universitas
Muhammadiyah.
71
Sintesis Aseton
Lampiran I. Tugas sebelum praktikum
1. Tulis mekanisme reaksi pembuatan aseton pada percobaan ini !

Jawab :
a. Pembentukan ion kromat
b. Reaksi isopropanol dengan ion kromat
72
Sintesis Aseton
2. Sebutkan penambahan masing-masing reagen yang digunakan !
Jawab :
1. Isopropil alcohol = Sebagai bahan dasar

2. Asam sulfat pekat = Sebagai katalis
3. Akuades = Sebagai pelarut
4. Kalium bikromat = Sebagai oksidator
73
Sintesis Aseton
Lampiran II. Struktur Senyawa yang digunakan
No Nama Senyawa Struktur

1 Isopropil alcohol
2 Asam Sulfat
3 Akuades
4 Kalium bikromat
74
Sintesis Aseton
Lampiran III . Analisis artikel ilmiah
I. JUDUL
Synthesis and characterization of cynamilillidine acetone – A study on turning of

band gap by vibrational spectroscopic tools.
Sintesis dan karakterisasi cynamillidine aseton- Sebuah studi tentang pergantian
kesenjangan pita oeh alat spektroskopi getaran.
II. TUJUAN PENELITIAN
Untuk menyintesis cynamillidine aseton (CA) dengan langkah tunggal dan dikatalis.
III. SKEMA KERJA
Cynnamillidine aseton
- Dimasukkan kegelas kimia 25 mL

- Ditambahkan 4 mL aseton
- Diaduk terus dan ditambahkan NaOH
- Diperhatikan endapan terbentuk
- Dilanjutkan pengendapan selama 20 menit
- Disaring endapan dicuci dengan etanol
- Dikeringkan endapan dan direkritalisasi
- Dikarakterisasi dengan FTIR, UV-Vis dan HPLC
Hasil
IV. HASIL
Berdasarkan percobaan didapatkan hasil :
1. Konfomer CA terstabil diidentifikasi : DTT/B3LYP
2. Celah energi dari CA : 3,801 EV dan 4,614 EV
3. Celah pita berkurang ketika cinnamaldehyde (aldehid) menjadi CA
1. Antara artikel dengan praktikum sama-sama mensintesis aseton, namun pada
artikel lebih kompleks yaitu CA (cynamillidine cetone).
2. Kesamaan dalam mengkarakterisasi produk dengan menggunakan FT-IR, UV-
Vis dan HPLC.
75
Sintesis Aseton
Journal of Molecular Structure 1184 (2019) 593e603
Contents lists available at ScienceDirect
Journal of Molecular Structure

journal homepage: http://www.elsevier.com/locate/molstruc
Synthesis and characterization of cinnamylidene acetone e A study on

tuning of band gap by vibrational spectroscopic tools
V. Ragavendran a, *, S. Muthunatesan b, V. Santhanam c, Biljana Arsic d
a
Department of Physics, Sri Chandrasekharendra Saraswathi Viswa Mahavidyalaya, Kanchipuram, 631561, Tamilnadu, India
b
Department of Physics, Government Arts College (Autonomous), Kumbakonam, 612001, Tamilnadu, India
c
Department of Chemistry, Sri Chandrasekharendra Saraswathi Viswa Mahavidyalaya, Kanchipuram, 631561, Tamilnadu, India
d
Department of Mathematics, University of NIS, Visegradska-33, 18000, Nis, Republic of Serbia
a r t i c l e i n f o a b s t r a c t
Article history: The title molecule Cinnamylidene acetone (CA) was synthesized through a single step base catalyzed
Received 1 November 2018 aldol type condensation between acetone and cinnamaldehyde. The prepared molecule has been char-
Received in revised form acterized using NMR (1H and 13C) spectral analysis, FTIR, UVeVis and Elemental analysis. The complete
13 February 2019
vibrational characterization of the molecule was performed using experimental (FTIR and FT-Raman)
Accepted 14 February 2019
Available online 15 February 2019
spectra and calculations at DFT level. In order to carry out a detailed vibrational spectroscopic analysis
of CA, Fourier Transform Infrared and Fourier Transform Raman spectra recorded in condensed phase
were used. To determine the optimized geometry and vibrational wavenumbers, Density functional
Keywords:
Synthesis
theory calculations in the B3LYP/6-31G** level have been carried out followed by scaling using the scaled
DFT quantum mechanical methodology. A root mean square deviation of 6.53 cm1 has resulted from the
SQM scaled quantum mechanical treatment. The ultraviolet visible spectra of the title compound dissolved in
Extended conjugation various solvents were recorded in the range of 300e600 nm. The natural bond orbital and frontier
Band gap tuning molecular orbital analyses were also performed using B3LYP/6-31G** method. These studies revealed a
reduction in the band gap of CA in comparison with that of cinnamaldehyde (CY).
© 2019 Elsevier B.V. All rights reserved.
1. Introduction of 245 mM in vitro was previously studied [7]. Through activation of

the mitogen-activated protein kinases (MAPK) pathway and pro-
Cinnamaldehyde is one of the phytochemicals found in cinna- apoptotic Bcl-2 family proteins, cinnamaldehydes were found to be
mon and exhibits several biological effects such as anti-tumoural, effective in inducing apoptotic cell death in a number of human
anti-oxidative, anti-hyperglycemic, anti-obesity and anticancer cells [11e14]. Cinnamaldehyde is also well-known as the
inflammatory activities to relieve heart injury in metabolic syn- principal agonist of transient receptor potential-ankyrin receptor 1
drome [1e4]. Earlier, the effects of cinnamaldehyde as an antimi- which is responsible for diverse sensory processes including cold
crobial agent have been described [5e7]. Cinnamaldehyde is a good and warm nociception, hearing or inflammatory pain. Cinnamon
food preserving agent and also used to enhance flavour and odour. extract has been linked to many different health benefits like
It was used as decorative cosmetics worldwide in the range against obesity and diabetic conditions [15e20]. Besides these,
100e1000 metric tonnes per annum [8]. Reports show that it in- hydrogenation of cinnamaldehyde, organocatalytic reaction
hibits the growth of Staphylococcus aureus [5], Salmonella enterica mechanism, its role as a catalyst, metal support interactions and
serovar Typhimurium [6], Clostridium botulinum [9] and Escherichia solvent effects were studied earlier [21e26]. Beyond the taste
coli O157:H7. The blockage of CD36-mediated TLR4/6-IRAK4/1 impact of spices, numerous health benefits have been ascribed to
signaling to suppress NLRP3 inflammasome activation by cinna- naturally derived flavouring molecules and are known for their use
maldehyde and allopurinol was studied earlier [10]. Its inhibition in traditional medicine and positive effects on human health. Many
property towards cyclooxygenase (COX)-2 activity with IC50 value reports were made with the aid of electron diffraction and micro-
wave spectroscopy in the structure determination of trans-cinna-
maldehyde [27,28]. However, the molecular mechanisms by which
* Corresponding author. these derivatives mediate their effects remain largely unknown and
E-mail address: ragav910@gmail.com (V. Ragavendran). their vibrational picture has not yet been elucidated.
https://doi.org/10.1016/j.molstruc.2019.02.057
0022-2860/© 2019 Elsevier B.V. All rights reserved.
594 V. Ragavendran et al. / Journal of Molecular Structure 1184 (2019) 593e603
Fig. 1. Reaction mechanism of the synthesis of Cinnamylidene acetone.
In molecular systems like cinnamaldehyde, as conjugation in- (ii) To investigate its complete vibrational behavior using Fourier
creases there will be a decrease in HOMO-LUMO energy gap and Transform Infrared (FTIR), Fourier Transform Raman (FT-
the position of p - p* absorption will shift to longer wavelength Raman) spectra along with Density Functional Theory (DFT)
[29]. More the conjugation, longer the absorption maximum. Also, level calculations.
the trans isomer absorbs at a longer wavelength and with a larger
molar extinction than cis conformer [29]. This phenomenon has Further, the crystallographic structure data of cinnamaldehyde
motivated us to take up the present study in which we have were obtained from literature [30] and the same was used for
investigated the effect of conjugation extension on the band gap, performing DFT calculations to obtain band gap and UVeVis ab-
utilizing tools like UV, NBO and HOMO-LUMO analyses, when sorption spectra of cinnamaldehyde. The results thus obtained
cinnamylidene acetone is formed from cinnamaldehyde. In the were compared with that of cinnamylidene acetone.
present study, (3E,5E)-6-phenyl-3,5-hexadien-2-one, also known
as Cinnamylidene acetone (CA), was synthesized taking Cinna-
maldehyde (CY) as the base compound and was characterized using 2. Methods
NMR, FTIR, UV-VIS and Elemental analyses.
The synthesized compound is further used: 2.1. Synthesis details
(i) To identify the most stable form of the title compound Cinnamylidene acetone was prepared through a single step base
among the different conformers, catalyzed aldol type condensation between acetone and cinna-
maldehyde which were taken in 1:1 mol ratio. The reaction
Fig. 2. Graphical representation of preparation process of Cinnamylidene acetone.

V. Ragavendran et al. / Journal of Molecular Structure 1184 (2019) 593e603 595
Fig. 3. Different conformers of Cinnamylidene acetone.
mechanism is as shown in Fig. 1 and the procedure is very well equipped with HeliumeNeon laser source, potassium bromide
illustrated in Fig. 2. All starting materials, cinnamaldehyde, NaOH (KBr) beam splitter and LiTaO3 detector in the region
(SD Fine Chemicals, India) and acetone (CDH, India) were pur- 4000e400 cm1 with a resolution of 1 cm1. The FT-Raman mea-
chased of high purity and used as received without further surements for CA was made using the Nicolet model 950 FT-Raman
purification. spectrometer using 1064 nm line of a Nd:YAG laser for excitation at
In a clean 25 ml beaker, 4 ml of ethanol was taken and cinna- a 200 mW output power in the range 4000-50 cm1 with a reso-
maldehyde (2.0 mmol, 0.2643 g) was added followed by acetone lution of 4 cm1.
(2.0 mmol, 0.1161 g) under magnetic stirring. With continuous The UVeVis absorption spectrum of the title compound was
stirring, 4 ml of 3 M NaOH was added in drops. After about 45 s, a recorded in the range 600-300 cm1 using Analytik Jena Specord
yellow precipitate of Cinnamylidene acetone was formed. The 200 Plus UVeVisible spectrophotometer (Germany). The 1H
stirring was continued for another 20 min to ensure the completion (400 MHz; CDCl3) and 13C (400 MHz; CDCl3) Nuclear Magnetic
of the reaction. A mixture of ethanol and water in 1:2 ratio (10 ml) Resonance (NMR) spectra were recorded on a Bruker HC400
was prepared and half of the mixture was added and stirred well;
after another 20 min remaining aqueous alcohol was added. The
reaction mixture was filtered under vacuum and the yellow solid Table 1
was washed with cold aqueous ethanol. The precipitate was dried Different conformers of Cinnamylidene acetone with their optimized
and recrystallized twice from boiling ethanol. The yield was found energies.
to be 63% (0.2169 g). The product was characterized by the spectral Conformers Optimized energy (Kcal/mol)
methods including FTIR, UVeVis and NMR (1H and 13C), and its
Conformer 1 539.72465815
composition confirmed using elemental analysis. Conformer 2 539.72302573
Conformer 3 539.71855398
Conformer 4 539.71855468
2.2. Experimental details Conformer 5a 539.72465824
Conformer 6 539.71713454
The FTIR spectrum of CA was recorded for the KBr disks pre- Conformer 7 539.71713452
a
pared using PerkineElmer spectrum RX1 spectrophotometer Most stable conformer of CA.
Table 2 recommended by Pulay et al. [34e37] followed by the subsequent

Optimized geometrical parameters of most stable conformer of CA obtained by normal coordinate analysis which includes the refinement of the
B3LYP/6e31G** density functional calculations.
scale factors by the least square fit, potential energy distribution
Bond length Value (Å) Bond angle Value ( ) (PED) calculation and prediction of IR and Raman intensities.
C1eC2 1.408 C1eC2eC3 117.99
C2eC3 1.409 C2eC3eC4 120.80 3. Results and discussion
C3eC4 1.390 C3eC4eC5 120.41
C4eC5 1.399 C4eC5eC6 119.59
C5eC6 1.395 C5eC6eC1 120.02 3.1. Investigation of conformational stability through DFT analysis
C1eH7 1.087 C6eC1eC2 121.19
C6eH8 1.086 H7eC1eC2 119.01 The initial assumption was that the title compound may exist in
C5eH9 1.086 H7eC1eC6 119.79
different conformations. Based on this, seven different possible
C4eH10 1.086 H8eC6eC1 119.81
C3eH11 1.085 H8eC6eC5 120.17
conformers were chosen for CA. The seven conformers were given
C2eC12 1.461 H9eC5eC6 120.25 names as conformer 1, conformer 2, conformer 3, conformer 4,
C12eH13 1.089 H9eC5eC4 120.15 conformer 5, conformer 6 and conformer 7 and their structures
C12eC14 1.354 H10eC4eC5 119.95 were given in Fig. 3(A) e 3(G). To obtain the most stable geometry,
C14eH15 1.089 H10eC4eC3 119.64
structure optimization was performed on all the seven conformers
C14eC16 1.439 H11eC3eC4 119.28
C16eH17 1.089 H11eC3eC2 119.92 using the DFT/B3LYP method at 6-31G** level. The optimized en-
C16eC18 1.352 C2eC12eH13 114.94 ergies of all the conformers were tabulated as shown in Table 1. Of
C18eH19 1.088 C2eC12eC14 127.86 the seven different energy conformers, the conformer 5 (Table 1,
C18eC20 1.481 C12eC14eH15 120.39
Fig. 3(E)) was found to have the lowest energy and thus it was
C20eO21 1.225 C12eC14eC16 122.65
C20eC22 1.519 C14eC16eH17 117.92
identified as the most stable conformer. Hence, conformer 5 was
C22eH23 1.097 C14eC16eC18 125.21 chosen for further investigation.
C22eH24 1.097 C16eC18eH19 120.64
C22eH25 1.090 C16eC18eC20 121.22
3.2. Molecular geometry
C18eC20eO21 122.19
C18eC20eC22 116.51
C20eC22eH23 110.47 The most stable conformer (conformer 5) was obtained when
C20eC22eH24 110.47 the dienyl moiety settles into all trans form (Table 1, Fig. 3(E)). The
C20eC22eH25 109.73
global minimum energy of the most stable conformer (conformer
5) obtained from DFT structure optimization was found to
instrument. Reports on chemical shifts for protons are made in be 539.72465824 kcal/mol. The optimized geometrical parame-
parts per million scales (d scale) downfield from tetramethylsilane. ters of the most stable conformer of CA were shown in Table 2.
CHO elemental composition of CA was determined using LECO
TruSpec Micro Analyser, and determination was done twice. 3.3. NMR analysis
2.3. Computational details The structure of synthesized CA molecule was confirmed by

using 1H and 13C NMR spectra. The experimental chemical shifts in
1
The Gaussian 09 Program suite [31] was utilized to perform H and 13C NMR spectra of (3E, 5E)-6-phenyl-3,5-hexadien-2-one
Quantum chemical calculations on CA by applying DFT method at (CA) were compared with the theoretically predicted chemical
the B3LYP level [32,33] using 6-31G** basis set. The stable shifts obtained using website www.nmrdb.org [38e43]. The values
conformer of CA was identified from the energy optimization at the are tabulated in Table 3 [1H shifts] and Table 4 [13C shifts].
DFT level of theory. During the optimization procedure, all the The 1H and 13C spectra of CA were shown in Fig. 4(A) and (B),
geometrical parameters were allowed to relax. Further, in order to respectively. The total number of signals in the spectra does not get
express the normal modes in a molecular fixed coordinate system, a correlated with the number of types of protons due to the over-
set of local symmetry coordinates was defined as recommended by lapping of the peaks of aromatic protons 6e10, in the region of
Pulay et al. [34] and are listed in Table S1. The Molvib 7.0 program 7.25e7.36 ppm. The terminal methyl protons are appearing as
written by Tom Sundius [35] was utilized to perform full normal singlet as expected in the moderately deshielded region, due to the
coordinate analysis (NCA) on cinnamylidene acetone. The force electron withdrawing nature of carbonyl group. The four alkenyl
fields were first transformed from Cartesian to local symmetry protons 2, 3, 4 and 5 appear in the deshielded region because of the
coordinates and scaled using selective scale factors as anisotropy of the ethylenic systems. Since there are considerable
Table 3
Comparison of predicted and experimental 1H NMR shifts of (3E, 5E)-6-phenyl-3,5-hexadien-2-one.
Protons 1 2 3 4 5 6 7 8 9 10
Theoretical value in ppma 2.34 6.03 7.01 7.25 7.42 7.43 7.43 7.44 7.50 7.50
Experimental value in ppm 2.16 6.57 6.95 7.00 7.26e7.36 7.26e7.36 7.26e7.36 7.26e7.36 7.48 7.48
a
Obtained theoretically by using the website www.nmrdb.org.38
Table 4
Comparison of predicted and experimental13C NMR shifts of (3E, 5E)-6-phenyl-3,5-hexadien-2-one.
Carbons 1 2 3 4 5 6 7 8 9 10
a
Theoretical value in ppm 28.05 126.81 127.33 128.68 128.75 128.92 136.58 139.17 144.91 197.74
Experimental value in ppm - 126.51 127.48 128.84 129.02 129.16 136.14 141.46 143.04 188.96
a
Obtained theoretically by using the website www.nmrdb.org.38
Fig. 4. (A)1H spectrum of (3E, 5E)-6-phenyl-3,5-hexadien-2-one. (B)13C spectrum of (3E, 5E)-6-phenyl-3,5-hexadien-2-one.

amounts of overlaps, calculation of coupling constants at this res- reflected in the values depicted in Table 5. The RMS deviation of
olution level becomes impossible. 60.1 cm1 was observed between unscaled and experimental
wavenumber of CA. However, using a set of transferable scale fac-
3.4. Elemental analysis tors recommended by Rauhut and Pulay [44,45], the force fields
were scaled in order to obtain reliable information of the vibra-
Elemental analysis shows 83.30% C, 7.00% H, and 9.30% O, which tional properties.
is the good agreement with the calculated values (83.69% C, 7.02% The calculated wavenumbers were subjected to three types of
H, and 9.29% O). These data together with IR, UV-VIS and NMR data scaling procedures namely, unscaled, uniform scaling and selective
confirmed the structure of cinnamylidene acetone as the synthe- scaling. In uniform scaling, an RMS deviation of 23.4 cm1 was
sized compound. obtained by applying a scale factor of 0.99 uniformly to all unscaled
wavenumbers. Further, in order to refine the calculated wave-
numbers, selective scaling using scale factors 0.99, 1.05, 0.95, 0.922
3.5. Molecular vibrations and simulated spectra
and 0.85 was done. The selective scaling procedure results in the
RMS deviation of 6.53 cm1 (Refer Table S1).
The title compound CA belongs to CS point symmetry and its 69
fundamentals are distributed among the symmetry species as:
3.6.1. Ring vibrations
Gvib ¼ 47A0 (ineplane) þ 22A00 (oute ofeplane).
3.6.1.1. CeH vibrations. The aromatic compounds exhibit CeH
The combined observed and calculated FTeIR and FTeRaman
stretching vibrations generally in the region 3105e3000 cm1
spectra of CA were presented in Fig. 5 and Fig. 6, respectively. For
[46e48]. This vibration in CA was observed in the IR spectrum at
the title compound CA, the results of vibrational analysis viz.,
3098, 3080, 3075, and 3056 cm1 and in the Raman spectrum at
calculated unscaled and scaled SQM wavenumbers, potential en-
3084 and 3059 cm1.
ergy distributions (PED) and assignment of the fundamentals, were
In general, the weak bands observed in the region 1250-
collected in Table 5.
990 cm1 correspond to CeH in-plane bending vibrations [49]. For
CA, these bands are observed at 1232, 1183, 1155 and 1068 cm1 in
3.6. Analysis of vibrational spectra by SQM methodology and
the IR spectrum and in the Raman spectrum at 1244, 1213, 1161 and
assignments
980 cm1. The CeH outeofeplane bending mode of the title com-
pound was observed in the IR spectrum at 890, 848, 750 and
Generally, the unscaled B3LYP/6e31G** vibrational wave-
692 cm1 and in the Raman spectrum at 876, 779 and 689 cm1,
numbers are somewhat larger than the observed values and is
respectively and are presented in Table 5.
3.6.1.2. Skeletal vibrations. The C]C stretching vibrations generally

occur in the region 1625-1430 cm1 [46e52]. The IR bands
observed at 1600 and 1494 cm1 were assigned to C]C stretching
vibrations of CA and their Raman counterparts were identified at
1566, 1491 and 1472 cm1. In CA, the CeC stretching vibration was
observed at 1316 and 1232 cm1 as IR bands and as Raman bands at
1315 and 1213 cm1 respectively.
The aromatic ring in-plane and out-of-plane deformation vi-
brations were observed in the region 630-605 cm1 and 560-
415 cm1, respectively. The IR band observed at 627 cm1 and the
Raman bands observed at 661 and 627 cm1 were attributed to the
ring in-plane bending vibrations. For CA, the bands due to ring
torsion vibrations were observed at 503 cm1 in IR spectrum and
their Raman counterparts were identified at 536 and 401 cm1.
3.6.2. Alkene vibrations

3.6.2.1. CeH vibrations. The trans CeH stretching vibrations are
generally observed as medium to strong bands in the region
3040e3010 cm1 [46e48]. This vibration of CA is observed as
strong band in the IR spectrum at 3024 cm1. In the Raman spec-
trum of CA it was observed at 3036 and 3020 cm1.
In general, the CeH in-plane bending vibrations were observed
as several bands with weak to medium intensity in the regions
1340-1260 cm1, 1305-1215 cm1 and 1000-910 cm1 respectively
[49]. For CA, these bands are observed at 1316 and 1274 cm1 in the
IR spectrum and in the Raman spectrum at 1385, 1335, 1315 and
1296 cm1. For dienes, the CeH outeofeplane bending modes were
generally observed in the region 980-955 cm1. In particular for
trans-trans system, the presence of conjugation increases frequency
and it may be around 1000 cm1. The CeH outeofeplane bending
modes of the title compound are observed in the IR spectrum at
926 cm1 and in the Raman spectrum at 999 and 926 cm1,
respectively and are presented in Table 5.
Fig. 5. Combined FT-IR spectra of Cinnamylidene acetone. (A) Observed, (B) Calculated
e Selective scaling, (C) Calculated e Uniform scaling and (D) Calculated - Unscaled. 3.6.2.2. C]C vibrations. The alkene C]C stretching vibrations are
Fig. 6. Combined FT-Raman spectra of Cinnamylidene acetone. (A) Observed, (B) Calculated e Selective scaling, (C) Calculated e Uniform scaling and (D) Calculated - Unscaled.
generally observed in the region 1670-1610 cm1 as medium to the presence of CH3 asymmetric stretching vibrations. The methyl
weak IR band and strong Raman band, and at 1610-1580 cm1 as symmetric stretching vibrations were usually expected in the re-
medium IR band and medium to weak Raman band [46e52]. For gion 2970-2840 cm1 [46e55]. The weak bands identified at
conjugated dienes, two absorption bands occur generally at 1650 2852 cm1 and 2851 cm1 in the IR and Raman spectra correspond
and 1600 cm1. The presence of 1600 cm1 confirms the presence to methyl symmetric stretching vibrations.
of conjugation. In cases similar to title compound, alkenes conju- The asymmetric methyl deformation vibrations were observed
gated to aromatic rings exhibit strong absorption near 1625 cm1 in the region 1465-1415 cm1 and 1440-1410 cm1 and the methyl
which shifts the ring C]C absorption to 1590 cm1. The IR band symmetric deformation vibrations were expected in the region
observed at 1568 cm1 was assigned to C]C stretching vibrations 1390-1340 cm1. For the title compound, the bands observed at
of CA and their Raman counterpart was identified at 1607 cm1. 1445 and 1406 cm1 in the FT-IR and Raman spectra indicates the
The Raman bands observed at 1152 and 1094 cm1 were presence of methyl asymmetric deformation vibrations. The IR
attributed to the C]C in-plane bending vibrations. Their IR coun- band observed at 1353 cm1 and the Raman band at 1356 cm1
terparts could not be observed. For CA, the bands due to C]C out- confirms the presence of methyl symmetric deformation
of-plane vibrations were observed as Raman bands at 554, 316, 162, vibrations.
85, 64 and 37 cm1. The methyl out-of-plane bending vibrations were generally
observed in the region 1155-1015 cm1 and 1070-900 cm1. For the
title compound, a shoulder observed in the IR spectrum at
3.6.3. C]O vibrations
951 cm1 and the weak bands observed in the Raman spectrum at
Generally, the C]O stretching vibration occurs in the region
1030 and 957 cm1 correspond to methyl out-of-plane bending
1730-1450 cm1 [50e52]. The band identified at 1657 cm1 in the
vibrations. The methyl torsional vibrations were generally expected
IR and Raman spectrum indicates the presence of C]O stretching
in the region 270-130 cm1. This vibration for the title compound
vibrations of CA. The C]O in-plane bending vibrations were
was identified as a weak Raman band at 239 cm1.
observed as Raman band at 1177 cm1 and the vibration observed
at 427 cm1 contributes to the C]O out-of-plane bending vibra-
tions of CA.
4. Frontier molecular orbital analysis and band gap tuning
3.6.4. Methyl group vibrations The HOMO, LUMO energies and the energy gap for CA and
The nine fundamental vibrations of methyl group were classi- cinnamaldehyde [30] were calculated using B3LYP/6-31G** method
fied into ns þ 2nas þ 2 das þ ds þ 2u þ t [46]. The methyl asymmetric [56,57] and the values thus obtained were properly tabulated as
stretching vibrations are generally expected in the region 3045- shown in Table 6. Their graphical illustration was presented in
2965 cm1 and 3010-2960 cm1 [46e55]. The IR band identified at Fig. 7. For CA, a total number of 46 occupied orbitals and 209 virtual
3000 cm1 and the Raman bands at 3000 and 2966 cm1 confirms orbitals were observed.
Table 5
Calculated wavenumbers (cm1) of Cinnamylidene acetone by B3LYP/6e31G** method and vibrational assignments based on potential energy distribution.
Observed IR intensity Raman activity Calculated Wavenumbers (cm1) using B3LYP/6 Characterization of normal modes with PED(%)b
Wavenumbersa e31G** force field
IR Raman Unscaled Uniform scaling Selective scaling
3098 w - 23.12 319.5 3210 3122 3092 n CHring (99)

3080 w 3084 vw 30.03 75.76 3203 3115 3084 n CHring (99)
3075 vw - 10.64 137.4 3194 3106 3076 n CHring (99)
- 3059 m 0.536 96.19 3184 3097 3067 n CHring (99)
3056 w - 7.323 22.821 3178 3091 3060 n CHring (99)
- - 22.86 8.396 3171 3084 3054 n CH (100)
- - 2.254 51.62 3166 3078 3047 n CH (99)
- 3036 sh 4.58 55.97 3164 3073 3043 n CH (99)
3024 s 3020 vw 7.274 35.07 3160 3061 3031 n CH (99)
3000 vw 3003 m 12.32 77.59 3148 3058 3000 nas CHme (100)
- 2966 w 16.38 146.2 3100 3008 2972 nas CHme (100)
2852 vw 2851 w 3.461 188.5 3040 2937 2854 ns CHme (100)
1657 s 1657 s 121.6 885.4 1774 1690 1647 n CO (65), n CC (23), g CH (15)
- 1607 vs 13.38 360.0 1681 1637 1617 n CC (57), g CH (28)
1600 vs - 5.844 566.3 1661 1616 1600 n CCring (62), g CH (26), b CCring (10)
1568 sh - 123.2 648.0 1648 1599 1575 n CC (54), g CH (25)
- 1566 vs 365.5 649.6 1627 1587 1569 n CCring (49), n CO (24), g CH (18)
1494 m - 1.528 156.3 1538 1520 1505 n CCring (67), g CH (32)
- 1491 m 6.739 32.45 1491 1475 1490 n CCring (74), das CHme (25)
- 1472 vw 55.93 174.7 1488 1466 1469 n CCring (54), ds CHme (27), n CO (19)
1445 s 1445 w 6.214 15.95 1477 1455 1462 das CHme (56), n CC (32)
1406 m 1406 vw 46.42 13.49 1399 1407 1408 das CHme (53), CHme g(32)
- 1385 vw 47.24 18.66 1383 1383 1373 g CH (81), ds CHme (19)
1353 s 1356 w 20.17 84.5 1369 1357 1348 ds CHme (71), b CH (19)
- 1335 vw 11.15 311.6 1349 1336 1326 g CH (87), b CCC (10)
1316 m 1315 w 8.476 117.8 1338 1323 1315 g CH (57), b CCC (10)
1274 s 1296 sh 151.3 755.7 1322 1304 1293 g CH (59), b CCring (22), das CHme (21)
1232 m 1244 vw 55.93 362.7 1268 1263 1248 g CHring (53), b CCO (21), b CCme (21)
- 1213 m 0.007 146.7 1250 1221 1210 g CHring (62), g CH (21), b CCring (16)
1183 w - 31.33 8.350 1211 1202 1190 g CHring (57), g CC (24)
- 1177 m 10.09 460.9 1205 1199 1187 g CO (54), g CH (24), d CCO (21)
1155 sh 1161 sh 4.301 49.02 1188 1181 1169 g CHring (69), b CC (29)
- 1152 s 78.02 746.9 1174 1159 1154 b CC (52), g CH (18), b CCC (15)
- 1094 m 2.662 2.095 1110 1087 1077 b CCring (58), g CH (34)
1068 vs 1067 m 14.70 4.608 1060 1059 1068 u CH (72), u CHme (11)
- - 37.42 0.188 1056 1032 1057 b CC (52), b CCring (42)
- 1030 w 2.154 26.56 1038 1028 1022 u CHme (72), u CH (22)
- - 0.449 2.125 1013 1007 1016 u CH (83), tring (14)
1001 vs - 3.308 0.362 1001 1003 1002 u CHring (82), u CH (17)
- 999 s 0.941 256.9 986 989 998 u CH (62), u CHring (33)
- 980 vw 0.017 0.822 971 976 980 g CHring (92)
951 sh 957 w 198.3 184.2 963 967 963 u CHme (66), b CC (26), b CCme (22)
926 sh 928 vw 0.042 15.12 933 938 954 u CH (77), u CHring (11), u CC (11)
- 909 vw 2.069 15.88 916 908 910 u CH (98)
890 m 876 w 0.471 6.663 906 905 887 u CHring (58), u CC (30), u CCme (21)
848 m - 4.847 3.193 853 854 858 u CHring (94)
- 841 w 2.395 5.163 852 844 851 u CH (89), t CCring (11)
- - 4.788 15.48 841 837 835 u CH (77), u CHme (21)
750 s 779 vw 23.56 1.571 767 768 781 u CHring (77), u CH (11),
692 s 689 vw 23.10 1.707 702 692 690 u CHring (56), u CH (33)
- 661 vw 13.45 0.542 647 656 652 b CCring (51), b CCC (28)
627 sh 627 w 0.523 9.733 633 635 638 b CCring (84), u CC (10)
- - 6.257 17.58 599 603 596 b CCring (49), b CO (33), u CCme (22)
- 554 vw 4.243 0.081 586 569 557 u CC (77), u CO (28), t CCC (13)
- 536 vw 2.811 0.304 518 519 530 t CCring (48), u CHring (22), u CCring (21)
503 m - 2.850 0.074 502 508 514 t CCring (88), u CC (10)
427 vw - 15.039 2.549 437 430 431 u CO (73), u CC (15)
- 401 w 0.002 0.050 412 403 399 t CCring (83), u CHring(17)
- 316 w 6.269 0.105 337 334 329 u CC (60), b CCCme (27), u CC (10)
- 272 w 0.087 1.804 327 327 311 u CCO (43), t CCring (37), u CH (17)
- 239 w 2.666 3.299 246 241 239 t CHme (40), u CO (40), b CCCme (27)
- - 1.088 2.333 236 235 215 u CC (60), t CCring (20), u CH (19)
- 185 vw 0.508 6.546 194 193 187 u CC (60), t CCCme (24), t CCring (21)
- 162 w 2.202 2.672 159 162 164 u CCC (76), u CCring (12)
- 104 w 0.050 0.054 103 103 103 u CHme (95)
- 85 w 0.500 2.453 88 87 84 u CCC (49), u CCCme(34), u CH (17)
- 68 w 0.319 0.175 59 61 62 u CCC (95)
- 37 vw 0.840 1.614 52 52 48 u CCC (71), u CH (22)
- - 2.213 0.357 31 31 28 u CCC (61), u CH (17), u CCCme (10)
a
vsevery strong; sestrong; m-medium; weweak; vwevery weak; sheshoulder.
b
PED ¼ potential energy distribution; only contribution larger than 10% were given.n- stretch; b - ineplane bending; d e deformation (methyl scissoring); g e in-plane
rocking; u e wagging; t etorsion; s e symmetric; as e asymmetric; me e methyl vibrations and ring e ring vibrations.
Table 6 5. Ultraviolet e visible spectral analysis

Comparison of HOMO, LUMO energies of CA and Cinnamaldehyde (CY) along with
their energy gap.
The UVeVis spectra of CA were recorded using ethanol,
Parameters Value (eV) dimethyl formamide (DMF) and ethyl acetate and are presented in
CA CY Fig. 8. The theoretical electronic excitation of CA obtained by TD-
DFT calculations using B3LYP/6-31G** method on the optimized
HOMO energy 5.910 6.626
LUMO energy 2.109 2.012 structure of CA [58] along with their corresponding wavelengths
Energy gap (DV) 3.801 4.614 and assignments were presented in Table 7. The experimental ex-
citations were observed at 374, 368 and 363 nm for ethanol, DMF
and ethyl acetate, respectively. Their calculated counterparts were
The analysis indicates that, the frontier molecular orbitals of CA observed at 362, 361 and 366 nm. Further, the crystallographic data
are mainly composed of p typeeatomic orbitals. The HOMO was of cinnamaldehyde (CY) obtained from literature [30] was used to
observed over the entire molecule except that of methyl group calculate the electronic absorption spectra. The calculated gas
whereas the LUMO spreads throughout the molecule. The calcu- phase absorption was observed at 278 nm and 382 nm for cinna-
lations show that the band gap was found to be 3.801 eV and maldehyde and CA, respectively. The absorption wavelength was
4.614 eV for CA and cinnamaldehyde, respectively. From the results found to be increased in cinnamylidene acetone as compared to
obtained, it was clear that the band gap has been reduced when cinnamaldehyde. This increase in absorption wavelength of CA
cinnamaldehyde becomes CA. This tuning effect in the band gap is implies that its band gap is reduced as compared to that of CY. This
because of the extended conjugation observed in CA. result further confirms our observations made in the Frontier mo-
lecular orbital analysis.
Fig. 7. Comparative HOMO and LUMO plot of cinnamaldehyde with cinnamylidene acetone.
In addition, strong hyperconjugative interactions for the tran-

sition from bond pair (p) of the ring atoms to its antibonding (p*)
orbitals with greater energy contributions of 18.87, 20.17, 16.38,
19.05, 19.83, 20.70 and 19.37 kcal/mol were observed.
7. Conclusion
The title molecule Cinnamylidene acetone was synthesized

through a single step base catalyzed aldol type condensation be-
tween acetone and cinnamaldehyde. The prepared molecule has
been characterized using 1H and 13C NMR, FTIR, UVeVis spectral
analyses and elemental analysis. The complete vibrational charac-
terization of the molecule was done by using experimental (FTIR
and FT-Raman) spectra and calculations at DFT level. From the
structure optimization, the most stable conformer of CA was
identified using DFT/B3LYP/6-31G** methodology.
Fig. 8. UltravioleteVisible absorption spectra of CA.
By adopting selective scaling procedure, a satisfactory assign-
ment of most of the fundamentals was made. The results from the
HOMO-LUMO analysis establish that CA and cinnamaldehyde
Table 7 possess energy gap of 3.801 eV and 4.614 eV, respectively. This
Electronic absorption spectra of CA along with their excitation and assignments. result establishes that the band gap has been reduced when cin-
Solvents Excitation Wavelength (nm) Assignment namaldehyde becomes CA. The reason for this tuning effect in band
gap is due to the extended conjugation observed in CA. The
Calc. Expt.
calculated comparative UVeVis analysis result confirms the
Gas Phase HOMO-1 / LUMO 382 (278)a - LP(1) O21 - LP(2)O21 reduction in band gap of cinnamylidene acetone when compared to
Ethanol HOMO-1 / LUMO 362 374 LP(1) O21 - LP(2)O21
DMF HOMO-1 / LUMO 361 368 LP(1) O21 - LP(2)O21
cinnamaldehyde. The results from NBO analysis establish that the
Ethyl acetate HOMO-1 / LUMO 366 363 LP(1) O21 - LP(2)O21 stabilization of CA seems to be highly dependent on the charge
a transfer from bond pairs (p) of the ring atoms to its antibonding
- For cinnamaldehyde (CY).
(p*) orbitals and from the lone pair (LP) of oxygen atom (O21) into
the bond pairs.
6. Natural bond orbital analysis
Conflicts of interest
The Natural Bond Orbital (NBO) analysis for the title compound
using NBO 5.1 program [59] as implemented in the Gaussian 09 W There are no conflicts of interest to declare.
package at the DFT/B3LYP/6-31G** level was carried out. The
donoreacceptor interactions involving electron density (ED) Acknowledgements
changes for the title compound were calculated employing second
order perturbation theory [60e63]. The authors are thankful to Sophisticated Analytical Instru-
For the title compound, the most predominant electron donor- mentation Facility (SAIF) - IIT Madras, IIT Ropar and Department of
acceptor interactions were presented in Table 8. The energy Optoelectronics, University of Kerala for providing spectral
transfer mechanism from the bond pairs (p) of the ring atoms to its measurements.
antibonding (p*) orbitals and from the lone pair (LP) of oxygen
atom (O21) into the bond pairs was found to be predominant. In Appendix A. Supplementary data
particular, for the transition from the lone pairs of oxygen (O21)
atom into the bond pairs, larger E(2) values of 19.56 and 20.45 kcal/ Supplementary data to this article can be found online at
mol were observed. https://doi.org/10.1016/j.molstruc.2019.02.057.
Funding
Table 8
Second order perturbation theory analysis by Fock matrix of CA using Natural Bond
Dr Biljana Arsic wants to thank the Ministry of Science, Educa-
Order analysis. tion and Technological Development of Republic of Serbia for the
financial support for this work [Proj. No 174007].
Donor (i) Acceptor (j) E(2)a (kcal/mol)
p (C1eC2) p* (C3eC4) 18.87 References

p* (C5eC6) 20.17
p*(C12eO14) 16.38
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OBJEK IV
SINTESIS KLOROFORM
MARTANIA ANGGRIANY, S.Si

“ Sebaik-baik manusia adalah manusia yang bermanfaat bagi orang lain”
TahunAkademik 2020/2021
SINTESIS KLOROFORM
I. TUJUAN
1. Membuat kloroform dengan bahan dasar aseton dan pupuk kaporit
2. Memahami mekanisme reaksi sintesis kloroform
II. LANDASAN TEORI

2.1 Kloroform
Kloroform (Trichloromethane, Methenyl Chloride) mempunyai rumusCHCl3
dimana pada tekanan dan temperatur normal wujudnya berupa cairan bening dan
berbau khas. Pada kondisi tersebut kloroform tidak mudah terbakar, tetapi campuran
uap panasnya dengan uap alkohol terbakar dengan nyala api berwarna hijau. Pada
temperatur tinggi kloroform akan menimbulkan nyala api dan dapat terbakar, juga
mengeluarkan gas beracun. Kloroform dapat larut dalam pelarut organik dan hanya
sedikit larut dalam air. Kloroform lebih dikenal karena kegunaanya sebagai bahan
pembius, walaupun pada kenyataannya kloroform lebih banyak digunakan sebagai
pelarut non-polar di laboratorium atau industri1.
Kloroform bisa digunakan sebagai obat bius dan sebagai pelarut lemak, lilin dan
minyak. Namun demikian efek samping dari kloroform dapat merusak hati sehingga
jarang digunakan sebagai obat bius kecuali penelitian dilaboratorium.Kloroform
berfungsi sebagai anastesi umum yang diperlukan untuk pembedahan karena dapat
menyebabkan penderita mengalami analgesa, amnesia dan tidak sadar sedangkan
otot-otot mengalami relaksasi dan suatu penekanan refleks yang tidak dikehendaki2.
Sifat Fisika Kloroform

Berat molekul (kg/kmol) : 119,38
Densitas (kg/m3, 32°C) : 1.489
Titik leleh (°C) : -63,5
Titik didih (°C) : 61,2
Viskositas (cP, 20°C) : 0,57
Tegangan permukaan (N/m, 25°C) : 0,0267
Sifat Kimia Kloroform
1. Reaksi kloroform dengan hidrogen florida akan membentuk fluorocarbons dengan
menggunakan katalis antimoni pentaklorida.
88
Sintesis Kloroform
2. Kloroform mengalami dekomposisi perlahan-lahan bila kontak dengansinar
matahari dalam waktu yang lama menjadi fosgen, hidrogenklorida, klorin,
karbondioksida, dan air.
3. Pada temperatur 225-275°C, reaksi brominasi pada uap kloroformakan
menghasilkan bromochloromethanes : CCl3Br, CCl2Br2, danCClBr3.
4. Bila kontak dengan potassium amalgam atau red-hot copper,kloroform bereaksi
menghasilkan asetilen.
5. Reaksi kloroform dengan amina dalam larutan alkali alkohol akan membentuk
isonitril.
6. Reaksi kloroform dengan fenol dalam larutan alkali akan menghasilkan p-
hydroxybenzaldehyde dan salicylaldehyde3.
Secara Umum kloroform dapat dibuat dengan empat cara yaitu :
a. Klorinasi Metana
Produksi kloroform yang banyak diaplikasikan dalam industri dapat dilakukan
melalui klorinasi metana dengan bantuan katalis alumina. Bahan baku yang
digunakan adalah metana dengan kemurnian tinggi. Adapun reaktor yang
digunakan adalah reaktor fixed bed katalitik. Suhu reaksi adalah275oC sampai
450oC. Proses halogenasi metana menghasilkan beberapa macam chlorinated
product, yaitu klorometana (CH3Cl), diklorometana (CH2Cl2), kloroform (CHCl3).
Selain itu terdapat reaksi samping klorinasi kloroform menjadi karbon tetraklorida
(CCl4).
b. Klorinasi Fotokimia
Proses klorinasi dengan metode klorinasi fotokimia didasarkanpada reaksi klorinasi
metana oleh aktivasi dari reaksi massa dengan radiasi sinar. Adapun pemisahan
molekul klorin (Cl2) menjadi radikal Cl adalah dengan meradiasikan reaksi massa
dengan sumber sinar yang mempunyai radiasi 3000-5000 A. Bahan baku yang
digunakan adalah metana dengan kemurnian tinggi. Yield proses ini adalah 90%.
Adapun reaktor yang digunakan adalah reaktor fotokimia.
c. Reduksi Karbon Tetraklorida
Karbon tetraklorida (CCl4) direduksi dengan hidrogen (H2) dengan bantuan katalis
besi pada suhu reaksi 15°C dan tekanan operasi 5– 80 atm.
CCl4 + 2(H) → CHCl3 + HCl Yield 70-80% (1.5)
Reduksi teratas dari karbon tetraklorida dengan etil alkohol akan menghasilkan
kloroform. Reaksi terjadi pada reaktor dengan suhu 200oC selama 25 jam akan
menghasilkan kloroform dalam jumlah kecil dan etil klorida. Radiasi ultraviolet
89
Sintesis Kloroform
pada karbon tetraklorida dengan alkohol menghasilkan kloroform dengan konversi
tinggi, tetapi reaksi berjalan sangat lambat.
d. Reaksi Aseton dengan Kaporit
Reaksi kaporit (CaOCl2.H2O) dengan aseton, asetaldehid, atau etil alkohol
menghasilkan crude kloroform, dimana hasil reaksi dimurnikandengan
penambahan zat kimia dan distilasi. Aseton bereaksi dengan perbandingan 0,045
kg aseton : 0,453 kg kaporit, dan suhu reaksinya dijaga sekitar 43,3oC dengan
menggunakan alat pendingin. Ketika aseton telah ditambahkan semuanya, suhunya
dinaikkan menjadi 56,7oC. Kemudian secara perlahan-lahan suhunya dinaikkan
menjadi 65,5oC dan kloroform mulai terbentuk1.
Berdasarkan kelebihan dan kekurangan yang dimiliki oleh masing-masing
reaksi kloroform maka dipilih pembuatan kloroform dari aseton dengan kaporit dengan
pertimbangan proses reaksinya cukup sederhana dengan temperatur operasi yang
relatif rendah, yield yang dihasilkan cukup tinggi yaitu sekitar 86-91%4.
Penggunaan kloroform antara lain untuk :
1. Bahan baku pembuatan polytetrafluoroethylene
2. Zat pengekstrak penisilin dalam industri farmasi
3. Bahan baku fungisida dan vermisida(winarni)
4. Obat bius hewan dalam bidang kedokteran3.
2.2 Aseton
Aseton merupakan senyawa karbonil yang memiliki gugus fungsi keton (-CO). Aseton,
juga dikenal sebagai propanon, dimetil keton, 2- propanon, propan-2-on,
dimetilformaldehida, dan β-ketopropana. Aseton dapat dibuat dari alkohol sekunder
dengan cara oksidasi. Aseton adalah senyawa organik yang berupa cairan tidak
berwarna dan mudah terbakar. Aseton merupakan senyawa keton yang paling
sederhana. Aseton larut dalam berbagai perbandingan air, etanol, dietil eter, dan lain-
lain. Aseton sendiri juga merupakan pelarut penting. Aseton dibuat secara langsung
maupun tidak langsung dari propena. Secara umum, melalui proses kumena, benzena
dialkilasi dengan propena dan produk proses kumena (isopropilbenzena) dioksidasi
untuk menghasilkan fenol dan aseton:
C6H5CH(CH3)2 + O2 → C6H5OH + OC(CH3)2
Konversi di atas terjadi melalui zat antara kumena hidroperoksida,
C6H5C(OOH)(CH3)2.Aseton juga diproduksi melalui propena yang dioksidasi langsung
dengan menggunakan katalis Pd(II)/Cu(II), mirip seperti 'proses wacker'. Aseton
adalah zat yang tidak berwarna dengan berat jenis 0.812 g/mL pada suhu 0°C. Aseton
90
Sintesis Kloroform
juga merupakan senyawa yang memiliki bau khas. Aseton juga merupakan suatu
pelarut yang baik bagi zat-zat organik. Salah satu ciri-ciri dari cairan aseton ini ialah
gampang sekali dalam menguapnya. Ciri-ciri dari aseton lainnya adalah gampang
sekali terbakar, dan biasanya dihasilkan tanpa ada warna. Kandungan dari aseton ini
mempunyai bau5.
91
Sintesis Kloroform
3.1 Alat dan Bahan
3.1.1 Alat dan Fungsi
No Alat Fungsi
1. Erlenmeyer Untuk tempat larutan
2. Labu Destilasi Untuk tempat mendistilasi
3. Pemanas Untuk pemanas larutan
4. Gelas Piala Untuk tempat zat
5. CorongPisah Untuk memisahkan dua larutan
3.1.2 Bahan dan Fungsi

No Bahan Fungsi
1. Aseton Sebagai bahan dasar sintesa
2. Kaporit Sebagai bahan dasar sintesa
3. NaOH 2% Sebagai pencuci larutan
4. Akuades Sebagai pencuci larutan
92
Sintesis Kloroform
3.2 Cara Kerja
1. Bubur kaporit dibuat, diambil sebanyak 50 gram kaporit dengan menambahkan
akuades dan dimasukkan ke dalam labu distilasi, kemudian dipasang alat.
2. Dimasukkan 20 mL aseton ke dalam corong pisah, dan dipasang corong pisah
tersebut pada labu distilasi. Dimana ujung corong pisah dimasukkan ke dalam
bubur kaporit dan dilakukan proses pemanasan.
3. Saat proses pemanasan akan timbul busa. Kemudian, kran corong pisah dibuka
sehingga asetondapat mengalir. Kran ditutup lagi dan dilanjutkan proses
pemanasan.
4. Corong pisah dibilas dengan air. Jika busa yang terbentuk menguap, dikompres
kepala labu dengan kain basah.
5. Pemanasan dilanjutkan sampai hasil distilat yang turun berwarna jernih.
6. Hasil akan berupa larutan dan membentuk dua lapisan dengan air dan dipisahkan
dengan corong pisah.
7. Hasil distilat dicuci dengan NaOH 2% dan air.
8. Zat penarik air ditambahkan dan disaring.
9. Kemudian dihitung rendemen.
10. Produk dikarakterisasi dengan spektrofotometer UV-VIS, FT-IR dan HPLC
93
Sintesis Kloroform
3.3 Skema Kerja
Kaporit
- Diambil 50 gram kaporit

- Ditambahkan akuades
Bubur Kaporit
- Dimasukkan kedalam labu distilasi dan dipasang alat

- Dimasukkan 20 mL aseton kedalam corong pisah dan dipasang
corong pisah tersebut pada labu distilasi. Ujung corong pisah
dimasukkan ke dalam bubur kaporit
- Dilakukan pemanasan dan Kran corong pisah dibuka sehingga
aseton mengalir.
- Ditutup lagi kran dan dilanjutkan pemanasan.
- Dilakukan pemanasan sampai hasil distilat yang turun berwarna
jernih
Distilat -
- Dicuci dengan NaOH 2 %
- Ditambahkan zat penarik air dan disaring
- Dihitung rendemen
- Produk dikarakterisasi
Hasil
94
Sintesis Kloroform
3.4 Skema Alat
5 11
10
6
1 2
7 3
Keterangan:
1. Labu distilasi
2. Kondensor
3. Erlenmeyer
4. Distilat
5. Standar
6. Klem
7. Pemanas
8. Termometer
9. Corong pisah
10. Air masuk
11. Air keluar
95
Sintesis Kloroform
4.1.1 Data
Massa kaporit : 50 g
Volume aseton : 20 mL
Volume kloroform : 14,4 mL
Mr aseton : 58 g/mol
Mr kaporit : 143 g/mol
Mr kloroform : 119,5 g/mol
Berat jenis aseton : 0,788 g/mL
Berat jenis kloroform : 1,49 g/mL
4.1.2 Perhitungan
A. Massa aseton : berat jenis aseton × volume aseton
: 0,788 g/mL × 20 mL
: 15,76 g
B. Mol larutan
massa aseton
Mol aseton :
Mr aseton
15,76 g
:
58 g/mol
: 0,271 mol
massa kaporit
Mol kaporit :
Mr kaporit
50 g
:
143 g/mol
: 0,349 mol
C. Reaksi
Ca(OCl)2 + C3H6O CHCl3
m: 0,349 mol 0,271 mol -
r: -0,271 mol -0,271 mol +0,271 mol
s: 0,078 mol - 0,271 mol
96
Sintesis Kloroform
D. Perhitungan teori
Massa kloroform teori : n × mr
: 0,271 mol × 119,5 g/mol
: 32,38 gram
massa kloroform
Volume kloroform teori :
berat jenis kloroform
32,38 g
:
1,49 g/mL
: 21,73 mL
volume percobaan
E. Rendemen : ×100%
volume teori
14,4 mL
: ×100%
21,73 mL
: 66,26%
97
Sintesis Kloroform
4.2 Pembahasan
Pada praktikum kali ini dilakukan percobaan mengenai sintesis kloroform yang
bertujuan untuk membuat kloroform dengan bahan dasar aseton dan bubur kaporit.
Prinsip reaksi pada percobaan ini adalah halogenasi yaitu reaksi substitusi yang
melibatkan penambahan satu atau lebih unsur halogen pada suatu senyawa.
Sedangkan Prinsip kerja pada percobaan ini adalah distilasi yaitu pemisahan senyawa
berdasarkan perbedaan titik didih yang cukup jauh.
Pada percobaan ini dilakukan pembuatan bubur kaporit dengan cara
mencampurkan air sebanyak 100 mL dengan bubuk kaporit sebanyak 50 g. Kemudian
bubur kaporit dipanaskan dalam labu didih dengan tujuan agar terbentuknya gas Cl 2
yang ditandai dengan timbulnya busa atau buih yang berperan dalam pembentukan
kloroform. Jika buih yang terbentuk terlalu banyak, maka labu harus dikompres
menggunakan kain basah. Hal ini bertujuan agar gas lain selain dari gas klor tidak
terbentuk, dan busa tidak masuk kedalam cabang labu didih. Selanjutnya, aseton
dialirkan melalui corong pisah dan dilanjutkan pemanasan. Penambahan aseton
dilakukan dalam keadaan panas atau pada saat proses pemanasan berlangsung.
Penambahan aseton ini merupakan tahap dalam proses halogenasi, halogenasi
merupakan proses penggantian atom H pada C alfa dengan atom Cl sehingga terjadi
reaksi subsitusi. Aseton dialirkan ke dalam labu didih tetes demi tetes yang bertujuan
untuk mencegah terjadinya penguapan dari aseton serta mencegah untuk terjadinya
bumping karena aseton bersifat mudah menguap.
Setelah aseton dialirkan dalam bubur kaporit, kemudian akan diuapkan dan diubah
menjadi cair atau didinginkan dengan kondensor. Pemasangan alonga harus tercelup
ke dalam akuades, hal ini bertujuan agar kloroform yang terbentuk tidak menguap,
karena kloroform memiliki berat jenis yang lebih besar dibandingkan dengan akuades
sehingga kloroform akan berada pada lapisan bawah dan air pada lapisan atas. Hal
ini juga dikarenakan perbedaan kepolaran, kloroform bersifat nonpolar dan air bersifat
polar. Distilasi dihentikan setelah mencapai suhu yang telah ditentukan, jika destilat
tersebut ditambahkan air maka akan membentuk dua lapisan. Lalu ditambahkan
NaOH 2%, NaOH berfungsi untuk mencuci larutan dari pengotor-pengotornya
sehingga terpisah dengan sempurna. Setelah itu lapisan air dari kloroform dipisahkan,
pada kloroform dimasukkan CaCl2 untuk menarik air yang masih tertinggal dalam
kloroform.
98
Sintesis Kloroform
Berdasarkan percobaan yang telah dilakukan, didapatkan kloroform sebanyak
14,4 mL dengan rendemen sebesar 66,26%. Dari persen rendemen yang didapat
dapat disimpulkan percobaan yang dilakukan sudah cukup teliti. Adapun faktor yang
dapat menyebabkan kurang atau tidak optimal produk yang diperoleh adalah adanya
kontaminan zat, dan kurang teliti pada saat merangkai alat destilasi sehingga larutan
menguap.
99
Sintesis Kloroform
5.1 Kesimpulan
Berdasarkan praktikum yang telah dilakukan dapat disimpulkan bahwa:
1. Kloroform dapat disintesis dari bahan dasar aseton dan bubur kaporit.
2. Prinsip reaksi dari sintesis kloroform adalah halogenasi.
3. Prinsip kerja dari sintesis kloroform adalah distilasi.
4. Volume kloroform yang diperoleh yaitu 14,4 mL.
5. Rendemen yang diperoleh pada percobaan adalah 66,26%
5.2 Saran
Untuk praktikum selanjutnya disarankan :
1. Teliti dalam merangkai alat.
2. Teliti dalam menimbang bubuk kaporit.
3. Berhati-hati saat membuka kran corong pisah agar aseton mengalir dengan
perlahan.
4. Teliti dalam mengamati suhu agar kloroform yang terbentuk tidak menguap.
100
Sintesis Kloroform
DAFTAR PUSTAKA
1. Rahman, Farid dan Febri Silva Akbar. 2018. Pra Rancangan Pabrik Chloroform
Dari Acetone Dan Sodium Hypochlorite Kapasitas Produksi 10.000 Ton/Tahun.
Yogyakarta: Universitas Islam Indonesia.
2. Susilowati, Tri. 2015. Sintesa Kloroform. Makassar: Universitas Muslim Indonesia
3. Winarni, Winarni. 2007. Prarancangan Pabrik Kloroform dari Aseton dan
Bleaching powder Kapasitas 20.000 Ton/Tahun. Surakarta: Universitas
Muhammadiyah Surakarta.
4. Nugroho, Dani Wahyu. 2013. Prarancangan Pabrik Kloroform dari Aseton dan
Kaporit Kapasitas 25.000 Ton/Tahun. Surakarta: Universitas Muhammadiyah
Surakarta
5. Lintang,GigihPrasetyo, dkk. 2017. Potensi Kandungan Aseton Dari Limbah
Puntung Rokok. Yogyakarta: Universitas Islam Indonesia Yogyakarta
101
Sintesis Kloroform
1. Buatlah mekanisme reaksi pembuatan kloroform!
Jawab:
a.)Pembuatan bubur kaporit
Ca(OCl)2 + H2O Ca(OH)2 + Cl2
b.)Reaksi antara halogen dengan NaOH membentuk endapan Na-hipoklorida
Cl2 + 2NaOH NaOCl + NaCl + HOCl2
c.)Reaksi halogenisasi
O H O
Cl Cl
CH3 C C H + HO Ca OH CH3 C C H
H H
O Cl
O Cl
Cl Cl
CH3 C C H + HO Ca OH CH3 C C
H H
O Cl
O Cl
Cl Cl
CH3 C C Cl + HO Ca OH CH3 C C Cl
O Cl
O Cl
CH3 C C Cl + HO Ca OH CH3 C C Cl
Cl Cl
Cl Cl
O O
CH3 C + C Cl CH3 C + H C Cl
O H Cl O Cl
102
Sintesis Kloroform
2. Jelaskan kegunaan kloroform!
Jawab:
a. Pelarut yang baik untuk senyawa organik seperti garam ammonium.
b. Pelarut untuk lemak, karet, alkaloid, lilin, dan damar.
c. Pelarut dalam spektroskopi.
d. Menurunkan suhu beku CCl4 dalam industri karet.
3. Penambahan etanol sebagai bahan dasar pembuatan kloroform: campuran etanoll
dan kaporit akan membentuk senyawa trikloroaseton. Apa tujuan penambahan
aseton? Jelaskan dengan reaksinya!
Jawab :
Tujuan penambahan etanol yaitu untuk mengikat gas fosgen yang terbentuk karena
gas fogen merupakan gas yang sangat beracun. Reaksinya sebagai berikut:
CH3COCH3 + 3Cl2 CCl3COCH3 + 3HCl
103
Sintesis Kloroform
Lampiran II. Struktur Senyawa yang Digunakan
No Senyawa Strruktur
1 Aseton
2 NaOH
3 Akuades
4 Kaporit
5 Kloroform
104
Sintesis Kloroform
Lampiran III. Analisa Artikel Ilmiah
I. Judul
Predicting chloroform production from organic precursors
(Memprediksi produksi kloroform dari prekursor organik)
II. TujuanPenelitian
Untuk mengembangkan alat matematika sederhana untuk memprediksi rendemen
kloroform (triklorometana) yang dihasilkan dari klorinasi air model prekursor
organik
III. Skema Kerja
Pemilihan Deskriptor
- disiapkan indeks karbonil (Cl)

- ditentukan perbedaan pendonor elektron atau karbon
- ditentukan nomor gugus fenol/karbon
- dihitung log perbandingan hidrogen pada karbon
- dilihan efek subsituen pada senyawa aromatik dan alifatik
- dijumlahkan senyawa organik yang berhubungan dengan
konstanta laju untuk klorin berair
Hasil
IV. Hasil
1. Nilai masing-masing diperoleh dari regresi pembentukan kloroform di seluruh
dataset dengan menggunakan tiga deskriptor yang sama adalah 0,90 dan 8,87%
mol/mol
2. Berdasarkan analisis domain penerapan, senyawa akan diklasifisikan fi ed
sebagai outlier jika: (i) mereka memiliki residu standar diatas β 2.5 atau di bawah
2.5 dan (ii) melebihi leverage peringatan 0,095
3. Menggunakan 10 prekursor yang belum teruji, menunjukkan perbedaan rata-rata
5,3% mol/mol antara hasil kloroform eksperimental dan prediksi
V. Perbandingan dengan Praktikum
1. Pada artikel memproduksi kloroform dengan menggunakan alat perkusor
sedangkan pada praktikum menggunakan cara laboratorium yaitu melalui
distilasi
2. Prinsip yang digunakan sama yaitu mendapatkan senyawa kloroform
105
Sintesis Kloroform
Water Research 124 (2017) 167e176
Water Research
journal homepage: www.elsevier.com/locate/watres
Predicting chloroform production from organic precursors

Tom Bond a, *, Nigel Graham b
a
Department of Civil and Environmental Engineering, University of Surrey, Guildford, GU2 7XH, UK
b
Department of Civil and Environmental Engineering, Imperial College London, London, SW7 2AZ, UK
Article history: Quantitative methods which link molecular descriptors for recognized precursors to formation of
Received 3 May 2017 drinking water disinfection byproducts are scarce. This study aimed to develop a simple mathematical
Received in revised form tool for predicting chloroform (trichloromethane) yields resulting from aqueous chlorination of model
17 July 2017
organic precursors. Experimental chloroform yields from 211 precursors were collated from 22 literature
Accepted 23 July 2017
Available online 24 July 2017
studies from 1977 onwards. Nineteen descriptors, some established and others developed during this
study, were used as inputs in a multiple linear regression model. The final model, calibrated using five-
way leave-many-out cross-validation, contains three descriptors. Two novel empirical descriptors, which
Keywords:
Trihalomethanes
quantify the impact of adjacent substituents on aromatic and enolizable chlorine substitution sites, were
THMs the most significant. The model has r2 ¼ 0.91 and a standard error of 8.93% mol/mol. Experimental
Disinfection byproducts validation, using 10 previously untested precursors, showed a mean discrepancy of 5.3% mol/mol be-
Model compounds tween experimental and predicted chloroform yields. The model gives insight to the influence that
QSAR specific functional groups, including hydroxyl, chlorine and carboxyl, have on chloroform formation and
the relative contributions made by separate substitution sites in the same molecule. It is anticipated that
the detailed approach can be updated and extended as new experimental data emerges, to encompass
additional precursors and groups of disinfection byproducts.
© 2017 Elsevier Ltd. All rights reserved.
1. Introduction toxicological evidence indicates that neither the trihalomethanes

nor the haloacetic acids are plausible bladder carcinogens at typical
The discovery, in the 1970s, that chloroform and other tri- drinking water concentrations (Hrudey, 2009). Thus, other disin-
halomethanes are generated from chlorination of natural organic fection byproducts such as the halobenzoquinones (Zhao et al.,
matter during water treatment (Rook, 1974) surprised the scientific 2012), various other halogenated aromatic byproducts (Zhang
community. This breakthrough led to much research into disin- et al., 2008), nitrosamines, haloacetonitriles and haloacetamides
fection byproducts and regulations for the four chlorinated and/or (Shah and Mitch, 2012) remain the focus of much current research
brominated trihalomethanes being introduced in the USA by the attention, as these may be more toxicologically-significant.
decade's end. The limit for total trihalomethanes is currently The trihalomethanes and haloacetic acids are essentially viewed
80 mg L1 in the USA, with five haloacetic acids, another group of by regulators of drinking water quality as indicators of the total
halogenated disinfection byproducts, regulated at a total of occurrence of chlorination disinfection byproducts (USEPA, 2015).
60 mg L1. Total trihalomethanes are also regulated in the EU at They also remain the most-studied disinfection byproducts,
100 mg L1. Initial concern about the trihalomethanes was based on particularly the trihalomethanes. Model compounds have been
results of a rodent bioassay which classified chloroform as a sus- heavily used to elucidate mechanistic formation pathways and
pected human carcinogen (NCI, 1976). Independently, epidemio- precursor characteristics from the early days of disinfection
logical studies have shown that long-term consumption of byproduct research (Bond et al., 2012; Rook, 1977). It was quickly
chlorinated drinking water is associated with an enhanced risk of appreciated that meta-substituted aromatic compounds are reac-
developing bladder cancer, although the underlying reasons remain tive chloroform precursors. For example, Rook (1977) reported that
obscure (Hrudey, 2009). However, analysis of more recent resorcinol (1,3-dihydroxybenzene) was converted into chloroform
at an 85% mol/mol yield during chlorination, whereas yields from
its regioisomers, catechol (1,2-dihydroxybenzene) and hydroqui-
* Corresponding author. none (1,4-dihydroxybenzene), were far lower at 0.5% and 1.5% mol/
E-mail address: t.bond@surrey.ac.uk (T. Bond). mol, respectively (see Fig. S2 for a simplified mechanism for
http://dx.doi.org/10.1016/j.watres.2017.07.063
0043-1354/© 2017 Elsevier Ltd. All rights reserved.
168 T. Bond, N. Graham / Water Research 124 (2017) 167e176
chloroform production from resorcinol). This variation can be representative of full-scale drinking water chlorination. Median
(qualitatively) explained by the two activating hydroxyl groups conditions from the studies included were pH ¼ 7, contact
promoting electrophilic substitution reactions at the ortho- and time ¼ 24 h, temperature ¼ 20 C and chlorine dose ¼ 20 mol/mol.
para-positions of the aromatic ring. However, the presence of One important difference with the chlorination of natural waters is
additional substituents complicates this pattern, as depending on that model compound studies are typically undertaken in the
their identity and position, chloroform yields can either be absence of bromide, and thus chloroform is the only one of the four
enhanced or suppressed. Thus, de Laat et al. (1982), reported chloro- and/or bromo-trihalomethanes monitored. In contrast,
chloroform yields for pyrogallol (1,2,3-trihydroxybenzene), 4- ambient bromide in natural waters leads to formation of varying
hydroxycatechol (1,2,4-trihydroxybenzene) and phloroglucinol amounts of brominated trihalomethanes.
(1,3,5- trihydroxybenzene) as 0.1, 15.5 and 93% mol/mol, respec- For compounds tested in multiple studies, mean values were
tively. Certain aliphatic compounds, notably b-dicarbonyl com- calculated and are given in Table S2. For example, chloroform yields
pounds (Boyce and Hornig, 1980; Dickenson et al., 2008), including from the well-studied precursor resorcinol have been reported 12
3-oxopentanedioic acid (Table 1), also act as reactive trihalo- times, giving a mean value of 81.1% mol/mol and a standard devi-
methane precursors. Formation of trihalomethanes from carbonyl ation of 17.3 (Table S2). In total there were 69 compounds included
compounds can be likened to the haloform reaction, used for the with multiple chloroform yields. The mean of the standard de-
synthetic preparation of trihalomethanes from methyl ketones viations for these repeated compounds is 5.1% mol/mol. The final
(Larson and Weber, 1994). Its rate is controlled by the initial eno- list of 211 precursors used for modelling, together with their
lization of the organic precursor and the mechanism proceeds via chloroform yields, structures and alternative names, is given in
electrophilic addition of chlorine at the carbon alpha to the Table S2.
carbonyl group (Fig. S1).
Despite the extensive amount of research effort on this subject 2.2. Descriptor selection
over the past ~40 years, quantitative methods to predict disinfec-
tion byproduct formation based on molecular descriptors are Three descriptors used by Luilo and Cabaniss (2011b) to model
scarce. Hence, the aim of this study was to develop a simple chloroform formation and another three used by the same authors
mathematical method for predicting chloroform yields from model to model total organic halogen formation (Luilo and Cabaniss,
compounds, with the expectation that this will prove a useful 2011a) were included. Respectively these are the carbonyl index
screening tool for compounds which have not been tested experi- (CI), the difference between the sum of strong electron-donating
mentally. To achieve this, descriptors are required which quanti- groups and the sum of carbonyls per carbon in each molecule
tatively link reactive precursor functionalities to chloroform yields (EDCORH), the number of 1,3-activated aromatic carbons (OTactC)
(and ultimately the key pathways leading from one to the other). A (chloroform descriptors) and the number of phenolic groups per
secondary aim was that such a mathematical framework would carbon (ArOH:C), the square root of the number of heteroatoms
illuminate our knowledge of the characteristics of reactive pre- (sqHeA) and the log of the hydrogen to carbon ratio (log H:C) (total
cursors. Although quantitative structure activity relationship organic halogen descriptors). Hammett and Taft constants account
(QSAR) and quantitative structureproperty relationship (QSPR) for substituent effects in aromatic and aliphatic compounds,
models are widely used in other fields, they have found limited use respectively, and have been used widely in the development of
in disinfection byproduct research, despite having the potential to QSARs and linear free energy relationships. In this study they were
streamline research efforts (Chen et al., 2015). While not focussed used in a manner following that described by Lee and von Gunten
on disinfection byproducts, the paper by Luilo and Cabaniss (2010) (2012) and Gallard and von Gunten (2002), who showed that the
is noteworthy as it details a QSPR, validated using literature on 201 sums of Hammett or Taft for organic compounds can be quantita-
organic compounds, for predicting chlorine demand based on eight tively linked to rate constants for reactions with aqueous chlorine.
molecular descriptors. The same authors subsequently developed a Taft/Hammett constants were taken from published sources
model for predicting chloroform formation from organic precursors (Hansch et al., 1995; Perrin et al., 1981). Four descriptors were
(Luilo and Cabaniss, 2011b), although this used a smaller subset of calculated by summing Taft constants for substituents around
117 model compounds. enolizable functionalities (Enol Taft and Enolizable Taft), alkenes
(Alkene Taft) and amino acids (AmAc Taft). Hammett constants
2. Methods were summed to account for ortho-, meta- and para-interactions in
aromatic compounds, as well as total interactions (HammettOrtho,
2.1. Literature on chloroform formation Hammett Meta, Hammett Para and Hammett Sum). Finally,
empirical constants were used to develop novel descriptors for five
Chloroform formation data from 22 studies (Bond et al., 2009, important precursor categories: alkenes (Alkene Score), enolizable
2014, 2016; Boyce and Hornig, 1980; Boyce and Hornig, 1983; Bull aliphatics (Enolizable Score), aromatic ketones (Aromatic Ketone
et al., 2006; Chaidou et al., 1999; Chang et al., 2011; de Laat et al., Score), beta-dicarbonyl (BDicarb Score) and aromatic compounds
1982; de Leer and Erkerlens, 1988; Dickenson et al., 2008; Gallard (Aromatic Score). These were calculated by giving each substituent
and von Gunten, 2002; Hong et al., 2009; Hureiki et al., 1994; around a potential chlorine substitution site a score, which were
Larson and Rockwell, 1979; Navalon et al., 2008; Norwood et al., then multiplied together to give a combined score for the substi-
1980; Rook, 1977; Rule et al., 2005; Tawk et al., 2015; Tomita tution site. Therefore, these descriptors quantify the influence of
et al., 1981; Westerhoff et al., 2004) spanning the years specific functional groups around a chlorine substitution site on
1977e2016 were collated and converted into units of % mol/mol chloroform formation.
where necessary. All studies measured chloroform formation from For more complex molecules, scores for individual substitution
organic precursors under formation potential conditions, i.e. using sites were summed to obtain a total score for the whole molecule.
excess chlorine. However, since there are no standard conditions Empirical substituent constants, used to derive a score for a sub-
for these tests, experimental conditions vary in the literature stitution site, were selected to minimise regression residuals, in a
(Table S1). In this study only data collected at pH 7e8 using an similar fashion to some descriptors developed by Luilo and
excess of chlorine and contact times over 0.5 h were included. Thus, Cabaniss (2010). The 19 descriptors introduced above were used
the modelling results only apply to these conditions, which are as inputs in a multiple linear regression model in SPSS, with no y-
T. Bond, N. Graham / Water Research 124 (2017) 167e176 169
Table 1
Selected chloroform precursors, taken from literaturea.
Name Alternative name Structure Chloroform yield

(% mol/mol)
Pyrogallol 1,2,3-trihydroxybenzene 0.8 ± 1.4
Catechol 1,2-dihydroxybenzene 0.9 ± 0.6
Phloroglucinol 1,3,5-trihydroxybenzene 74.6 ± 22.4
Resorcinol 1,3-dihydroxybenzene 81.1 ± 17.3
2,4-dihydroxybenzoic acid b-resorcylic acid 83.3 ± 9.6
Phenol 4.8 ± 3.9
L-tryptophan 29.5 ± 27.4
Salicylic acid 2-hydroxybenzoic acid 3.0 ± 1.2
p-coumaric acid 4-hydroxycinnamic acid 1.3 ± 0.6
3-oxopentanedioic acid 1,3-acetonedicarboxylic acid 59.8 ± 15.9
L-tyrosine 16.0 ± 16.4
Hydroquinone 1,4-dihydroxybenzene 1.7 ± 1.1
Fumaric acid (2E)-2-butenedioic acid 23.0
Benzaldehyde 0.1
3-acetylphenol 1-(3-hydroxyphenyl)ethanone 45.0
(continued on next page)

Table 1 (continued )
Name Alternative name Structure Chloroform yield

(% mol/mol)
4-hydroxycatechol 1,2,4-trihydroxybenzene 15.5
Maltotriose 11.8
Tembotrione 99.0
a
The full list, including references, is given in the supporting information (Table S2).
Table 2 Table 3
Average model descriptors and standard errors obtained using leave-many-out Empirical constants used to calculate the Enolizable Score descriptor.
cross-validation.
Carbonyl (R1) Constant R2/R3a Constant
Descriptor (xj) value value
Enolizable Score SqHeA Aromatic Score COO 0.1 H 1

CHO 0.1 OH 1.3
Coefficient (bj) 17.89 0.78 14.13
COCH3 0.6 CH2OH 1.1
Standard error 0.88 0.49 0.61
COCH2CH3 0.8 OCH3 1.1
CONH2 0.05 CH3 0.8
COCOO 0.05 C6H5 1
COCOCH2CH3 0.4 OC6H5 1
intercept, and with chloroform yield (% mol/mol) as the dependent
COCHOH 0.1 CH2COO 1.5
variable, i.e.: CONHCH3 0.4 CONH2 1
COC6H5 (OH para 0.7 CH2CH3 0.8
and OCH3 meta)
X
M
CHCl3 ¼ b j xj COC6H5 (no substituents)
COC6H5 (OH ortho)
0.8
0.7
CH2CH2CH3
CH2COCH3
0.9
0.4
j¼1
COC6H5 (3 OCH3 in 0.8 CH2NH2 1.1
3, 4 and 5)
Significant descriptors were then identified by successively
COC6H5 (OH para) 1.2 NHCOCH3 0.8
eliminating the least significant descriptor (that with the highest p COC6H5 (2 OCH3 1 NH2 1.1
value) until all remaining descriptors were significant (p < 0.05), meta, OH para)
following previous work (Luilo and Cabaniss, 2010; 2011b). This COC6H5 (OH meta) 1 Inactivated 1
aromatic ring
gave four significant descriptors: Enolizable Score, SqHeA, OTactC
COC6H5 (2 OH ortho 1 Activated 5.6
and Aromatic Score. However, a correlation of r ¼ 0.833 between and para, ether ortho) aromatic ring
Aromatic Score and OTactC indicated these two descriptors were COCH2COO 0.6 COO 3.9
not independent (Table S5), so OTactC was removed as it had the COCH2COCH3 0.3 CH(OH)CH3 1.1
higher p value. All other pairwise correlations between these de- Amino acid 0.2 NHCH3 1.1
C(OH)COO 1.2
scriptors had r < 0.7, indicating they are sufficiently independent to
CH2CH2OH 1.1
be used in multiple linear regression modelling (Eriksson et al., COCH2CH3 4.9
2003). The three named descriptors were used in all subsequent CH2CHO 1.2
modelling procedures and will now be described in more detail. CH2CH2COCH3 1.2
COC6H5 2 (R2) or
The Enolizable Score multiplies empirical constants for a carbonyl
1.5 (R3)a
group, denoted as R1, with those for the other substituents (R2 and COCH3 7.2
R3) surrounding an enolizable site (Table 3). An alpha proton CH(CH3)2 0.9
combined with a carbonyl group is defined as enolizable, although CH2CONH2 1
the proton is excluded from the calculation, as it is present in all SH 1.2
CH2C6H5 1
enolizable precursors. This classification includes carboxylic acids,
CH]CHNH2 0.8
as well as aldehydes and ketones. One descriptor value is calculated CH]CH2 1.5
for each enolizable group, even if multiple enolizable protons are CH](CH3)(COO) 1.8
present. Two carbonyls alpha (1,2-) or beta (1,3-) to each other CH]CHCOCH3 0.8
CH]CHCOO 1.8
constitute a single enolizable group. Two carbonyls gamma (1,4-) to
a
each other, or more distant, constitute two separate enolizable R2 and R3 value are identical with one exception: where both are carbonyls,
groups. Assigning a single descriptor value to each enolizable group which only applies to sulcotrione and tembotrione.
is reasonable as introduction of one chlorine alpha to an enolizable

carbonyl promotes additional chlorine substitution at the same site summed together. For example, for 3-acetylphenol (Table 1) the R1
(Larson and Weber, 1994). However, multiple enolizable groups in group is COC6H5 (OH meta), while R2 and R3 are both H (Table 3), so
the same molecule are given separate scores, which are then the Enolizable Score is 1 1 1 ¼ 1 (section 4.1 of the
supplementary material). SqHeA is defined as the square root of the stratified data splitting was used, so that each compound was used
number of heteroatoms present in a precursor (Luilo and Cabaniss, at least once for cross-validation (see the supplementary material,
2011a). For 3-acetylphenol there are two heteroatoms (Table 1), so section 7). Multiple linear regression modelling was used to obtain
SqHeA is 1.41 (Table S3). Finally, the Aromatic Score descriptor gives a separate equation for each calibration subset of 111 compounds.
each substituent in an aromatic precursor an empirical substituent Each of these five equations was used to predict chloroform yields
score (Table 4). These are then multiplied together to give a com- of the respective cross-validation subsets, with their performance
bined score for the whole ring, which accounts for interactions determined by comparing experimental and predicted values. The
between the substituents. Benzene is given a baseline score of 1 and final predictive model was obtained by averaging coefficients from
heterocycles 0.2. Depending on the substituents present and their these five calibration datasets. Chloroform yields of the external
interactions these values can then either increase or decrease. The validation dataset (n ¼ 53) were predicted using the individual and
Aromatic Score for the ring in 3-acetylphenol is 1 (baseline score for average equations. The applicability domain was assessed by
benzene) x 1 (OH in C1 position) x 0.7 (COCH3 in C3 position) ¼ 0.7 calculating standardised residuals of cross-validation and leverage
(section 4.3 of the supplementary material). Scores for separate for both training and external validation datasets. Using this
aromatic groups are summed to produce the final Aromatic Score approach data points can be defined as outliers if they have
value. Multiple detailed examples of how these three descriptors standardised residuals above þ2.5 or below 2.5 (Luilo and
were calculated are given in the section 4 of the supplementary Cabaniss, 2010). The warning leverage was calculated using 3k0 /N
material. where k0 is the number of descriptors plus one, and N is the number
of compounds used to develop the model. Molecules in the training
2.3. Model calibration and validation data and external validation which exceed the warning leverage
indicate molecules which are: (i) excessively influential in deter-
Initially, the complete dataset (n ¼ 211) was randomly split into mining the model parameters, and (ii), are predicted due to over-
training data (n ¼ 158) and an external validation dataset (n ¼ 53). extrapolation of the model (i.e. they fall outside the applicability
Then the training data was split five times into a calibration subset domain).
(n ¼ 111) and an internal validation (cross validation) subset
(n ¼ 47), to facilitate leave-many-out cross-validation. For this step, 2.4. Experimental validation
Experimental chloroform formation from compounds whose

Table 4 yields have not been reported previously in literature was
Empirical constants used to calculate the Aromatic Score descriptor. measured using gas chromatography with electron capture detec-
Baseline values: 1 (benzene) or 0.1 (heterocycles) tion (GC-ECD, Perkin Elmer Clarus 500 GC), a modified version of
Substituent C1 C2 C3 C4 C5 C6
USEPA method 551.1 (USEPA, 1995) and a Restek Rxi-5 Sil MS col-
umn (30 m 0.25 mm x 0.25 mM). All samples were prepared in
OH 1 0.3 5.5 0.3 0.5 0.6
duplicate at pH 7 (10 mM phosphate buffer). The method detection
Cl 0.1 0.6/0.9 2.2 0.6/1.4 1.5 0.5/0.7
NH2 0.99 0.3 1.3 0.5 0.4 0.4 limit for chloroform was 0.2 mg L1. Precursor concentrations
N(C2H5)2 1.1 ranged from 1 to 10 mM (Table 5) and the chlorine dose was 20 mol/
NO2 0.2 0.2 0.8 0.2 mol. All reagents were of at least analytical purity and chlorine
OCH3 0.3 0.5 0.5 0.5 0.5 0.2 concentrations were measured using the DPD-FAS titration method
OCH2CH3 0.3 0.3 0.4 0.3 0.3 0.2
OCH]CH2 0.5 0.9 0.9 0.9 0.9 0.5
(APHA et al., 2005). After 24 h contact time the residual chlorine
CH2COOe 0.2 0.3 0.3 0.3 0.3 0.15 was quenched using sodium sulphite (APHA et al., 2005).
CH2OH 0.2 0.4 0.4 0.3 0.3
CH3 0.3 0.85 0.8 0.8 0.8 0.5 3. Results
CH2CH3 0.3 0.5 0.7 0.5 0.7 0.4
Large alkyl group 0.3 0.4 0.6 0.4 0.5 0.3
CH]CH2 0.25 3.1. Model performance
COOe Ignore
(see text) Leave-many-out cross-validation produced five QSAR equations
COOCH3 0.05 0.05 0.05 0.05 0.05 0.05 (Table S7), which were averaged to generate the final equation
CHO 0.05 0.2 0.4 0.05 0.05
COCH3 0.05 0.6 0.7 0.6 0.6 0.6
shown in Table 2. The average model has r2 ¼ 0.91 and a standard
COCHC]CH2 0.1 0.8 0.8 0.8 0.8 0.8 error of 8.93% mol/mol (Table S7). Respective values obtained from
OCH2COOe 0.05 regression of chloroform formation across the complete dataset
CONH2 0.2 0.3 0.05 0.3 using the same three descriptors were 0.90 and 8.87% mol/mol
CSNH2 0.3
(Table S7). The similarity of these values indicates that the data
NHCOCH3 0.2
fused ring 0.3 0.8 0.8 0.8 0.8 0.5 splitting procedures and leave-many-out cross-validation did not
Other aryl (not fused) 0.3 0.2 0.4 0.1 introduce any meaningful bias into the average model.
C]O (as part of ring) 0.05 0.5 0.5 0.5 0.5 0.5 For comparison, chloroform formation was also modelled by the
CH2CH(NH2)COOe 0.1 0.7 0.8 0.7 three descriptors (CI, OTactC and EDCORH) used previously for this
CH2CH2CH2OH 0.3
CH]NOH 0.3
purpose by Luilo and Cabaniss (2011b), although in the earlier case
CH]CHCHO 0.2 0.4 0.5 0.3 with a smaller dataset of 117 precursors. Using these same de-
CH2CH2COOe 0.2 0.3 0.4 0.3 0.3 scriptors and the 211 precursors included in the current study gave
CH]CHCOOe 0.2 0.4 0.5 0.3 0.3 a model with r2 ¼ 0.77 and a standard error of 13.87% mol/mol
CH]CHCH2OH 0.05 0.4 0.5 0.3
(Table SI 11). The improved performance of the current model
SO2CH3 0.2 0.3 0.5 0.4 0.4 0.3
I 1 highlights how the selected descriptors more accurately reflect
CN 1 how the functionality around chlorine substitution sites relates to
*Chlorine (Cl) ortho (C2 or C6) or para (C4) to a strongly-activating group (OH or
chloroform yields. The OTactC and CI descriptors can only take a
NH2) takes a higher values than in the presence of other (more weakly-activating) limited number of values (e.g. 0 or 1 for OTactC), whereas the Ar-
substituents. The higher values are shown in italics above. omatic Score and Enolizable Score descriptors can assume a range
Table 5
Experimental chloroform yields from previously untested precursors.
Name Structure Precursor concentration (mM) Experimental (and predicted)

(alternative name) chloroform formation (% mol/mol)
Acetoacetamide 1 7.6 ± 0.7 (9.4)

(3-oxobutanamide)
Cyclohexanone 3 2.0 ± 0.6 (10.5)
4-chloro-2-methylphenol 1 37.3 ± 0.4 (21.3)

(4-chloro-o-cresol)
Crotonic acid 3 6.1 ± 4.1 (1.6)

((2E)-2-butenoic acid)
2,6-dichlorophenol 1 8.6 ± 0.9 (7.6)
2,3-dimethylphenol 3 8.4 ± 0.6 (13.4)

(2,3-xylenol)
2,4-dimethylphenol 3 2.9 ± 1.4 (10.9)

(2,4-xylenol)
2,4-dinitrophenol 10 1.6 ± 1.1 (0.6)
Sorbic acid 1 3.8 ± 2.2 (1.6)

((2E,4E)-2,4-hexadienoic acid)
Thymol 3 10.1 ± 0.6 (5.0)

(2-isopropyl-5-methylphenol)
of values, depending on the specific chemical identity of the sub- cross validation datasets, as well as to the training set (n ¼ 158) also
stituents present (see below). had high predictive power (Table S9; Fig. 1). Thus, it can be
Mean statistical parameters for the fivefold leave-many-out concluded that the predictive model is robust.
cross-validation show the five individual equations have high Chloroform yields for the 53 precursors in the external valida-
predictive power, since r2 > 0.6; q2 > 0.5; 0.85 < k or k0 < 1.15 and tion dataset were predicted using the average model (Fig. 1), as well
r2-r20/r2 < 0.1 (Table S8) (Golbraikh and Tropsha, 2002). In this as for the five individual equations derived during cross validation
context q2 is the predicted r2 value; with k/k0 and r2/r20 the gradient (Table S10). The mean statistics from the five individual equations
and r2 values with/without the y-intercept, respectively. The latter are also indicative of high predictive power since they fulfil the
two were obtained from plotting predicted versus chloroform for- criteria noted above. They also agree well with equivalent statistics
mation. The average model, when applied to the five individual from the average equation (Table S10). Plotting predicted
120
(a)
100
Predicted chloroform yield (% mol/mol) 80
60
40
20
0
0 20 40 60 80 100 120
-20
Experimental chloroform yield (% mol/mol)
120
(b)
Predicted chloroform yield (% mol/mol)
100
80
60
40
20
0
0 20 40 60 80 100 120
-20
Experimental chloroform yield (% mol/mol)
Fig. 1. Predicted versus experimental chloroform formation for (a) the training set (n ¼ 158; r2 ¼ 0.91, standard error ¼ 8.75) and (b) the external validation set (n ¼ 53; r2 ¼ 0.90,
standard error ¼ 9.70) using the average model.
chloroform yields against standardised residuals (Fig. SI 6) shows deciding the model descriptors. In the external validation dataset,
that there is no pattern amongst the compounds with higher re- tembotrione has a leverage above the warning value. Thus, its
siduals, again evidencing that the developed model is appropriate predicted chloroform yield was over-extrapolated, although its
for the dataset. standardised residual still lies within the applicability domain
Based on the applicability domain analysis, compounds would (Fig. S5). Other authors have reported improved performance when
be classified as outliers if: (i) they have standardised residuals predicting log transformed disinfection byproduct formation using
above þ2.5 or below 2.5 and (ii) they exceed the warning leverage water quality parameters (Obolensky and Singer, 2005). However,
of 0.095. Based on these criteria no precursors in either the training in this study a model generated with log transformed chloroform
set or external validation dataset were outliers (Fig. S1). Nonethe- data did not improve upon that shown in Table 2 (see Table S6).
less, there are a number of compounds which fulfil one of these two
conditions. In the training set there are four compounds which 3.2. Experimental model validation
have standardised residuals above 2.5. These are phlorizin, arg-lys-
glu-val-tyr, 3-oxohexanedioic acid and epigallocatechin gallate. The 10 previously untested precursors comprised six phenols
However, in all these cases leverage values are well below the and four aliphatic carbonyls (Table 5). The latter include alkene,
warning value and thus they are not considered influential in carboxylic acid and b-dicarbonyl functionalities (Table 5). Predicted
chloroform yields, estimated using the coefficients in Table 2, activated than resorcinol, whereas phloroglucinol (1,3,5-
ranged from 0.6% to 21.3% mol/mol, whereas experimental values trihydroxybenzene) is less activated (in terms of the sum of their
were from 1.6 to 37.3% mol/mol (Table 5). In general, experimental Hammett constants). However, this does not correlate with
and predicted values compared well, with a mean difference of 5.3% trihalomethane formation (Table 1).
mol/mol across the 10 precursors, which is lower than the standard In contrast, the Aromatic Score descriptor is a product, so can
error of 8.93% associated with use of the average model. None- either increase or decrease as substituents are added to the aro-
theless, for 4-chloro-2-methylphenol, experimental and predicted matic ring: respective values for these three precursors are 1.80,
chloroform yields differed by 16.0% (Table 5). This is a chlorinated 5.50 and 5.50 (Table 4). Another feature of the Aromatic Score
phenol, a precursor category discussed in section 3.3.2. descriptor is that it accounts for blocked meta interactions. Aro-
matic precursors where a resorcinol-type structure is bisected by
3.3. Insights from the model an additional substituent tend to have low chloroform yields, as the
preferred chlorine substitution site is already occupied. For
3.3.1. Role of significant descriptors example, pyrogallol (1,2,3-trihydroxybenzene) generates 0.8 ± 1.4%
The Aromatic Score and Enolizable Score descriptors are the mol/mol of chloroform (Table 1). When calculating the Aromatic
most significant regarding the model's operation (p ¼ 0.000 for Score descriptors blocked meta interactions, such as in pyrogallol,
both) and their role is to quantify reactivity in these two crucial were not considered.
precursor groups. While the contribution of SqHeA (p ¼ 0.033) is There is one substituent which represents an exception to this
less obvious, its negative coefficient (Table 2) indicates chloroform rule: chlorine, as chlorine substitution can either occur where the
formation from more complex precursors would otherwise be existing chlorine is located, or elsewhere in the ring. Chlorinated
typically slightly overestimated by the model. The absence of any phenols have variable chloroform yields: from 6.8 ± 4.6% for 2,4,6-
descriptors involving Taft or Hammett constants highlights their trichlorophenol to 98% for 4-chloro-1,3-benzenediol (Table S2).
limited utility in predicting trihalomethane formation. Since both Aromatic Score values for a chlorine substituent ortho (C2 or C6) or
have been quantitatively linked to rate constants of reactions be- para (C4) to a strongly-activating group (OH or NH2) are higher
tween organic pollutants and chlorine (Gallard and von Gunten, than when more weakly-activating substituents are in the ortho- or
2002; Lee and von Gunten, 2012), in turn this indicates that the para-positions (Table 4). This indicates that additional chlorine
kinetics (of the initial reaction step) are not strongly correlated with substitution proceeds at the carbon bonded to the existing chlorine.
trihalomethane formation. Since the mechanistic routes which lead Nonetheless, there are several examples of meta-substituted
to trihalomethane formation are complex and involve multiple chlorinated phenols which are highly reactive precursors, for
steps this is perhaps not unexpected. example, 3,5-dichlorophenol, which generates 71.7% chloroform
(Table S2) and chlorine has the second highest C3 Aromatic Score
3.3.2. Aromatic precursors value of 2.2 (Table 4). Since both chlorine and OH are ortho/para
Hammett constants for the substituent OH do not reflect the directors (although they are respectively deactivating and acti-
potency of phenols as chloroform precursors, especially for meta- vating) this indicates that chlorine substitution occurs elsewhere
substituted compounds. The sigma meta value for OH is 0.12 and than the original chlorine group. For other precursors with multiple
it is therefore less activating than CH3 and NH2, which have sigma chlorine groups, e.g. 2,3,4,6-tetrachlorophenol, it is unclear where
meta values of 0.07 and 0.16, respectively. Chloroform yields for subsequent chlorination occurs. Predicted and experimental chlo-
resorcinol (1,3-dihydroxybenzene), 3-aminophenol and meta- roform yields for 4-chloro-2-methylphenol differed by 15.6%
cresol (3-methylphenol) are 81.1 ± 17.3%, 13.9 ± 5.9% and (Table 5). This indicates that the empirical descriptor values used to
6.1 ± 0.4% mol/mol, respectively, which illustrates the difficulties calculate Aromatic Score values could be further optimised if
associated with quantitatively linking Hammett constants to additional experimental chloroform yields were available.
trihalomethane formation. Similarly, OTactC scores for the first two Another substituent which forms an exception in the model is
of these compounds are both 1. This descriptor, which applies to carboxyl (eCO2). There are a number of phenols containing a CO2
1,3-activated aromatic carbons, can only take a value of 0 or 1 (Luilo group in addition to a resorcinol structure which generate similar
and Cabaniss, 2011b). All precursors (n ¼ 28) with a 1,3-activated amounts of chloroform to resorcinol itself. For instance, chloroform
aromatic carbon have a OTactC value of 1, even though their yields for 2,4-dihydroxybenzoic acid, 2,6-dihydroxybenzoic acid
experimental chloroform yields vary widely, from 4.6 to 98.0% mol/ and 3,5-dihydroxybenzoic acid are 83.3 ± 9.6%, 82.5 ± 10.6% and
mol. 59.4 ± 19.8%, respectively, versus 81.1 ± 17.3% for resorcinol
These comparisons explain why new empirical descriptors were (Table S2). Similarly, salicylic acid (2-hydroxybenzoic acid), 3-
developed during the course of this study. Constants for OH, CH3 hydroxybenzoic acid and 4-hydroxybenzoic acid all form a com-
and NH2 in the C3 (meta) position, as used when calculating the parable amount of chloroform to phenol: from 3.0 to 6.9% for the
Aromatic Score descriptor, are 5.5, 0.8 and 1.3 (Table 4), which re- three isomers, compared with 4.8 ± 3.9% for phenol (Table S2).
flects the fact that precursors containing a resorcinol structure are These similarities are explained by decarboxylation of carboxylic
more reactive chloroform precursors than the corresponding cre- acids during chlorination (Larson and Rockwell, 1979) and are dealt
sols or anilines. While aliphatic amine groups, e.g. in amino acids, with by the model ignoring CO2 groups in aromatic precursors.
are typically protonated under water treatment conditions (e.g. the
pKa for ammonium (þNH4) is 9.25), when calculating Aromatic 3.3.3. Enolizable precursors
Score and Enolizable Score values no attempt is made to distinguish One helpful feature of the model is that, for molecules with
between the protonated and non-protonated forms. multiple substitution sites, it highlights which are primarily
Another issue with using Hammett constants to explain the responsible for chloroform formation. Whereas benzaldehyde is an
formation of halogenated products is that in water disinfection unreactive precursor, with a chloroform yield of 0.1%, there are
applications they are typically used in an additive manner (Gallard seven aromatic ketones, all containing an acetophenone structure,
and von Gunten, 2002; Lee and von Gunten, 2012). Thus, their sum including 3-acetylphenol (Table 1), with chloroform yields from 10
will increase/decrease with an increasing number of electron- to 45% (Table S2). Both eCHO and eCOCH3 are deactivating sub-
withdrawing/electron-donating substituents around an aromatic stituents with respect to electrophilic aromatic substitution, as
ring. In turn, 4-hydroxycatechol (1,2,4-trihydroxybenzene) is more shown by respective Hammett meta constants of 0.35 and 0.38.
This indicates that chlorination occurs at the eCOCH3 group rather produce chlorohydrins (Larson and Weber, 1994) and eventually
than the aromatic ring. In turn, Aromatic Score values are also low - chloroform (Fig. S3). It can be hypothesized that the presence of
0.05 for both substituents in the C1 position - whereas the Eno- adjacent electron-donating groups will encourage the formation of
lizable Score R1 value for COC6H5 (no substituents) is relatively halogenated products, by making the alkene more nucleophilic.
high at 0.8 (Table 3). For 3-acetylphenol, the most reactive aromatic Since the Enolizable (and Aromatic) Score descriptors are empirical
ketone, the model suggests that both the aliphatic eCOCH3 group this means they can be updated as new experimental data emerges.
and the aromatic meta-substituted moiety contribute significantly Similarly, it is anticipated the detailed approach can serve as a
to its experimental chloroform yield of 45%. In contrast, for aceto- starting point for predicting the formation of other disinfection
phenone itself, which generates 10% mol/mol chloroform (Table 1), byproducts. This includes the haloacetic acids and total organic
the eCOCH3 group is the principal substitution site. halogen, for which modified descriptors may be developed. At
Cinnamic acid derivatives also contain aromatic and aliphatic present there is less data available for these groups than for the
functionalities, with both assumed to be substitution sites. These trihalomethanes. Nonetheless, it is clear that formation of tri-
precursors, and other aliphatic alkenes, are classified as enolizable halomethanes is accompanied by other groups of halogenated
as there is a carbonyl (carboxylic acid) alpha to the alkene. Two byproducts, with their relative yields dependent on the specific
descriptors e Alkene Taft and Alkene Score e were developed to chemical functionality present and proceeding via common pre-
quantify chloroform production from alkenes but neither are sig- cursor structures. For example, b-dicarbonyls can generate signifi-
nificant in the final model. This is because of the relatively small cant concentrations of both trihalomethanes and haloacetic acids
number of aliphatic alkenes in the dataset and their generally (Dickenson et al., 2008). Some of the high variability in chloroform
modest chloroform yields, of up to 23% for fumaric acid. While it is yields between studies for 3-oxopentanedioic acid, 59.8 ± 15.9%
expedient for the model to treat these precursors as enolizable; it is mol/mol (Table 1), can be attributed to selected experimental
likely that chlorination actually occurs via electrophilic addition to conditions favoring one halogenated product over another. As seen
the alkene. from their respective R2/R3 Enolizable Score values of 3.3, 7.2 and
Another simplification in the model is how amino acids are 4,6, the substituent COO promotes chloroform formation less than
treated. Chlorination of this group has been well studied (Bond COCH3 or COCH2CH3; with respect to haloacetic acid formation the
et al., 2009; Hong et al., 2009; Hureiki et al., 1994) and proceeds opposite can be postulated. Something comparable applies to L-
via conversion of the amino group to either a nitrile or aldehyde tyrosine and L-tryptophan (Table 1), which are also known to
(Fig. S4). The proportion of the aldehyde and nitrile products de- generate significant amounts of dichloroacetic acid, trichloroacetic
pends on experimental conditions, but as both can be chlorinated acid and dichloroacetonitrile (Bond et al., 2009). The model is a
(Wyman et al., 1964), the alpha carbon is assigned a composite screening tool for organic molecules whose chloroform yields have
score in the Enolizable Score descriptor. The low R1 value of 0.2 for not been experimentally tested. It is not designed for use with bulk
amino acids reflects the fact that chloroform yields from alpha water quality parameters (e.g. total organic carbon and ultraviolet
amino acids are generally modest. The two exceptions are L-tyro- absorbance). Nonetheless, there is scope to use analyses which
sine and L-tryptophan, where an activated aromatic ring can provide information about the specific chemical identity of aquatic
interact with the enolizable carbon by resonance, as evidenced by a organics (e.g. gas or liquid chromatography with mass spectrom-
high R2/R3 value of 5.6 (Table 3). etry detection) to link the model to natural waters.
There is only one substituent which enhances chloroform for-
mation to a greater extent, this being COCH3, which has a R2/R3
5. Conclusions
value of 7.2 (Table 3). This only occurs in the R2/R3 position in
certain b-dicarbonyls which are potent chloroform precursors, for
This study details and validates a comprehensive mathematical
example 3-oxopentanedioic acid (Table 1). Molecules with three
framework to predict the amount of chloroform produced from
carbonyl groups around an alpha proton, i.e. b-tricarbonyls, are
reactions between aqueous chlorine and organic precursors. The
extremely potent precursors. There are only two precursors in this
key findings are as follows:
subset: sulcotrione and tembotrione. This explains their high
Enolizable Score, 5.89 for both, and chloroform formation, 91.0%
The final model, calibrated using five-way leave-many-out
and 99.0%, respectively (Table S2). Meanwhile, 3-oxopentanedioic
cross-validation, has r2 ¼ 0.91 and a standard error of 8.93% mol/
acid has two separate b-dicarbonyl groups (and enolization sites)
mol. It contains three descriptors, the two most significant,
(Table 1), which explains its high Enolizable Score value of 4.68
developed specifically for this study, empirically quantify the
(Table S4).
impact of adjacent substituents on aromatic and enolizable
In contrast, R2/R3 values for other substituents are much lower,
chlorine substitution sites.
which reflects the low chloroform formation of most enolizable
Experimental validation, using 10 previously untested pre-
compounds. This includes monosaccharides, which the model as-
cursors, showed a mean discrepancy of 5.3% mol/mol between
sumes exist in the linear (aldehyde or ketone) form, rather than as
experimental and predicted chloroform yields.
the ether ring. Monosaccharides with multiple enolizable groups -
Aromatic carboxyl groups are ignored by the model, which ac-
maltose, maltotriose and maltopentaose - have higher chloroform
counts for blocked meta interactions. For molecules with mul-
formation, up to 18.9% for the latter. The model sums the contri-
tiple substitution sites the model is helpful for evaluating which
butions from the individual enolizable groups in these precursors.
are primarily responsible for chloroform formation. Notably, the
ketone side-group in acetophenone derivatives is a significant
4. Discussion: future research directions
source of chloroform formation.
An empirical model of the type described in this study is only as
comprehensive as the experimental data available. For some groups Acknowledgments
of precursors - phenols, amino acids and monosaccharides - there is
extensive data on how the presence of various substituents affects The first author acknowledges the support of the Imperial Col-
chloroform production. The converse applies for other categories. lege Junior Research Fellowship scheme. Thanks also to Jineesha
One is the alkenes, which initially react with aqueous chlorine to Mehta for helpful discussions.
Appendix A. Supplementary data Hureiki, L., Croue , J.-P., Legube, B., 1994. Chlorination studies of free and combined
amino acids. Water Res. 28 (12), 2521e2531.
Larson, R.A., Rockwell, A.L., 1979. Chloroform and chlorophenol production by
Supplementary data related to this article can be found at http:// decarboxylation of natural acids during aqueous chlorination. Environ. Sci.
dx.doi.org/10.1016/j.watres.2017.07.063. Technol. 13 (3), 325e329.
Larson, R.A., Weber, E.J., 1994. Reaction Mechanisms in Environmental Organic
Chemistry. Lewis Publishers, Ann Arbor, MI.
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OBJEK V
SINTESIS ASETANILIDA
RIFKI RINALDI, S.Si

“ Jangan terjebak dengan kesalahan yang sama, karena masih ada kesalahan
lain yang patut di coba”
SINTESIS ASETANILIDA
I. TUJUAN
1. Mempelajari reaksi pembentukan senyawa amida
2. Mensintesis asetanilida dari aniline dan anhidrida asetat
II. LANDASAN TEORI

2.1 Asam Karboksilat
Asam karboksilat (RCO2H) adalah senyawa organik dengan gugus karboksil. Gugus
ini mengandung gugus karbonil dan gugus hidroksil. Senyawa karboksilat cukup
penting sebagai bahan dasar sintesis golongan senyawa lain seperti ester, klorida
asam, amida, anhidrida asam, dan nitril. Senyawa-senyawa ini disebut sebagai
derivat atau turunan asam karboksilat yaitu suatu senyawa yang apabila dihidrolisis
akan menghasilkan asam karboksilat. Cuka atau asam asetat salah satu golongan
asam karboksilat yang banyak digunakan sebagai pelengkap makanan. 1
2.2 Amida
Amida merupakan derivat asam karboksilat yang paling tidak reaktif. Amida banyak
ditemukan di alam terutama sebagai protein yaitu suatu poliamida. Amida dapat
mengalami reaksi hidrolisi dan reaksi reduksi dengan hidrida logam. Reaksi hidrolisis
amida akan menghasilkan asam karboksilat dan amonia. Sedangkan amida yang
direduksi dengan anhidrida logam (LiAlH4) akan membentuk senyawa amina. Amida
dapat dibuat dari turunan asam karboksilat dengan amoniak. 2
Amida dapat diturunkan dari asam, dimana gugus -OH diganti dengan -NH2
atau dari amoniak, dimana 1 H diganti dengan asil. Sifat fisika amida yaitu zat padat
kecuali formamida yang berbentuk cair, tak berwarna, suku-suku yang rendah larut
dalam air, bereaksi kira-kira netral. Sifat kimia pada amida apabila di hidrolisis akan
menghasilkan asam karboksilat (R-COOH) dan NH3 dengan bantuan katalis asam
atau basa. Pengawahidratan dengan penarik air misalnya P2O5 akan menghasilkan
nitril (R-CN).3
Penggunaan dari amida yaitu formamida berbentuk cair dipakai sebagai
pelarut. Umumnya amida berhablur maka dipakai untuk identifikasi asam yang
berbentuk cair. Untuk sintesis, banyak zat terkenal mengandung gugus amida
misalnya nylon dan sebagainya.4
2.3 Asetanilida
Asetanilida merupakan senyawa turunan asetil amina aromatis yang digolongkan
117
Sintesis Asetanilida
sebagai amida primer, dimana satu atom hidrogen pada anilin digantikan dengan
satu gugus asetil. Asetinilida berbentuk butiran berwarna putih tidak larut dalam
minyak parafin dan larut dalam air dengan bantuan kloral anhidrat. Metode ini
merupakan metode awal yang masih digunakan karena lebih ekonomis. Anilin dan
asam asetat berlebih 100% direaksikan dalam sebuah tangki yang dilengkapi
dengan pengaduk. Reaksi berlangsung selama 6 jam pada suhu 150°C–160°C.
Produk dalam keadaan panas dikristalisasi dengan menggunakan kristalizer. 4
Senyawa asetanilida merupakan bahan baku yang dapat menunjang industri
kimia. Kebutuhan akan senyawa ini semakin meningkat sehingga dilakukan berbagai
cara dalam memperoleh senyawa ini. Pada sintesis senyawa ini biasanya digunakan
metode pemanasan agar kedua senyawa dapat bereaksi sempurna. Mula – mula
anilin bereaksi dengan asam asetat membentuk suatu amida dalam keadaan
transisi, kemudian diikuti dengan reduksi H2O membentuk asetanilida.4
Asetanilida merupakan suatu amida dengan bentuk berupa padatan kristal
putih dengan massa jenis 1,21 gram/mL, titik lebur 113°C-114°C, titik didih 305°C,
berat molekul 135,17 gram/mol. Sangat larut dalam alkohol, sedangkan kelarutan
dalam air adalah 0,53 g dalam 100 mL dan kelarutan dalam eter adalah 7 g dalam
100 mL.3
Asetanilida atau sering disebut phenilasetamida memiliki rumus molekul
C6H5NHCOCH3. Asetanilida pertama kali ditemukan oleh Friedel Kraft pada tahun
1872 dengan cara mereaksikan asethopenon dengan NH2OH sehingga terbentuk
asethopenon oxime yang kemudian dengan bantuan katalis dapat diubah menjadi
asetanilida.3
2.4 Sintesis Asetanilida

Sintesis organik adalah suatu percobaan untuk membuat senyawa yang diinginkan
melalui suatu reaksi kimia. Sebelum melakukan sintesis organik perlu diperhatikan
beberapa langkah dalam merancang sintesis tersebut. Bahan baku sintesis produk,
serta cara mensintesisnya. Oleh karena itu diperlukan pemahaman mengenai proses
pembentukan ikatan. Proses sintesis dapat dikatakan berhasil dan berjalan dengan
baik bergantung pada banyaknya produk, ketersediaan bahan awal, dan proses yang
dilakukan.3
Terdapat beberapa proses pembuatan asetanilida, yaitu:
a. Pembuatan asetanilida dari asam asetat anhidrid dan anilin.
Larutan anilin dan 1,4 bagian asam asetat anhidrid berlebih 150% dengan
118
konversi 90% dan yield 65%, direfluks hingga tidak ada anilin yang tersisa pada
temperatur 30°C-110°C. Campuran hasil reaksi disaring kemudian kristal
dipisahkan dari air panasnya dengan proses pendinginan. Sedangkan filtratnya
digunakan kembali.
b. Pembuatan asetanilida dari anilin dan asam asetat.
Metode ini merupakan metode awal yang masih digunakan karena ekonomis jika
dibandingkan dengan semua proses pembuatan asetanilidalain. Anilin dan asam
asetat direaksikan dalam sebuah tangki yang dilengkapi dengan pengaduk.
Reaksi yang berlangsung selama 8 jam pada suhu 150°C-160°C dan tekanan
2,5 atm dengan yield mencapai 98% dan konversi 99,5%. Hasil produk dalam
keadaan panas dikristalisasi dengan menggunakan kristalizer untuk membentuk
butiran Kristal asetanilida
c. Pembuatan asetanilida dari ketena dan anilin.
Sebuah turunan asetil lebih mudah diperoleh dengan mereaksikan asam asetat
anhidrida dengan aniline. Secara teori, asetanilida sederhana adalah dengan
mereaksikan aniline dengan asam asetat anhidrid.
Anilin merupakan amina aromatis primer. Reaksi substitusi terhadap amina
aromatis dapat berupa substitusi pada cincin benzene atau substitusi pada gugus
amina. Asetilasi amina aromatis primer atau sekunder banyak dilakukan dengan
asam klorida dalam suasana basa atau dengan cara mereaksikan amina dengan
asetat anhidrida.3
2.5 Pembentukan Kristal

Hasil pelarutan bahan yang direkristalisasi kemudian disaring baik dengan penyaring
vakum (Buchner) maupun dengan penyaring panas. Selanjutnya filtrat yang berisi
bahan yang direkristalisasi (kotoran atau impuritis tinggal dalam corong pisah) di
kristalkan kembali dengan cara pendinginan. Bila pada suhu kamar tidak terbentuk
kristal maka maka dilakukan langkah-langkah sebagai berikut:
1. Filtrat dipekatkan selanjutnya dibiarkan pada suhu kamar.
2. Bila kristal belum terbentuk maka dilakukan penggerusan terhadap dinding gelas
dengan batang pengaduk.
3. Apabila langkah 2 belum terbentuk kristal maka dilakukan rekristalisasi dengan
pelarut yang tidak melarutkan sama sekali.
4. Apabila kristal belum juga terbentuk maka lakukan pengujian ulang untuk
mendapatkan pelarut yang sesuai.
119
Proses pengkristalan kembali tidak boleh dilakukan dengan menurunkan suhu
secara drastis (ekstrim), baik melalui pendinginan dengan es maupun dengan lemari
pendingin, tetapi penurunan suhu harus secara alami sampai suhu kamar. 2
Prinsip rekristalisasi adalah pemurnian padatan organik dari zat pengotor
melalui beberapa tahap yaitu melarutkan padatan organik dengan pelarut yang
sesuai dalam keadaan panas kemudian disaring dan didinginkan kembali sehingga
dapat terbentuk Kristal. Factor-faktor yang mempengaruhi terbentuknya Kristal pada
saat rekristalisasi adalah temperature dan bibit Kristal. Selain itu faktor penentu
keberhasilan proses kristalisasi adalah pemilihan zat pelarut. Pelarut yang baik,
sebaiknya memiliki gradien temperatur yang besar dalam sifat kelarutannya, titik
didih pelarut dibawah titik lebur senyawa yang akan dikristalkan bersifat inert (tidak
bereaksi) terhadap senyawa yang akan dikristalkan.4
120
3.1 Alat dan Bahan
No Alat Fungsi
1 Labu alas bulat 100 ml Untuk wadah sampel saat

direfluks
2 Gelas ukur Untuk pengukur volume
sampel
3 Kondensor Untuk pendingin uap
4 Gelas piala Untuk wadah bahan sebelum
direfluks
5 Corong Untuk alat memudahkan
menyaring Kristal
6 Pemanas Untuk alat memanaskan
sampel saat direfluks
7 Ice bath Untuk alat untuk mendinginkan
larutan
3.1.2 Bahan dan Kegunaannya

No Bahan Fungsi
1 Anilin Sebagai bahan dasar
2 Anhidrida Asetat Sebagai bahan dasar
3 Serbuk Zn Sebagai katalis
121
3.2 Cara Kerja
1. 2,3 mL anilin, 2,4 mL anhidrida asetat dan sedikit serbuk Zn
dimasukkan kedalam labu didih 100 mL
2. Dipasang kondensor pada labu dan kemudian campuran
dididihkan selama 30 menit
3. Campuran panas ini dituangkan dengan cara mengalirkan ke dalam
100 mL air dingin
4. Campuran ditempatkan kedalam ice bath lebih kurang 10 menit
5. Produk yang terbentuk disaring dan dicuci dengan air dingin
6. Padatan yang diperoleh dikeringkan dan ditimbang
7. Ditentukan titik lelehnya
8. Dihitung rendemennya
9. Produk dikarakterisasi dengan spektofotometer UV-Vis dan FT-IR
122
3.3 Skema Kerja
2,3 mL anilin, 2,4 mL anhidrida

asetat dan sedikit serbuk Zn
- Dimasukkan ke dalam labu didih 100 mL
Campuran
- Dipanaskan selama 30 menit

- Dituangkan dengan mengalirkan ke dalam 100 mL air
dingin
- Ditempatkan campuran setelah dingin ke dalam ice bath
±10 menit
Kristal
- Disaring dan dicuci dengan air dingin
- Dikeringkan dan ditimbang
- Ditentukan titik leleh
- Ditentukan rendemen
- Dikarakterisasi dengan spektrofotometer UV-Vis dan FT-IR
Hasil
123
3.4 Skema Alat
Keterangan:
1. Standar
2. Klem
3. Kondensor
4. Labu didih
5. Pemanas
6. Kertas saring
7. Corong
8. Gelas piala
124
4.1.1 Data
Volume anilin = 2,3 mL
Massa jenis anilin = 1,022 g/mL
Volume anhidrida asetat = 2,4 mL
Massa jenis anhidrida asetat = 1,081 g/mL
Mr anilin = 93 g/mol
Mr anhidrida asetat = 102 g/mol
Massa asetanilida = 0,488 g
Mr asetanilida = 135 g/mol
4.1.2 Perhitungan
 Anilin
Massa = ρ ×V
1,022 g
= ×2,3 mL
1 mL
= 2,3506 g
Massa
Mol =
Mr
1 mol
= 2,3506 g ×
93 g
= 0,0252 mol
 Anhidrida Asetat
Massa = ρ ×V
1,081 g
= ×2,4 mL
1 mL
= 2,5944 g
Massa
Mol =
Mr
1 mol
= 2,5944 g ×
102 g
= 0,0254 mol
125
C6H5NH2 + (CH3CO)2O C6H5NHCOCH3 + CH3COOH
Mula-mula 0,0254 0,0254

Bereaksi 0,0254 0,0254 0,0254 0,0254
Sisa - - 0,0254
mol asetanilida = 0,0254
135 g
massa asetanilida= 0,0254 ×
1 mol
= 3,429 g
massa percobaan = 0,488 g
massa percobaan
rendemen = × 100%
massa teori
0,488 g
= ×100%
3,429 g
= 14,23%
126
4.2 Hasil Karakterisasis
Gambar 1. Spektrum Hasil Karakterisasi FT-IR
No Bilangan gelombang Gugus Fungsi
1. 3382,24 N–H
2. 1729,21 C=O
3. 1646,27 C=C
4. 1440,85 C–H
5. 1373,34 C–H
6. 1260,50 C–N
7. 845,80 C–H
Tabel 1.Hasil karakterisasi FT-IR
127
4.3 Pembahasan
Praktikum kali ini, dilakukan sintesis asetanilida yang bertujuan untuk mempelajari
rakasi pembentukan senyawa amida dan mensintesis asetanilida. Bahan yagn
digunakan adalah anilin dan anhidrida asetat dengan katalis serbuk Zn. Prinsip
reaksi sintesis asetanilida adalah asetilasi, yaitu penggantian atom H oleh gugus
asetat, sehingga terbentuk asetanilida. Asetanilida merupakan senyawa turunan
asetil amina aromatis yang digolongkan sebagai amida sekunder. Prinsip kerja
percobaan ini adalah refluks dan rekristalisasi. Refluks, yaitu pemanasan berulang-
ulang yang dilakukan untuk menghomogenkan larutan dan menyempurnakan reaksi
yang terjadi. Rekristalisasi adalah pemurnian suatu zat padat dari campuran atau
pengotornya dengan cara mengkristalkan kembali zat tersebut setelah dilarutkan
dalam pelarut yang sesuai.
Pertama 2,3 mL anilin dan 2,4 mL anhidrida asetat dimasukkan ke dalam labu
didih. Reaksi yang terjadi pada pencampuran ini merupakan reaksi eksoterm karena
adanya panas yang dilepaskan ke lingkungan ditandai dengan panasnya labu didih.
Setelah itu, ditambahkan serbuk Zn yang berfungsi sebagai katalis positif yang dapat
menurunkan energi aktivasi sehingga dapat mempercepat reaksi pembentukan
asetanilida. Katalis yang digunakan berupa serbuk Zn, karena merupakan katalis
heterogen sehingga mudah dipisahkan dari produk yang terbentuk. Selain itu, serbuk
Zn juga berfungsi sebagai pelindung untuk mengurangi kereaktifan atom oksigen dari
gugus karbonil. Setelah itu, ditambahkan batu didih kedalam labu didih tersebut.
Tujuan dari penambahan batu didih pada percobaan ini adalah untuk meratakan
panas sehingga dapat mencegah terjadinya bumping.
Campuran ini kemudian di refluks selama 30 menit. Hal ini bertujuan untuk
menghomogenkan campuran dan mempercepat reaksi. Pemanasan ini akan
meningkatkan suhu dalam sistem sehingga tumbukan antar molekul akan lebih
banyak dan cepat, sehingga dapat mempercepat reaksi. Pemilihan metode refluks
dalam percobaan ini karena apabila digunakan pemanasan biasa maka akan
terbentuk uap yang akan mengurangi hasil kuantitatif dari reaksi, sedangkan pada
refluks uap yang terbentuk akan mengembun kembali pada kondensor dan mengalir
ke labu didih sehingga volume larutan akan tetap sama. Refluks dilakukan selama 30
menit, karena merupakan waktu yang optimal untuk anilin dan anhidrida asetat
bereaksi membentuk asetanilida.
Setelah direfluks, larutan yang masih panas dituangkan dengan mengalirkan
128
kedalam 100 mL akuades dingin. Hal ini bertujuan untuk mempercepat terbentuknya
kristal asetanilida akibat adanya perubahan suhu yang signifikan. Setelah itu, labu
didih ditempatkan ke dalam ice bath selama kurang lebih 10 menit. Hal ini bertujuan
agar kristal yang terbentuk lebih sempurna. Kristal asetanilida yang terbentuk
disaring dengan menggunakan kertas saring dan dicuci dengan air dingin. Hal ini
bertujuan untuk menghilangkan zat-zat pengotor yang masih menempel. Setelah itu,
kristal dikeringkan dengan cara dikering anginkan dan ditimbang untuk menentukan
persen rendemennya.
Berdasarkan percobaan yang telah dilakukan, massa kristal asetanilida yang
diperoleh adalah sebanyak 0,488 gram, sedangkan menurut teori massa kristal
asetanilida adalah 3,429 gram sehingga diperoleh persen rendemen sebesar
14,23%. Hasil rendemen yang diperoleh kurang dari 50% menandakan kristal
asetanilida yang terbentuk belum murni. Hal ini disebabkan karena masih terdapat
pengotor didalamnya, berupa sisa reaktan dan hasil samping dari reaksi, seperti
serbuk Zn, asam asetat serta anilin dan anhidrida asetat yang belum bereaksi
membentuk asetanilida. Selain itu, juga dikarenakan kurang sempurnanya proses
refluks, baik itu pada waktu ataupun pada pemasangan alat yang masih terdapat
celah udara sehingga reaksi yang terjadi tidak sempurna dan tentunya akan
berpengaruh terhadap massa asetanilida dan rendemen yang didapat pada
percobaan.
Selanjutnya produk yang diperoleh dikarakterisasi menggunakan FTIR dimana
hasil karakterisasi menunjukan spektrum-spektrum dari gugus fungsi yang
terkandung dalam produk yang diperoleh. Dari data karakterisasi dapat diketahui
bahwa pada produk terdapat gugus fungsi amida (N – H) pada bilangan gelombang
3382,24; gugus fungsi aldehida (C – O) pada bilangan gelombang 1729,21; gugus
fungsi alkena (C = C) pada bilangan gelombang 1646,27; gugus fungsi alkane (C –
C) pada bilangan gelombang 1440,85 dan 1373,34; dan gugus fungsi amida (C – N)
pada bilang gelombang 1260,50. Dari data karakterisasi dapat diketahui bahwa pada
produk yang diperoleh terkandung asetanilida yang mengandung gugus fungsi
amida.
Adapun struktur senyawa dari asetanilida yaitu:
N
H
129
5.1 Kesimpulan
Berdasarkan praktikum yang telah dilakukan, dapat disimpulkan bahwa :
1. Asetanilida merupakan amida primer yang dapat disintesis dari anilin dan
anhidrida asetat dengan katalis Zn.
2. Prinsip kerja dari percobaan ini adalah refluks dan rekristalisasi.
3. Kristal asetanilida yang diperoleh adalah sebanyak 0,488 gram.
4. Persen rendemen yang diperoleh adalah sebesar 14,23%.
5.2 Saran
Berdasarkan praktikum yang telah dilakukan, untuk praktikum selanjutnya
disarankan :
1. Pastikan tidak ada celah pada rangkaian alat refluks sehingga tidak ada uap
yang keluar.
2. Jangan terlalu banyak menambahkan serbuk Zn.
3. Perhatikan waktu pada saat merefluks.
4. Teliti saat melakukan penyaringan.
130
DAFTAR PUSTAKA
1 Riawan. Kimia Organik; Binarupa Aksara: Jakarta, 1990.

2 Ibrahim, S. S. M. Teknik Laboratorium Kimia Organik; Graha Ilmu: Yogyakarta,
2013.
3 Bulan Tahta Alfina*, Lailatus Sa’idah, Muthia Naila Rachmah, Lalu
Habiburrahman AKS, dan Y. E. Sintesis Asetanilida. Univ. Brawijaya.
4 Wardiyah. Kimia Organik. In Modul Bahan Ajar Cetak Farmasi; Pusdik SDM
Kesehatan: Jakarta, 2016; p hal 124;136-137.
131
Lampiran I Tugas Sebelum Praktikum
1. Tuliskan mekanisme reaksi dari sintesis asetanilida pada percobaan ini!
NH2 O O
O H2N C O C CH3
H3C C
O Zn CH3
+
H3C C
O
H O
O H N+ C CH3
H3C C O +
H N C CH3
+ H3C C OH
2. Selain asetat anhidrida senyawa lain apa yang bereaksi dengan anilin juga
menghasilkan asetanilida?
Jawab :
- asam asetat
- ketene
- asam tioasetat
132
Lampiran II Struktur Senyawa
No Senyawa Struktur
1. Anilin NH2
2. Anhidrida Asetat O O
3. Asetanilida
O
N
H
133
Lampiran III Analisa Artikel Ilmiah
I. JUDUL
Synthesis, Characterization, and Anticancer Activity (MCF-7) of Some Acetanilide -
based Heterocycles
Sintesis, karakterisasi, dan aktivitas antikanker (MCF-7) beberapa heterosiklik

berbasis asetanilida
II. TUJUAN
Untuk menjelaskan sintesis dan aktivitas antikanker asetanilida yang mengandung
tiofen,tiazol,piridin dan kelompok pirol melalui ikatan yang berbeda
III. SKEMA KERJA
4-aminoasetanilida (1,5 g) dan kalium karbonat anhidrat ( 1,38 g)
- diaduk dalam 40 mL aseton

- ditambahkan 1,2 mL kloroasetil klorida secara perlahan lahan sambil
diaduk selama 2 jam
- kristal yang didapat dimasukkan kedalam air dingin
- Padatan yang diperoleh dari pengenceran dengan air dingin tadi
disaring dan direkristalisasi dari etil alkohol.
- dikarakterisasi menggunakan FT-IR
N- ( 4-asetamidofenil) -2-kloroasetamida
Larutan turunan kloroasetamida 3 (1,13 g)
- dilarutkan dalam 30-mL etil alkohol, di samping 0,5 g natrium asetat

ditambahkan.
- Campuran itu dipanaskan di bawah reflux selama 3 jam kemudian
dituangkan ke dalam air es.
- Endapan yang terbentuk diisolasi dengan filtrasi dan purifikasi
dengan rekristalisasi dari etil alkohol
N- ( 4-Asetamidofenil) -2- (benzotiazol-2-thio) asetamida
134
IV. HASIL
Beberapa dari senyawa yang baru disintesis menunjukkan aktivitas yang
signifikan dibandingkan dengan obat doksorubisin, ada senyawa yang
merupakan sitotoksik kuat dan aktivitas sedang

- Sama sama membahas sintesis asetanilida tapi dengan senyawa yang lebih
kompleks untuk mengidentifikasi aktivitas antikanker
- Perlakuan yang berbeda dari praktikum yang mana praktikum lebih sederhana
135
Month 2018 Synthesis, Characterization, and Anticancer Activity (MCF-7) of Some
Acetanilide-based Heterocycles
Ehab Abdel-Latif,* Eman M. Keshk, Abdel-Galil M. Khalil, Ali Saeed, and Heba M. Metwally
Department of Chemistry, Faculty of Science, Mansoura University, 35516 Mansoura, Egypt
*E-mail: ehabattia00@gmx.net
Received April 8, 2018
DOI 10.1002/jhet.3294
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
A series of some novel 4-(N-substituted amino)-acetanilide scaffolds was synthesized through the
nucleophilic substitution reactions of the highly versatile N-(4-acetamidophenyl)-2-chloroacetamide (3) with
various types of nucleophilic reagents such as benzothiazole-2-thiol, ethyl 2-mercaptoacetate, 4,6-dimethyl-
2-mercapto-nicotinonitrile, various thiocarbamoyl derivatives, ammonium thiocyanate, 3-cyano-4,6-
dimethyl-5-arylazopyridin-2-ones, and malononitrile. The synthesized 4-(N-substituted amino) acetanilide
scaffolds were characterized by spectral analyses and assayed in vitro for breast anticancer activity. 2-(4-
Acetamidophenylaminocarbonyl)-3-amino-thiophenes 11, 13a, and 13b showed the highest cytotoxic
activity.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION compounds [18] (Fig. 1) were found to have a potent effect

against A549 and C6 tumor cell lines. Histone deacetylase
Since the discovery of acetanilide as analgesic under the inhibitors (HDACi) such as suberoylanilide hydroxamic
name of Antifebrin [1], acetanilide derivatives have gained acid [19,20] (Fig. 1) has shown potent cytotoxic effects
much attention in medicinal chemistry. Literature studies against several tumor types with low toxicity towards
expose that acetanilide derivatives are an important normal cells.
structural backbone of biologically active molecules. Chloroacetamides are valuable synthetic intermediates
They showed various activities such as antimicrobial as they allow the incorporation of unmined heteroatoms
[2,3], antiviral [4,5], anthelmintic [6], anti-inflammatory to afford a wide range of heterocycles. In this paper, we
[7], cytotoxic [8,9], antifungal, and antibacterial [10,11]. describe the synthesis and anticancer activity of many
Moreover, they possess anti-arthritic [12], analgesic [13], acetanilides incorporating thiophene, thiazole, pyridine,
antileishmanial [14], antitumor [15], and insecticidal [16] and/or pyrrole moieties through different linkages.
properties.
Away from the famous activity of acetanilides, literature
studies reveal a potent anticancer activity for those RESULTS AND DISCUSSION
compounds. For example, AZD1152 [17] (Fig. 1)
inhibited cell division and cell proliferation in Aurora Chemistry. The starting scaffold N-(4-acetamidophenyl)-
kinase B overexpressed tumor cells. 2-[Benzimidazole-2- 2-chloroacetamide (3) has been prepared by the
yl)sulfanyl]-N-[4-(2-methylthiazol-4-yl)phenyl]acetamide reported experimental conditions through treatment of
© 2018 Wiley Periodicals, Inc.

E. Abdel-Latif, E. M. Keshk, A.-G. M. Khalil, A. Saeed, and H. M. Metwally Vol 000
Figure 1. Selected representative examples for anticancer activity of acetanilide derivatives.
p-aminoacetanilide with chloroacetyl chloride in dry Refluxing equimolar amounts of 3 and 2-mercapto-4,6-
acetone in the presence of anhydrous potassium dimethylnicotinonitrile (10) in ethanolic solution of
carbonate [21] (Scheme 1). The chemical behavior of sodium ethoxide furnished the corresponding 3-
2-chloroacetamide derivative 3 was tested towards aminothieno[2,3-b] pyridine scaffold 11, the reaction
the reaction with several sulfur nucleophiles. Thus, starts through nucleophilic substitution of the chlorine
heating of chloroacetamide derivative 3 with 2- atom from chloroacetamide 3 followed by intramolecular
mercaptobenzothiazole, 2-mercaptoethanol, and/or ethyl cyclization at the nitrile function (Scheme 2). The IR
2-mercaptoacetate in absolute ethanol and sodium acetate spectrum of 11 indicated the absence of any absorption
afforded the corresponding sulfide derivatives 5, 7, and 9, due to nitrile function and showed sharp bands of NH2
respectively. The sulfide derivatives were isolated in 67 group at 3490 and 3290 cm1. The 1H NMR spectrum of
to 90% yields, and their structures were established based 11 clearly secured the disappearance of any signal due to
on spectral and elemental analyses. In the infrared the methylene function and showed the recoupment
spectrum of sulfide 5, the absorption bands at 3286, singlet signal at 6.92 ppm for the protons of amino
3150, and 1654 cm1 clearly indicated the presence of function.
NH and carbonyl functions. The 1H NMR spectrum of 5 Stirring of 2-chloroacetamide derivative 3 with
displayed the protons of methyl and methylene groups as thiocarbamoyl derivatives 12 that are derived from ethyl
two singlet signals at 2.02 and 4.37 ppm. The aromatic cyanoacetate and cyanoacetamide [22,23] in ethanolic
protons resonated as multiplet and doublet signals in the solution of sodium ethoxide followed by refluxing at
region 7.34–8.02 ppm. The protons of NH functions 60–70°C yielded the corresponding 2-(4-
resonated as two singlet signals at 9.87 and 10.35 ppm. acetamidophenylaminocarbonyl)-3-aminothiophenes 13a
Scheme 1. Synthesis of sulfide derivatives 5, 7, and 9.
Journal of Heterocyclic Chemistry DOI 10.1002/jhet

Month 2018 Acetanilide-based Heterocycles
Scheme 2. Synthesis of 2-(4-acetamidophenylaminocarbonyl)-3-amino Scheme 3. Synthesis of 2-(4-acetamidophenyl-imino)thiazolidin-4-ones

(hydroxyl)-thiophenes 11, 13, and 15. 18 and 20.
and 13b. Elemental and spectral analyses were utilized to through intramolecular cyclization of the thiocyanate
secure the chemical structure of compounds 13, the IR intermediate 17 and the Dimroth-like rearrangements
absorption bands of 13b at 3432, 3397, 3268, 3161, and [26]. The amino–imino tautomerism of the 2-arylimino-
1661 referred to functional groups (NH, NH2, and C¼O), thiazolidin-4-one 18 was established through the analysis
and the absence of nitrile function. In addition, the 1H of IR and 1H NMR spectral data. The tautomeric
NMR signals of the same compound resonated as singlet structure 18i finds support through the appearance of a
at 2.01 ppm for three protons (CH3), singlet at 4.98 for lactam proton (-CONH-) in the 1H NMR spectrum as
two protons (NH2), multiplet in the region 6.93– singlet at lower field (11.12 ppm) rather than the imine
7.52 ppm for the aromatic protons, three singlet at 8.80, proton of 18ii which should appears at higher field
9.32, and 10.24 ppm for the protons of three NH groups, (≈9.70 ppm). The IR absorption of the lactam NH group
and singlet at 9.89 ppm for two protons (NH2). at 3109 cm1, together with a strong band at 1662 cm1,
Treatment of 2-chloroacetamide derivative 3 confirms the γ-lactam tautomeric form 18i in the solid
with 2-(arylhydrazono)-2-ethoxycarbonyl-thioacetanilide state. The possibility of the tautomeric structure 18iii
derivatives 14 [24] in ethanolic sodium ethoxide yielded involving a hydroxylic group was diminished due to the
the corresponding 2-(4-acetamidophenylaminocarbonyl)- absence of typical signals for OH group in IR and 1H
4-arylazo-3-hydroxythiophenes 15a–c. The reaction NMR spectra.
starts via nucleophilic substitution of the chlorine atom The methylene group in this thiazolidin-4-one derivative
from chloroacetamide 3 followed by intramolecular 18 proved to be reactive towards Knoevenagel
elimination of ethanol molecule to furnish the target 3- condensation reaction with substituted benzaldehyde
hydroxythiophene products. The chemical structures of derivatives. The condensation proceeded readily by
15a–c were established based on their spectral and heating in glacial acetic acid and fused sodium acetate to
elemental analyses. The 1H NMR spectrum of 15b (as an furnish the corresponding 5-(substituted benzylidene)-
example) displayed signals that agree with the designed thiazolidin-4-one derivatives 20a–d with 70–85% yield.
structure, the two methyl substituents appeared at 2.03 The structures of these targeted thiazolidine-4-ones were
and 2.35 ppm as two singlet signals. Aromatic protons assigned based on spectroscopic and analytical data. The
were observed in the region 7.28 to 7.75 ppm as characteristic stretching absorptions for AcN–H, N–H,
multiplet and doublet. The protons of NH and OH and C¼O bonds were observed at 3218–3214, 3162–
functions were observed as four singlet signals at 9.41, 3103, and 1676–1661 cm1, respectively. The 1H NMR
9.90, 13.24, and 14.35 ppm. spectra of 20a–c showed singlet for the proton of
Heterocyclization of 2-chloroacetamide 3 upon methine function (CH¼C) deshielded to the range 7.72–
treatment with ammonium thiocyanate to generate the 7.77 ppm.
2-(p-acetamidophenylimino)-thiazolidin-4-one (18) has In an attempt to prepare the furo[2,3-b] pyridine
been achieved by heating in ethyl alcohol under reflux derivatives 24 via intramolecular cyclization of the O-
for 4 h (Scheme 3). The formation of this lactam alkylated compounds 23, heating of 2-chloroacetamide
structure 18 proceeded as mentioned by Vicini et al. [25] derivative 3 with 5-arylazo-3-cyano-4,6-dimethylpyridin-

Scheme 4. Reaction of chloroacetamide 3 with 5-arylazo-3-cyano-4,6-dimethylpyridin-2-ones.
2-ones 21 in dimethylformamide containing potassium designed and identified as the 1-acetamidophenyl-2-

carbonate furnished the corresponding N-alkylated aminopyrrole scaffold 27 because of its correct elemental
product, 2-(3-cyano-2-oxo-5-arylazopyridin-1-yl)-N-(p- and spectral analyses. IR absorptions for the NH2 and NH
acetamidophenyl)-acetamide derivatives 22a–d, as a sole were observed at 3328, 3225, and 3185 cm1. The
product (Scheme 4). The reaction failed to substitute the stretching absorptions at 2175, 1728, and 1647 cm1 were
chlorine atom by the nucleophilic oxygen (O-alkylation), recorded for CN and C¼O bonds. The 1H NMR
and the substitution proceeded by the more powerful spectrum clearly indicated the protons of methylene and
nucleophilic nitrogen of the pyridine ring. Elemental and amino functions as singlet signals at 3.36 and 6.78 ppm.
spectral analyses were utilized to secure the chemical In vitro anticancer screening. In vitro cytotoxic action
structure of these synthesized pyridones 22a–d, of the synthesized 4-(N-substituted amino)-acetanilide
characteristic stretching infrared absorptions for N–H and scaffolds was assessed against human breast cancer cell
CN bonds were observed at 3315–3275 and 2224– line, MCF7. Doxorubicin, which is a standout among the
2223 cm1, respectively. The stretching absorption at best anticancer agents, was utilized as the reference
about 1666–1661 cm1 was recorded for C¼O double sedate as a part of this work. The relationship between
bonds. In the 1H NMR spectra, the methylene of relative viability of cells (%) and concentration (μg/mL)
acetamide moiety (NHCOCH2) was observed as singlet at was plotted to acquire the survival curve of MCF7. The
5.01–5.09 ppm. results of statistical analysis of drug in vitro anticancer
The reaction of 2-chloroacetamide derivative 3 with revealed a significant rapprochement between the control
malononitrile as an example carbon nucleophile proceeded and the tested 2-(4-acetamidophenylaminocarbonyl)-3-
by heating in ethyl alcohol in the presence of base such as amino-thiophene compounds 11, 13a, and 13b that
triethylamine (Scheme 5). The reaction product was proved to be the most active members in our study. They
showed very strong potency towards MCF7.
In vitro cytotoxic activities of the synthesized scaffolds
Scheme 5. Synthesis of 1-(p-acetamidophenyl)-2-amino-3-cyano-5-
oxopyrrole 27.
were recognized in (Table 1). IC50 values refer to the
concentration required for 100% inhibition of cell
viability. Analysis of the data in Table 1 indicated that
compounds 11, 13a, and 13b containing the thiophene
moiety exhibited the lowest IC50, which means that they
are the most effective cytotoxic drugs. Accordingly,
compounds 15a–c and 27 can be used as very potent
cytotoxic drugs for breast carcinoma cell, while
compounds 3, 20b, and 22d have moderate IC50, which
means that they are lower effective cytotoxic drugs for
breast carcinoma cell. On the other hand, the remaining
compounds 5, 7, 9, 18, 20a, 20c, 20d, 22a, and 22b are

Table 1 iS10 FTIR spectrometer (Waltham, MA). The 1H NMR

Cytotoxic activity of the synthesized scaffolds against MCF-7 cell line. spectra were recorded on a Varian XL 300 MHz
apparatus (Palo Alto, CA) using DMSO-d6 as a solvent.
In vitro cytotoxicity IC50 (μg/mL)
The mass spectra were recorded on a Quadrupole GC/MS
Compound MCF-7 Thermo Scientific Focus/DSQII (Waltham, MA) at 70 eV.
DOX 4.17 ± 0.2 Elemental analyses (C, H, and N) were determined on
3 28.94 ± 1.9 Perkin-Elmer 2400 analyzer (PerkinElmer Instruments,
5 81.65 ± 3.3
7 90.66 ± 4.3
Shelton, CT). The NMR spectra of the products 15c, 20d,
9 67.04 ± 3.0 and 22d are not provided due to their limited solubility in
11 8.96 ± 0.7 common NMR solvents.
13a 9.45 ± 0.9 Synthesis of N-(4-acetamidophenyl)-2-chloroacetamide
13b 10.4 ± 0.88
(3). To a stirred suspension of 4-aminoacetanilide
15a 11.71 ± 1.0
15b 19.39 ± 1.6 (10 mmol, 1.5 g) and anhydrous potassium carbonate
15c 17.34 ± 1.4 (10 mmol, 1.38 g) in 40-mL acetone, 1.2 mL
18 52.70 ± 2.8 chloroacetyl chloride (15 mmol) has been added drop by
20a 88.97 ± 3.8
20b 46.83 ± 2.5
drop while the stirring is continued for 2 h. The solid that
20c 72.43 ± 3.2 obtained on dilution with cold water was filtered and
20d 94.26 ± 4.7 recrystallized from ethyl alcohol.
22a 59.84 ± 2.9 White crystals, yield 72%, mp 248–250°C; lit. mp 240–
22b 84.72 ± 3.6
22c <100
243°C [21]; IR (ν/cm1): 3269, 3171 (NH), 1668 (C¼O);
22d 38.92 ± 2.1
1
H NMR (DMSO-d6): δ/ppm = 2.01 (s, 3H, CH3), 3.47
27 13.80 ± 1.2 (s, 2H, CH2), 7.49 (s, 4H, Ar–H), 9.84 (s, 1H, NH),
IC50 (μg/mL): 1–10 (very strong); 11–20 (strong); 21–50 (moderate); 51– 10.04 (s, 1H, NH). Anal. Calcd. for C10H11ClN2O2
100 (weak); above 100 (non-cytotoxic). DOX, Doxorubicin. (226.05): C, 52.99; H, 4.89; N, 12.36%. Found: C, 52.91;
H, 4.85; N, 12.38%.
very weak cytotoxic drugs compared with the reference General procedure for the synthesis of sulfide derivatives 5,
drug, Doxorubicin. 7, and 9. To a solution of chloroacetamide derivative 3
Based on these preliminary screening results, (1.13 g, 5 mmol) in 30-mL ethyl alcohol, 2-
aminothiophene compounds 11, 13a, and 13b showed the mercaptobenzothiazole, 2-mercaptoethanol, and/or ethyl
highest cytotoxic activity in the tested cancer cell. In 2-mercaptoacetate (5 mmol) in addition to 0.5 g sodium
addition, the newly synthesized thiophene scaffolds 15a–c acetate was added. The mixture was heated under reflux
exhibited good efficacy relative to the standard anticancer for 3 h and then poured into ice water. The precipitate
drug Doxorubicin. They could be important leads in that formed was isolated by filtration and purified by
continuing development against anticancer disease. recrystallization from the ethyl alcohol to furnish sulfide
derivatives 5, 7, and/or 9, respectively.
N-(4-Acetamidophenyl)-2-(benzothiazol-2-thio)acetamide
CONCLUSION (5). White crystals, yield 90%, mp 208–210°C; IR (ν/
cm1): 3286, 3150 (NH), 1654 (C¼O); 1H NMR
The present study has been focused on the synthesis of (DMSO-d6): δ/ppm = 2.02 (s, 3H, CH3), 4.37 (s, 2H,
new thiophene, thiazolidine-4-one, pyridine, and pyrrole CH2), 7.34–7.44 (m, 2H, Ar–H), 7.50 (s, 4H, Ar–H),
derivatives containing biologically active acetanilide 7.83 (d, J = 8.1 Hz, 1H, Ar–H), 8.02 (d, J = 7.8 Hz, 1H,
nucleus and evaluation of their anticancer activity. Some Ar–H), 9.87 (s, 1H, NH), 10.35 (s, 1H, NH). Anal.
of the newly synthesized compounds 11, 13a, and 13b Calcd. for C17H15N3O2S2 (357.06): C, 57.12; H, 4.23; N,
exhibited significant activity (very strong) compared with 11.76%. Found: C, 57.26; H, 4.25; N, 11.84%.
N-(4-Acetamidophenyl)-2-((2-hydroxyethyl)thio)acetamide
the control drug, Doxorubicin. Compounds 15a–c and 27 (7). White powder, yield 70%, mp 143–145°C; IR (ν/
are strong cytotoxic drugs while compounds 3, 20b, and cm1): 3259, 3169 (NH and OH), 1649 (C¼O); 1H NMR
22d exhibited a moderate activity. (DMSO-d6): δ/ppm = 2.01 (s, 3H, CH3), 2.70 (t,
J = 6.75 Hz, 2H, CH2), 3.28 (s, 2H, CH2), 3.56 (t,
J = 6.75 Hz, 2H, CH2), 4.85 (s, 1H, OH), 7.48 (s, 4H,
EXPERIMENTAL Ar–H), 9.86 (s, 1H, NH), 9.98 (s, 1H, NH). Anal. Calcd.
for C12H16N2O3S (268.09): C, 53.71; H, 6.01; N,
All melting points (uncorrected) were measured on 10.44%. Found: C, 53.81; H, 6.04; N, 10.36%.
Gallenkamp electric melting point apparatus. The infrared N-(4-Acetamidophenyl)-2-(ethoxycarbonyl-methylthio)
spectra were determined on a Thermo Scientific Nicolet acetamide (9). White powder, yield 67%, mp 148–150°C;

IR ( ν /cm1): 3293, 3155 (NH), 1742, 1657 (C¼O); 1H C20H19N5O3S (409.12): C, 58.67; H, 4.68; N, 17.10%.
NMR (DMSO-d6): δ/ppm = 1.18 (t, J = 7.20 Hz, 3H, Found: C, 58.78; H, 4.71; N, 17.16%.
CH3), 2.01 (s, 3H, CH3), 3.40 (s, 2H, CH2), 3.49 (s, 2H, 2-(4-Acetamidophenylaminocarbonyl)-3-hydroxy-5-
CH2), 4.08 (q, J = 7.20 Hz, 2H, CH2), 7.48 (s, 4H, Ar– phenylamino-4-phenylazo-thiophene (15a). Reddish brown
H), 9.84 (s, 1H, NH), 10.00 (s, 1H, NH). Anal. Calcd. for crystals, yield 58%, mp 224–225°C; IR ( ν /cm1): 3364
C14H18N2O4S (310.10): C, 54.18; H, 5.85; N, 9.03%. (NH and OH), 1664, 1628 (C¼O); 1H NMR (DMSO-d6):
Found: C, 54.07; H, 5.90; N, 9.08%. δ/ppm = 2.08 (s, 3H, CH3), 7.32–7.89 (m, 14H, Ar–H),
General procedure for the synthesis of 2-(4- 9.46 (s, 1H, NH), 9.94 (s, 1H, NH), 13.32 (s, 1H, NH),
acetamidophenylaminocarbonyl)-3-amino (hydroxyl)-thiophenes 14.28 (s, 1H, OH). Anal. Calcd. for C25H21N5O3S
11, 13, and 15. N-(4-Acetamidophenyl)-2-chloroacetamide (471.14): C, 63.68; H, 4.49; N, 14.85%. Found: C, 63.82;
3 (5 mmol, 1.13 g) was stirred for 10 min in sodium H, 4.43; N, 14.95%.
ethoxide solution (previously prepared by dissolving small 2-(4-Acetamidophenylaminocarbonyl)-3-hydroxy-5-
granules of sodium, 0.23 g, in 30-mL absolute ethanol) phenylamino-4-(4-tolylazo)-thiophene (15b). Reddish
and then the thiol derivatives (5 mmol) [namely, 2- brown crystals, yield 80%, mp 235–237°C; IR (ν/cm1):
mercapto-4,6-dimethylnicotinonitrile (10), thiocarbamoyl 3364, 3297 (NH and OH), 1662, 1631 (C¼O); 1H NMR
derivatives (12), or 2-(arylhydrazono)-2-ethoxycarbonyl- (DMSO-d6): δ/ppm = 2.03 (s, 3H, CH3), 2.35 (s, 3H,
thioacetanilide derivatives (14)] were added. The reaction CH3), 7.28–7.53 (m, 11H, Ar–H), 7.75 (d, J = 8.7 Hz,
mixture was heated on a steam bath for 4 h and then 2H, Ar–H), 9.41 (s, 1H, NH), 9.90 (s, 1H, NH), 13.24 (s,
allowed to pour into ice water. The solid that formed after 1H, NH), 14.35 (s, 1H, OH); MS m/z (%): 485 (M+,
neutralization by dilute HCl was filtered and recrystallized 56.40), 428 (45.44), 381 (73.22), 337 (51.68), 150
from EtOH/DMF mixture (4:1) to afford the thiophene (48.81), 80 (100), 64 (97.98). Anal. Calcd. for
products 11, 13, or 15, respectively. C26H23N5O3S (485.15): C, 64.31; H, 4.77; N, 14.42%.
N-(4-Acetamidophenyl)-3-amino-4,6-dimethylthieno[2,3-b] Found: C, 64.38; H, 4.79; N, 14.38%.
pyridine-2-carboxamide (11). Orange powder, yield 88%, 2-(4-Acetamidophenylaminocarbonyl)-4-(4-bromophenylazo)-
1
mp 278–280°C; IR ( ν /cm ): 3490, 3333, 3290, 3251 3-hydroxy-5-phenyl amino-thiophene (15c). Brown powder,
(NH and NH2), 1684 (C¼O); 1H NMR (DMSO-d6): yield 76%, mp 290–292°C; IR (ν/cm1): 3298 (NH and
δ/ppm = 2.02 (s, 3H, CH3), 2.74 (s, 3H, CH3), 2.88 (s, OH), 1657 (br, C¼O); MS m/z (%): 551 (M+, Br-81,
3H, CH3), 6.92 (s, 2H, NH2), 7.05 (s, 1H, pyridine-H5), 9.94), 549 (M+, Br-79, 6.08), 495 (32.6), 479 (61.26),
7.50 (d, J = 9 Hz, 2H, Ar–H), 7.56 (d, J = 9 Hz, 2H, Ar– 447 (100), 330 (28.7), 174 (45.04), 134 (25.8),
H), 9.33 (s, 1H, NH), 9.88 (s, 1H, NH); MS m/z (%): 355 108 (29.8), 91 (16.85), 77 (56.10), 65 (43.70), 43 (49.4).
(M+ +1, 16.15), 354 (M+, 71.93), 205 (82.62), 177 Anal. Calcd. for C25H20BrN5O3S (549.05): C, 54.55;
(19.46), 150 (100), 133 (26.56), 108 (40.74). Anal. H, 3.66; N, 12.72%. Found: C, 54.55; H, 3.61; N, 12.80%.
Synthesis of 2-(4-acetamidophenylimino)-thiazolidin-4-one
Calcd. for C18H18N2O3S (354.12): C, 61.00; H, 5.12; N,
(18). A suspension of chloroacetamide 3 (5 mmol,
15.81%. Found: C, 61.16; H, 5.06; N, 15.90%.
1.13 g) and ammonium thiocyanate (10 mmol, 0.76 g) in
Ethyl 5-((4-acetamidophenyl)carbamoyl)-4-amino-2-
(phenylamino)thiophene-3-carboxylate (13a). Green 30-mL ethyl alcohol was heated under reflux for 4 h. The
powder, yield 66%, mp 208–210°C; IR (ν /cm1): 3301, precipitate that obtained on cooling was picked up by
3267, 3173 (NH and NH2), 1668, 1653 (C¼O); 1H NMR filtration and then recrystallized by heating in ethyl alcohol.
(DMSO-d6): δ/ppm = 1.21 (t, J = 7.20 Hz, 3H, CH3), Beige crystals, yield 70%, mp 280–282°C; IR (ν/cm1):
2.04 (s, 3H, CH3), 4.16 (q, J = 7.20 Hz, 2H, CH2), 6.07 3248, 3109 (NH), 1662 (br, C¼O); 1H NMR (DMSO-d6):
(s, 2H, NH2), 7.14–7.72 (m, 9H, Ar–H), 9.84 (s, 1H, δ/ppm = 2.08 (s, 3H, CH3), 4.00 (s, 2H, CH2), 7.56–7.59 (s,
NH), 10.17 (s, 1H, NH), 11.53 (s, 1H, NH). MS m/z (%): 4H, Ar–H), 9.95 (s, 1H, NH), 11.12 (s, 1H, NH). Anal.
439 (M+ +1, 38.50), 438 (M+, 53.00), 428 (52.50), 408 Calcd. for C11H11N3O2S (249.06): C, 53.00; H, 4.45; N,
(56.00), 398 (46.50), 390 (50.50), 368 (46.50), 342 16.86%. Found: C, 53.12; H, 4.42; N, 16.79%.
(43.00), 323 (54.50), 314 (42.00), 288 (58.39), 215 General procedure for synthesis of 2-(4-
(91.26), 187 (47.89), 143, (30.75), 77 (100.00). Anal. acetamidophenylimino)-5-arylidene-thiazolidin-4-ones 20a–
Calcd. for C22H22N4O4S (438.14): C, 60.26; H, 5.06; N, d. To a suspension of 2-(4-acetamidophenylimino)
12.78%. Found: C, 60.12; H, 5.00; N, 12.70%. thiazolidin-4-one (18) (2 mmol, 0.5 g) and 0.5 g fused
N2-(4-Acetamidophenyl)-3-amino-5-(phenylamino) sodium acetate in 15-mL glacial acetic acid, the
thiophene-2,4-dicarboxamide (13b). Beige powder, yield appropriate aromatic aldehyde derivative (2 mmol) was
70%, mp 230–232°C; IR ( ν /cm1): 3432, 3397, 3268, added. The reaction mixture was refluxed for 4 h and
3161 (NH and NH2), 1661 (br, C¼O); 1H NMR (DMSO- then allowed to cool to 25°C. The solid that formed, after
d6): δ/ppm = 2.01 (s, 3H, CH3), 4.98 (s, 2H, NH2), 6.93– dilution with cold water, was isolated by filtration. The
7.52 (m, 9H, Ar–H), 8.80 (s, 1H, NH), 9.32 (s, 1H, NH), resulting crude product was purified by recrystallization
9.89 (s, 2H, NH2), 10.24 (s, 1H, NH). Anal. Calcd. for from EtOH/DMF mixture (1:1) to yield 20a–d.

2-(4-Acetamidophenylimino)-5-(4-methoxybenzylidene)- N-(4-Acetamidophenyl)-2-(3-cyano-4,6-dimethyl-2-oxo-5-(4-
thiazolidin-4-one (20a). Orange crystals, yield 80%, mp tolylazo)pyridin-1(2H)-yl)acetamide (22b). Orange powder,
294–295°C; IR ( ν /cm1): 3218, 3103 (NH), 1661 (br, yield 67%, mp 285–286°C; IR ( ν /cm1): 3275, 3171
C¼O); 1H NMR (DMSO-d6): δ/ppm = 2.06 (s, 3H, CH3), (NH), 2224 (CN), 1664 (C¼O); 1H NMR (DMSO-d6):
3.82 (s, 3H, OCH3), 7.14 (d, J = 8.00 Hz, 2H, Ar–H), δ/ppm = 2.03 (s, 3H, CH3), 2.33 (s, 3H, CH3), 2.53 (s,
7.43–7.53 (m, 4H, Ar–H), 7.62 (d, J = 8.00 Hz, 2H, Ar– 3H, CH3), 2.66 (s, 3H, CH3), 5.01 (s, 2H, CH2), 7.32 (d,
H), 7.72 (s, 1H, CH¼C), 9.98 (s, 1H, NH), 12.30 (s, 1H, J = 8.80 Hz, 2H, Ar–H), 7.41–7.47 (m, 4H, Ar–H), 7.67
NH). Anal. Calcd. for C19H17N3O3S (367.10): C, 62.11; (d, J = 8.80 Hz, 2H, Ar–H), 9.82 (s, 1H, NH), 10.39 (s,
H, 4.66; N, 11.44%. Found: C, 62.18; H, 4.61; N, 11.49%. 1H, NH). Anal. Calcd. for C25H24N6O3 (456.19): C,
2-(4-Acetamidophenylimino)-5-(2,5-dimethoxybenzylidene)- 65.78; H, 5.30; N, 18.41%. Found: C, 65.66; H, 5.34; N,
thiazolidin-4-one (20b). Orange crystals, yield 75%, mp 18.32%.
>300°C; IR ( ν /cm1): 3217, 3107 (NH), 1662 (br, N-(4-Acetamidophenyl)-2-(3-cyano-4,6-dimethyl-2-oxo-5-(4-
C¼O); 1H NMR (DMSO-d6): δ/ppm = 2.05 (s, 3H, methoxyphenyl-azo)pyridin-1(2H)-yl)acetamide (22c).
CH3), 3.78 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 6.84 (s, Orange powder, yield 75%, mp 289–290°C; IR (ν/cm1):
1H, Ar–H), 6.98–7.06 (dd, 2H, Ar–H), 7.58–7.65 (m, 3295 (NH), 2223 (CN), 1665 (C¼O); 1H NMR
4H, Ar–H), 7.74 (s, 1H, CH¼C), 9.99 (s, 1H, NH), 12.26 (DMSO-d6): δ/ppm = 2.02 (s, 3H, CH3), 2.46 (s, 3H,
(s, 1H, NH). Anal. Calcd. for C20H19N3O4S (397.11): C, CH3), 2.70 (s, 3H, CH3), 3.83 (s, 3H, OCH3), 5.09 (s,
60.44; H, 4.82; N, 10.57%. Found: C, 60.33; H, 4.85; N, 2H, CH2), 7.11 (d, J = 8.80 Hz, 2H, Ar–H), 7.51–7.53
10.49%. (m, 4H, Ar–H), 7.84 (d, J = 8.80 Hz, 2H, Ar–H), 9.89 (s,
(5Z)-2-(4-Acetamidophenylimino)-5-(4-nitrobenzylidene)- 1H, NH), 10.47 (s, 1H, NH). Anal. Calcd. for
thiazolidin-4-one (20c). Orange crystals, yield 70%, mp C25H24N6O4 (472.19): C, 63.55; H, 5.12; N, 17.79%.
>300°C; IR ( ν /cm1): 3214, 3162 (NH), 1676 (br, Found: C, 63.40; H, 5.06; N, 17.87%.
C¼O); 1H NMR (DMSO-d6): δ/ppm = 2.05 (s, 3H, N-(4-Acetamidophenyl)-2-(3-cyano-4,6-dimethyl-2-oxo-5-(4-
CH3), 7.63–7.75 (m, 4H, Ar–H), 7.77 (s, 1H, CH¼C), chlorophenyl-azo)pyridin-1(2H)-yl)acetamide (22d). Brown
7.83 (d, J = 8.80 Hz, 2H, Ar–H), 8.34 (d, J = 8.40 Hz, powder, yield 70%, mp 268–270°C; IR ( ν /cm1): 3315
2H, Ar–H), 10.21 (s, 1H, NH), 12.40 (s, 1H, NH). Anal. (NH), 2224 (CN), 1661 (C¼O); MS m/z (%): 476 (M+,
Calcd. for C18H14N4O4S (382.07): C, 56.54; H, 3.69; N, 34.60), 416 (100), 415 (88.67), 374 (16.73), 353 (16.93),
14.65%. Found: C, 56.71; H, 3.63; N, 14.56%. 329 (17.43), 327 (47.46). Anal. Calcd. for C24H21ClN6O3
2-(4-Acetamidophenylimino)-5-(4-bromobenzylidene)- (476.14): C, 60.44; H, 4.44; N, 17.62%. Found: C, 60.62;
thiazolidin-4-one (20d). Brown powder, yield 65%, mp H, 4.37; N, 17.74%.
>300°C; IR ( ν /cm1): 3218, 3106 (NH), 1662 (br, Synthesis of 2-amino-1-(4-acetamidophenyl)-3-cyano-5-oxo-
C¼O); MS m/z (%): 417 (M+, Br-81, 100), 415 (M+, Br- 4,5-dihydro-1H-pyrrole (27). A mixture of 3 (1.13 g,
79, 95.38), 375 (15.99). Anal. Calcd. for C18H14BrN3O2S 5 mmol) and malononitrile (5 mmol) in EtOH (30 mL)
(415.00): C, 51.93; H, 3.39; N, 10.09%. Found: C, 51.77; containing 0.5 mL triethylamine was heated under reflux
H, 3.31; N, 10.21%. for 3 h. After cooling, the precipitate that formed was
General procedure for the synthesis of N-(4- picked up by filtration and then recrystallized from the
acetamidophenyl)-2-(3-cyano-4,6-dimethyl-2-oxo-5-(substituted dioxane.
phenylazo)pyridinyl)acetamides 22a–d. A suspension of Gray powder, yield 78%, mp >300°C; IR ( ν /cm1):
chloroacetamide derivative 3 (5 mmol, 1.13 g), 5-arylazo- 3328, 3225, 3185 (NH and NH2), 2175 (CN), 1728,
3-cyano-4,6-dimethyl-pyridin-2-one (5 mmol), and 0.70 g 1647 (C¼O); 1H NMR (DMSO-d6): δ/ppm = 2.07 (s, 3H,
of anhydrous potassium carbonate in 20-mL CH3), 3.36 (s, 2H, CH2), 6.78 (s, 2H, NH2), 7.17 (d,
dimethylformamide was heated on water bath for 4 h. J = 8.70 Hz, 2H, Ar–H), 7.69 (d, J = 8.70 Hz, 2H, Ar–
The reaction mixture was cooled and then poured onto H), 10.13 (s, 1H, NH). Anal. Calcd. for C13H12N4O2
ice water. The precipitate that formed was filtered off and (256.10): C, 60.93; H, 4.72; N, 21.86%. Found: C, 60.81;
recrystallized from dioxane to give N-substituted pyridine H, 4.75; N, 21.78%.
derivatives 22a–d. In vitro anticancer activity. The evaluation of in vitro
N-(4-Acetamidophenyl)-2-(3-cyano-4,6-dimethyl-2-oxo-5- cytotoxicity effects of the synthesized aminoacetanilide
phenylazopyridin-1(2H)-yl)acetamide (22a). Red crystals, scaffolds was carried out against mammary gland breast
yield 55%, mp 278–280°C; IR ( ν /cm1): 3303 (NH), cancer (MCF-7) cell line. This cell line was obtained
2224 (CN), 1666 (C¼O); 1H NMR (DMSO-d6): from ATCC via Holding company for biological products
δ/ppm = 2.02 (s, 3H, CH3), 2.55 (s, 3H, CH3), 2.64 (s, and vaccines (VACSERA), Cairo, Egypt. Cytotoxicity de-
3H, CH3), 5.05 (s, 2H, CH2), 7.26–7.64 (m, 9H, Ar–H), terminations are based the transformation of the yellow
9.90 (s, 1H, NH), 10.41 (s, 1H, NH). Anal. Calcd. for 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bro-
C24H22N6O3 (442.18): C, 65.15; H, 5.01; N, 18.99%. mide (MTT) to a purple formazan derivative by mitochon-
Found: C, 65.22; H, 5.06; N, 19.06%. drial succinate dehydrogenase in practical cells. The

method of this MTT test was performed as previously [16] Counihan, J. L.; Duckering, M.; Dalvie, E.; Ku, W.; Bateman,
L. A.; Fisher, K. J.; Nomura, D. K. ACS Chem Biol 2017, 12, 635.
described in detail [27,30].
[17] Mortlock, A. A.; Foote, K. M.; Heron, N. M.; Jung, F. H.;
Pasquet, G.; Lohmann, J. J.; Warin, N.; Renaud, F.; De-Savi, C.; Roberts,
N. J.; Johnson, T.; Dousson, C. B.; Hill, G. B.; Perkins, D.; Hatter, G.;
REFERENCES AND NOTES Wilkinson, R. W.; Wedge, S. R.; Heaton, S. P.; Odedra, R.; Keen, N. J.;
Crafter, C.; Brown, E.; Thompson, K.; Brightwell, S.; Khatri, L.; Brady,
[1] Cahn, A.; Hepp, P. Centralblatt Klinische Medizin 1886, 7, M. C.; Kearney, S.; McKillop, D.; Rhead, S.; Parry, T.; Green, S. J Med
561. Chem 2007, 50, 2213.
[2] Patel, R. V.; Kumari, P.; Rajani, D. P.; Chikhalia, K. H. Med [18] Yurttas, L.; Ozkay, Y.; Akalin-Ciftci, G.; Ulusoylar-Yildirim,
Chem Res 2013, 22, 195. S. J Enzyme Inhib Med Chem 2014, 29, 175.
[3] Patel, A. B.; Kumari, P.; Chikhalia, K. H. Indian J Chem 2015, [19] Mann, B. S.; Johnson, J. R.; He, K.; Sridhara, R.; Abraham, S.;
54B, 260. Booth, B. P.; Verbois, L.; Morse, D. E.; Jee, J. M.; Pope, S.; Harapanhalli,
[4] Pandeya, S. N.; Sriram, D.; Nath, G.; Declercq, E. Eur J Pharm R. S.; Dagher, R.; Farrell, A.; Justice, R.; Pazdur, R. Clin Cancer Res
Sci 1999, 9, 25. 2007, 13, 2318.
[5] Paramonova, M. P.; Khandazhinskaya, A. L.; Seley-Radtke, [20] Kelly, W. K.; OConnor, O. A.; Krug, L. M.; Chiao, J. H.;
K. L.; Novikov, M. S. Mendeleev Commun 2017, 27, 85. Heaney, M.; Curley, T.; Cortelli, B. M.; Tong, W.; Secrist, J. P.;
[6] Wollweber, H.; Kölling, H.; Niemers, E.; Widdig, A.; Schwartz, L.; Richardson, S.; Chu, E.; Olgac, S.; Marks, P. A.; Scher,
Andrews, P.; Schulz, H. P.; Thomas, H. Arzneimittelforschung 1984, H.; Richon, V. M. J Clin Oncol 2005, 23, 3923.
34, 531. [21] Patel, R. V.; Patel, P. K.; Kumari, P.; Rajani, D. P.; Chikhalia,
[7] Helal, M. H.; El-Awdan, S. A.; Salem, M. A.; Abd-elaziz, T. H. K. Eur J Med Chem 2012, 53, 41.
A.; Moahamed, Y. A.; El-Sherif, A. A.; Mohamed, G. A. M. Spectrochim [22] Goerdeler, J.; Keuser, U. Chem Ber 1964, 97, 3106.
Acta A Mol Biomol Spectrosc 2015, 135, 764. [23] Kaminskii, V. A.; Slabko, O. Y.; Kachanov, A. V.;
[8] Catarro, M.; Serrano, J.; Cavalheiro, E.; Ramos, S.; Santos, A. Buchvetskii, B. V. Tetrahedron Lett 2003, 44, 139.
O.; Silvestre, S.; Almeida, P. Bioorg Med Chem 2017, 25, 4304. [24] Harhash, A. H.; Amer, F. A.; Nour-Eldin, M. A.; Awad, M. L.
[9] Ramos, S. S.; Almeida, S. S.; Leite, P. M.; Boto, R. E. F.; Zeitschrifte fuer Naturforschung 1976, 31B, 846.
Silvestre, S.; Almeida, P. Tetrahedron 2014, 70, 8930. [25] Vicini, P.; Geronikaki, A.; Anastasia, K.; Incerti, M.; Zani, F.
[10] Patel, A. B.; Patel, R. V.; Kumari, P.; Rajani, D. P.; Chikhalia, Bioorg Med Chem 2006, 14, 3859.
K. H. Med Chem Res 2013, 22, 367. [26] Subbotina, J. O.; Fabian, W. M. F.; Tarasov, E. V.; Volkova,
[11] Ertan, T.; Yildizi, I.; Ozkan, S.; Temiz-Arpaci, O.; Kaynak, F.; N. N.; Bakulev, V. A. Eur J Org Chem 2005, 2914, 2005.
Yalcin, I.; Aki-Sener, E.; Abbasoglu, U. Bioorg Med Chem 2007, 15, [27] Mosmann, T. J Immunol Methods 1983, 65, 55.
2032. [28] Francois, D.; Rita, L. J Immunol Methods 1986, 89, 271.
[12] Jawed, H.; Shah, S. U. A.; Jamall, S.; Simjee, S. U. Int [29] Helena, J. M.; Nader, N. H.; Micheal, A. B.; David, H. G.;
Immunopharmacol 2010, 10, 900. Mary, J. S.; Kerri, A. S.; Kevin, B.; Ruth, H.; Stephen, G.; Mohanraj,
[13] Ozkay, D. U.; Ozkay, Y.; Can, O. D. Med Chem Res 2011, 20, D.; Gerald, A. S.; Vikas, P. S.; Donald, W. K.; Ralph, R. W. Nature
152. 1998, 394, 287.
[14] Pacheco, D. J.; Trilleras, J.; Quiroga, J.; Gutiérrez, J.; Prent, L.; [30] Abdel-Latif, E.; Keshk, E. M.; Saeed, A.; Khalil, A. M. Mod-
Coavas, T.; Marín, J. C.; Delgado, G. J Braz Chem Soc 2013, 24, 1685. ern Organic Chemistry Research 2017, 2, 112.
[15] Kaldrikyan, M. A.; Grigoryan, L. A.; Melik-Ogandzhanyan, R.
G.; Arsenyan, F. G. Pharm Chem J 2009, 43, 242.

OBJEK VI
SINTESIS ASPIRIN
RIFKI RINALDI, S.Si

“ Jika tidak ingin bermanfaat, jadilah orang yang tidak bermanfaat”
SINTESIS ASPIRIN
I. TUJUAN
1. Mempelajari reaksi sintesis suatu ester dari asam benzoat yang tersubstitusi
gugus hidroksi
2. Mensintesis aspirin dari asam o-hidroksi benzoat dengan anhidrida asetat
II. LANDASAN TEORI

2.1 Asam Salisilat ( C6H4(OH)COOH )
Asam salisilat adalah salah satu bahan kimia penting di dalam kehidupan sehari-hari
dan mempunyai suatu nilai ekonomis yang lumayan tinggi karena asam salisilat bisa
digunakan untuk bahan intermediet dari pembuatan obat-obatan, contohnya obat
analgensik dan antiseptik serta keperluan bahan baku farmasi. Asam salisilat dengan
rumus molekulnya C6H4COOHOH memiliki bentuk kristal kecil berwarna merah muda
terang, hingga kecokelatan dengan berat molekul sebesar 138,123 g/mol dengan titik
leleh sebesar 156˚C dan densitas pada 25˚C sebesar 1,443 g/mL.1
Aspirin atau asam asetilsalisilat merupakan senyawa derivat dari asam
salisilat. Asam asetilsalisilat juga disebut dengan asetosal. Aspirin berupa kristal
terbentuk seperti jarum. Kristal asam asetilsalisilat umumnya tidak berwarna sampai
berwarna putih. Asam ini stabil dengan kondisi udara kering namun terdegradasi
perlahan jika terkena uap air menjadi asam asetat dan asam salisilat. Asam
asetilsalisilat merupakan analgesik antipiretik dan anti-inflamasi yang sering
digunakan sebagai obat bebas. Asam salisilat sangat iritatif, sehingga hanya
digunakan sebagai obat luar. Derivatnya yang dapat dipakai secara sistematik
adalah ester salisilat dari asam organik dengan substitusi pada gugus hidroksil,
misalnya asetosal.1
2.2 Asal Asam Salisilat

Aspirin mempunyai rumus molekul C9H8O4; Mr 180.157 g/mol; kerapatan 1,40
g/cm³; titik lebur 135 °C (275 °F); titik didih 140 °C (284 °F) serta kelarutan dalam air
sebesar 3 mg/mL (20 °C). Aspirin bersifat asam sehingga untuk mengetahui
konsentrasi/kadar aspirin dapat dilakukan dengan cara titrasi asam basa atau asidi
alkalimetri (dengan NaOH atau KOH).1
Asam o-hidroksibenzoat atau asam salisilat adalah senyawa terpenting
golongan fenol. Nama ini berasal dari salikosida. Metilester asam salisilat, yang
145
Sintesis Aspirin
penting sebagai zat wangi-wangian terdapat dalam minyak eteris dari Gaultheria
procumbens ( Inggr. Oil of winter green).
Asam salisilat ditemukan oleh PIRIA (1838) dan dahulu dibuat dengan jalan
oksidasi saligenol, akan tetapi sekarang dibuat secara teknik menurut cara KOLBE
(1874) yang diubah oleh SCHMIDT. Dalam hal ini, karbondioksida direaksikan
dengan natriumfenolat pada 130⁰C dengan tekanan. Pada temperatur biasa dan
suatu tekanan kira-kira satu setengah atmosfer terjadi natriumfenilkarbonat karena
oleh asam-asam encer terurainya menjadi fenol, karbondioksida dan natrium klorida.
Natrium fenil karbonat ini dapat di pandang sebagai hasil antara pada pembentukan
natrium salisilat. Asam salisilat dapat dibuat pula dengan jalan oksidsi o-kresol
dengan kalium hidroksida dan timbal peroksida, dengan jalan mereaksikan asam
antranilat dengan asam nitrit atau dari asam o-chlor atau brombenzoat dilebur
dengan kalium.2
2.3 Reaksi Esterifikasi

Suatu ester dari asam karboksilat adalah suatu senyawa yang mengandung gugus –
CO2R dengan R dapat berbentuk alkil maupun aril. Ester merupakan salah satu
senyawa yang berguna. Pemanfaatan ester yang telah banyak digunakan adalah
ester atsiri yang memiliki aroma dalam berbagai buah dan parfum. Suatu ester dapat
dibentuk dengan reaksi langsung antara asam karboksilat dan alkohol. Esterifikasi
asam karboksilat dengan alkohol dengan katalis asam merupakan reaksi reversibel.
Laju esterifikasi asam karboksilat bergantung pada halangan sterik dalam alkohol
dan asam karboksilatnya. Kuat asam dari asam karboksilat hanya memainkan
peranan kecil dalam laju pembentukan ester.
Esterifikasi asam karboksilat berlangsung melalui serangkain tahap protonasi
dan deprotonasi. Oksigen karbonil diprotonasi, alkohol nukleofilik menyerang karbon
3
positif, dan eleminasi air akan menghasilkan ester.
Untuk memperoleh hasil yang optimum digunakan pereaksi berlebih yaitu
dengan memperbanyak jumlah mol dari alkohol. Dengan mol alkohol yang lebih
besar maka akan terjadi pergeseran kesetimbangan sehingga produk ester akan
lebih banyak. Ada tiga faktor yang mempengaruhi proses esterifikasi, yaitu jumlah
asam sulfat yang ditambahkan, lama waktu reaski, dan komposisi jumlah pereaksi
yang digunakan.4
146
Sintesis Aspirin
2.4 Reaksi Asetilasi Friedel-Craft
Reaksi Friedel-Craft pertama kali ditemukan oleh Charles Friedel dan James Mason
Craft pada tahun 1877. Reaksi Friedel-Craft merupakan reaksi yang terjadi pada
senyawa aromatis. Reaksi ini dibagi menjadi dua berdasarkan gugus elektrofil yang
akan tersubstitusi dalam senyawa aromatis yaitu reaksi alkilasi dan asilasi. Pada
reaksi alkilasi elektrofil dari karbokation dapat dibentuk dengan melepaskan suatu
ion halida dari sebuah alkil halida dengan katalis asam Lewis, contohnya aluminium
klorida (AlCl3) atau dengan menambahkan proton pada alkena. Mekanisme reaksi
asilasi juga sama seperti reaksi alkilasi. Elektrofilnya merupakan suatu kation asil
dari turunan asam, biasanya adalah asil halida.
Elektrofil yang reaktif merupakan suatu kation asil terstabilisai oleh resonansi
yang terbentuk dari reaksi antara asil kolrida dengan AlCl3. Kation asil dapat
distabilisasi dari interaksi antara orbital kosong dari karbon dengan pasangan
elektron bebas dari atom oksigen dekat dengan karbon. Karena stabilisasi ini, maka
5
tidak terjadi penata-ulangan karbokation pada reaksi asilasi.
2.5 Proses Pembuatan Aspirin

Aspirin dibuar dengan cara mereaksikan asam salisilat dengan anhidrida asam
asetat dengan menggunakan katalis H2SO4 pekat sebagai zat penghidrasi. Asam
salisilat adalah asam bifungsional yang mengandung dua gugus –OH dan –COOH.
Karena asam salisilat ini dapat mengalami dua jenis reaksi yang berbeda. Anhidrida
asam karboksilat dibentuk lewat kondensasi dua molekul asam karboksilat.
Pembuatan aspirin dapat dibagi menjadi dua, yaitu :
1. Sintesa Aspirin menurut Kolbe.
Pembuatan asam salisilat dilakukan dengan Sintesis Kolbe, metode ini ditemukan
oleh ahli kimia Jerman yang bernama Hermann Kolbe. Pada sintesis ini, sodium
phenoxide dipanaskan bersama CO2 pada tekanan tinggi, lalu ditambahkan asam
untuk menghasilkan asam salisilat. Asam salisilat yang dihasilkan kemudian di
reaksikan dengan asetat anhidrat dengan bantuan asam sulfat sehingga dihasilkan
asam asetilsalisilat dan asam asetat.
2. Sintesa aspirin setelah dimodifikasi sintesa Kolbe oleh Schmitt.
Larutan sodium phenoxide masuk kedalam revolving heated ball mill yang memiliki
tekanan vakum dan panas (130˚C). Sodium phnoxide berubah menjadi serbuk halus
yang kering, kemudian dikontakkan dengan CO2 pada tekanan 700 kPa dan
temperatur 100˚C sehingga membentuk sodium salicylate. Sodium salicylate
147
Sintesis Aspirin
dilarutkan keluar dari mill dan kemudian dihilangkan warnanya dengan
menggunakan karbon aktif. Kemudian ditambahkan asam sulfat untuk
mengendapkan asam salisilat, asam salisilat dimurnikan dengan sublimasi. Untuk
membentuk aspirin, asam salisilat direfluks bersama asetat anhidrat di dalam pelarut
toluene selama 20 jam. Campuran reaksi kemudian di dinginkan dalam tangki
pendingin aluminium, asam astilsalisilat mengendap sebagai kristal besar. Kristal
6
dipisahkan dengan cara filtrasi atau sentrifugasi, dibilas, dan kemudian dikeringkan.
2.6 Rekristalisasi
Rekristalisasi adalah teknik pemurnian suatu zat padat dari campuran atau
pengotornya dengan cara mengkristalkan kembali zat tersebut setelah dilarutkan
dalam pelarut yang sesuai. Prinsip rekristalisasi adalah perbedaan kelarutan antara
zat yang akan dimurnikan dengan zat pengotornya. Karena konsentrasi total
pengotor biasanya lebih kecil dari konsentrasi zat yang dimurnikan, dalam kondisi
dingin, konsentrasi pengotor yang rendah tetap dalam larutan, sementara zat yang
berkonsentrasi tinggi akan mengendap.
Kemudahan suatu endapan dapat disaring dan dicuci tergantung sebagian
besar pada struktur morfologi endapan, yaitu bentuk dan ukuran-ukuran kristalnya.
Semakin besar kristal-kristal yang terbentuk selama berlangsungnya pengendapan,
makin mudah endapan disaring dan mungkin makin cepat kristal-kristal akan keluar
dari larutan, yang akan membantu penyaringan. Pada dasarnya peristiwa
rekristalisasi berhubungan dengan reaski pengendapan.7
148
Sintesis Aspirin
3.1 Alat dan Bahan
No Alat Fungsinya
1 Labu alas bulat 100 mL untuk wadah larutan saat refluks
2 Gelas ukur untuk wadah mengukur volume larutan
3 Kondensor untuk alat pendinginan mengubah uap menjadi
cairan
4 Gelas piala untuk wadah larutan
5 Corong untuk alat membantu memindahkan larutan
6 Penangas air untuk wadah pemanasan
7 Bak air es untuk wadah mendinginkan larutan
3.1.2 Bahan dan Kegunaannnya

No Bahan Kegunaannya
1 Asam salisilat sebagai bahan dasar
2 Anhidrida asetat sebagai bahan dasar
3 Asam fosfat 85% sebagai katalis
4 Akuades sebagai pencuci kristal dan media rekristalisasi
produk
149
Sintesis Aspirin
3.2 Cara Kerja
1. Asam salisilat sebanyak 1,38 gram dan anhidridaasetat sebanyak 2,8 mL
dimasukkan kedalam labu didih 100 mL.
2. Sebanyak3 tetes asam fosfat 85% dimasukkan ke dalam campuran dan
diaduk dengan menggoyangkan labu.
3. Kondensor dipasang pada labu dan direfluks campuran selama 10 menit.
4. Tanpa melakukan pendinginan, ditambahkan 1 mL akuades melalui
kondensor kemudian dibiarkan campuran direfluks lagi selama 20 menit.
5. Air dingin sebanyak 25 mL ditambahkan kedalam campuran dan seterusnya
didinginkan pada suhu kamar sambil diaduk.
6. Labu ditempatkan ke dalam bak isi es selama 10 menit.
7. Kristal yang terbentuk disaring dan dicuci dengan akuades.
8. Kristal dikeringkan dan ditimbang.
9. Rendemen produk dihitung.
150
Sintesis Aspirin
3.3 Skema Kerja
Asam Salisilat Anhidrida Asetat

Asetat
- ditimbang sebanyak - dipipipet sebanyak 2,8 mL

1,38 gram
- dimasukkan ke dalam labu didih 100 mL

- ditambahkan 3 tetes asam fosfat 85%
- diaduk dengan menggoyangkan labu
Campuran
- direfluks selama 10 menit
- ditambahkan 1 mL akuades melalui
kondensor
- direfluks kembali selama 20 menit
- ditambahkan 25 mL akuades dingin
- didinginkan pada suhu kamar sambil diaduk
- ditempatkan labu dalam bak isi es selama 10
menit
Kristal
- disaring
- dicuci dengan akuades
- dikeringkan
- ditimbang
- dihitung rendemennya
Hasil
151
Sintesis Aspirin
3.4 Skema Alat
1
4
3
2
Keterangan :
1. Standar
2. Klem
3. Kondensor
4. Air keluar
5. Air masuk
6. Labu didih
7. Penangas
152
Sintesis Aspirin
4.1.1 Data
Massa asam salisilat = 1,38 gram
Mr asam salisilat = 138 gram/mol
Volum anhidrida asetat = 2,8 mL
Berat jenis anhidrida asetat = 1,08 gram/mL
Mr anhidrida asetat = 102 gram/mol
Massa kertas saring = 1,1863 gram
Massa aspirin + kertas saring = 2,3667 gram
Massa aspirin percobaan = 1,1804 gram
Mr aspirin = 180,157 gram/mol
4.1.2 Perhitungan
- Mol asam salisilat (C7H6O3)
massa
n=
Mr
1 mol
= 1,38 gram ×
138 gram
= 0,01 mol
- Massa anhidrida asetat (C4H6O3)
massa = V × ρ
1,08 gram
= 2,8 mL ×
1 mL
= 3,024 gram
- Mol anhidrida asetat (C4H6O3)
massa
n=
Mr
1 mol
= 3,024 gram ×
102 gram
= 0,03 mol
153
Sintesis Aspirin
C7H6O3 + C4H6O3 C9H8O4 + CH3COOH
Mula-mula 0,01 0,03

Bereaksi 0,01 0,01 0,01 0,01
Sisa - 0,02 0,01 0,01
- Massa aspirin teori (C9H8O4)

mol aspirin = 0,01 mol
massa aspirin teori = mol×Mr
180,157 gram
= 0,01 mol ×
1 mol
=1,80 gram
- Rendemen
massa percobaan
rendemen = ×100%
massa teori
1,1804 gram
= ×100%
1,80 gram
= 65,58 %
154
Sintesis Aspirin
Gambar 1. Spektrum Hasil Karakterisasi FT-IR
No. Bilangan Gelombang (cm-1) Gugus Fungsi

1 887,27 C-H
2 964,42 C-H
3 1207,46 C=O
4 1290,40 C=O
5 1382,98 C-O
6 1440,85 C-O
7 1608,66 C=C
8 1653,02 C=C
9 2591,41 O-H
10 3231,79 O-H
Tabel 1. Hasil Karakterisasi FT-IR
155
Sintesis Aspirin
4.3 Pembahasan
Praktikum kali ini, dilakukan sintesis aspirin yang bertujuan untuk mempelajari reaksi
sintesis suatu ester dari asam benzoat yang tersubtitusi gugus hidroksi dan untuk
mensintesis aspirin dari asam o-hidroksi benzoat dengan anhidrida asetat. Prinsip
kerja percobaan ini adalah refluks dan rekristalisasi. Refluks, yaitu pemanasan
berulang-ulang dengan kondensor yang dilakukan untuk menghomogenkan larutan
dan menyempurnakan reaksi yang terjadi. Rekristalisasi adalah pemurnian suatu zat
padat dari campuran atau pengotornya dengan cara mengkristalkan kembali zat
tersebut setelah dilarutkan dalam pelarut yang sesuai. Prinsip reaksi sintesis adalah
esterifikasi yaitu pembentukan senyawa ester dengan cara mereaksikan suatu
alkohol dengan asam karboksilat. Dalam percobaan ini digunakan asam salisilat
sebagai asam karboksilat, sedangkan anhidrida asetat sebagai alkohol. Pada
percobaan ini, digunakan asam fosfat sebagai katalis.
Langkah pertama, sebanyak 1,38 gram asam salisilat dan 2,8 ml anhidrida
asetat dimasukkan ke dalam labu didih kemudian ditambahkan tiga tetes asam fosfat
sebagai katalis untuk mempercepat reaksi. Asam fosfat digunakan sebagai katalis
karena asam fosfat memiliki atom hidrogen yang lebih banyak sehingga anhidrida
asetat lebih cepat terprotonasi. Reaksi yang terjadi pada pencampuran ini
merupakan reaksi eksoterm karena adanya panas yang dilepaskan ke lingkungan
ditandai dengan panasnya labu didih. Setelah itu, ditambahkan batu didih kedalam
labu didih tersebut. Tujuan dari penambahan batu didih pada percobaan ini adalah
untuk meratakan panas sehingga dapat mencegah terjadinya bumping.
Campuran kemudian direfluks selama 10 menit, pemanasan ini bertujuan
untuk mempercepat reaksi dan menghomogenkan campuran. Reaksi yang terjadi
pada pencampuran berjalan lambat sehingga diperlukan pemanasan. Pemanasan ini
akan meningkatkan suhu dalam sistem sehingga tumbukan antar molekul akan lebih
banyak dan cepat, sehingga dapat mempercepat laju reaksi. Setelah itu, tanpa
melakukan pendinginan ditambahkan 1 ml air melalui kondensor. Penambahan air ini
bertujuan untuk mengganti kehilangan air dan mempercepat pembentukan endapan.
Campuran kemudian dididihkan selama 20 menit. Sebanyak 25 ml akuades
dingin ditambahkan ke dalam campuran. Hal ini bertujuan untuk mempercepat
pengkristalan karena adanya perbedaan suhu yang signifikan akan menyebabkan
proses pengkristalan yang terjadi lebih cepat. Untuk mendapatkan kristal aspirin
yang lebih sempurna, maka labu didih ditempatkan di dalam ice bath selama kurang
lebih 10 menit. Kristal yang terbentuk disaring dan dicuci dengan akuades untuk
156
Sintesis Aspirin
menghilangkan pengotor-pengotor yang masih tersisa dan aspirin yang didapat
murni. Kristal dikumpulkan dan diletakkan pada kertas saring untuk dikeringkan.
Setelah kristal aspirin tersebut kering, dilakukan penimbangan untuk mengetahui
massa kristal.
Berdasarkan percobaan yang telah dilakukukan, massa kristal aspirin yang
diperoleh adalah sebesar1,1804 gram sedangkan secara teori massa aspirin adalah
sebesar 1,80 gram. Persen rendemen yang didapat adalah sebesar 65,58%. Nilai
rendemen yang didapat cukup baik namun masih terdapat beberapa kesalahan
diantaranya yaitu, kurang telitinya dalam menambahkan volume bahan yang
digunakan, katalis asam fosfat yang digunakan lebih dari 3 tetes. Selain itu, juga
dikarenakan kurang sempurnanya proses refluks, baik itu pada waktu ataupun pada
pemasangan alat yang masih terdapat celah udara sehingga reaksi yang terjadi tidak
sempurna dan tentunya akan berpengaruh terhadap massa aspirin dan rendemen
yang didapat pada percobaan.
Selanjutnya, kristal aspirin yang terbentuk pada percobaan dikarakterisasi
menggunakan FT-IR dimana hasil karakterisasi menunjukkan spektrum-spektrum
dari gugus fungsi yang terkandung dalam produk yang diperoleh. Berdasarkan data
karakterisasi dapat diketahui bahwa pada produk terdapat gugus fungsi alkana (C-H)
pada bilangan gelombang 887,27 cm-1; 964,42 cm-1. Pada daerah ikatan ganda yaitu
pada rentang bilangan gelombang (1600 cm-1 sampai 2000 cm-1) terdapat puncak
gelombang 1207,46 cm-1; 1290,40 cm-1; yang mengindikasikan adanya gugus
karbonil (C=O). Selain itu, puncak lain yang terdeteksi ialah pada bilangan
gelombang 1382,98 cm-1 dan 1440,85 cm-1 menandakan adanya gugus keton (C-O).
Pada bilangan gelombang 1608,66 cm-1 dan 1653,02 cm-1 terindikasi adanya gugus
alkena (C=C). Pada puncak gelombang 2591,41 cm-1 dan 3231 cm-1 terindikasi
adanya gugus hidroksi (O-H).
Berdasarkan data karaterisasi dapat disimpulkan sudah terbentuknya aspirin
ditandai dengan adanya gugus fungsi karbonil, keton, alkena, alkana dan hidroksi
yang merupakan gugus fungsi penyusun aspirin. Selain aspirin, didapatkan juga hasil
zat lain diantaranya asam salisilat, metil salisilat, asam fosfat dan senyawa lainnya.
Hal tersebut kemungkinan besar disebabkan oleh kontaminasi dari bahan dasar yaitu
asam salisilat, anhidrida asetat dan asam fosfat yang belum bereaksi sempurna
membentuk aspirin. Hal ini juga disebabkan karena pemanasan yang tidak sempurna
sehingga aspirin yang dihasilkan belum maksimal.
157
Sintesis Aspirin
5.1 Kesimpulan
Berdasarkan praktikum yang telah dilakukan, dapat disimpulkan bahwa:
1. Aspirin dapat disintesis dari asam salisilat dan anhidrida asetat dengan
bantuan katalis asam fosfat.
2. Prinsip kerja dari percobaan ini adalah refluks dan kristalisasi.
3. Prinsip reaksi sintesis adalah esterifikasi.
4. Kristal aspirin yang diperoleh adalah sebanyak 1,1804 gram.
5. Persen rendemen yang diperoleh adalah sebesar 65,58%.
5.2 Saran
Berdasarkan praktikum yang telah dilakukan, untuk praktikum selanjutnya
disarankan:
1. Pastikan tidak ada celah pada rangkaian alat refluks sehingga tidak ada uap
yang keluar.
2. Jangan terlalu banyak menambahkan katalis asam fosfat.
3. Usahakan tidak ada aspirin yang tertinggal dalam labu didih supaya tidak
mengurangi rendemen.
4. Hati-hati saat mencampurkan zat.
158
Sintesis Aspirin
Daftar pustaka
1 Priambodo, W. S.; Saleh, C.; Kimia, J.; Mulawarman, U. Pembuatan Metil

Salisilat Menggunakan Katalis Asam Dengan Metode Tanpa Pelarut. Atomik
2019, 04 (1), 41–44.
2 Holleman, W. j. Kimia Organik; J.B Wolters: Jakarta, 1961.
3 Putri, E. S. Y. Esterifikasi Asam P-Hidroksi Benzoat Dengan Universitas

Indonesia Esterifikasi Asam P-Hidroksi Benzoat Dengan. 2010, 13.
4 Dwipa, I. B. M. A.; Nurlita, F.; Tika, I. N. Optimasi Proses Esterifikasi Asam

Salisilat Dengan N-Oktanol. J. Wahana Mat. dan Sains 2014, 8 (1), 1–11.
5 Kimia, J.; Matematika, F.; Ilmu, D. A. N.; Alam, P.; Brawijaya, U. Sintesis Asam
5-Asetil-2-Hidroksibenzoat Dari Metil Salisilat Dalam Minyak Gandapura
Dengan Variasi Mol Anhidrida Asetat Serta Uji Aktivitas Antioksidan Oleh :
Risna Rasyida Ratri LEMBAR PENGESAHAN SKRIPSI Sintesis Asam 5-
Asetil-2-Hidroksibenzoat Dari Met. 2017.
6 Novianty, S. Pra Rancangan Pabrik Asam Asetilsalisilat (Aspirin) Dari Asam

Salisilat Dan Asetat Anhidrat Dengan Proses Sistesis Kalsium Oksida
Kapasitas. Skripsi, Progr. Stud. Tek. Kim. Fak. Teknol. Ind. Univ. Islam
Indones. Yogyakarta 2018.
7 Pinalia, A. Penentuan Metode Rekristalisasi Yang Tepat Untuk Meningkatkan

Kemurnian Kristal Amonium Perklorat (Ap). Maj. Sains dan Teknol. Dirgant.
2012, 6 (2), 64–70.
159
Sintesis Aspirin
Lampiran I Tugas Sebelum Praktikum
1. Tulislah mekanisme reaksi dari sintesis aspirin pada percobaan ini!

Jawab:
O O O OH O O H
H O O H
P
P O
O
CH3 O CH3 H O O CH3 O CH3
H
O
O
C OH
OH O
O O H
CH3
CH3 O CH3 O O CH3

O H
H O
H
O
O O H
OH O
P
O O
O
H3C CH3
O CH3 H
OH O H O O H
P
O
H O O
H3C CH3
O CH3
2. Apa fungsi penambahan asam fosfat?

Jawab:
Penambahan asam fosfat berfungsi sebagai katalis.
3. Apa fungsi penambahan air sebanyak 1 mL?

Jawab:
Penambahan 1 mL air berfungsi untuk untuk mengganti kehilangan air yang
terdapat dalam campuran dan mengendapkan aspirin yang terbentuk.
160
Sintesis Aspirin
Lampiran II Struktur Senyawa
No Senyawa Struktur
1. Asam Salisilat O
OH
OH
2. Anhidrida Asetat O O
O
3. Asam Fosfat O
HO P OH
OH
4. Akuades
O
H H
161
Sintesis Aspirin
Lampiran III Analisa Artikel Ilmiah
I. Judul
Free available chlorine initiated BaeyereVilliger oxidation: A key mechanism for
chloroform formation during aqueous chlorination of benzophenone UV filters.
Turunan baru dari asam asetil asetat salisilat dan karnosin : sintesis, sifat fisik dan
kimia, aktivitas biologi.
II. Tujuan
Untuk membuat dan menilai aktivtas biologis senyawa baru berbasis karnosin dan
asam asetil salisilat.
III. Skema Kerja
2 gram asam salisilat
- Dilakukan dalam 40 mL asetanilida
- Didinginginkan hingga mencapai suhu -5°C
- Dicampur dengan larutan karnosin
- Ditahan campuran reaksi selama 1 jam
- Dilarutkan residu dengan methanol
- Diendapkan produk yang dihasilkan
- Disaring endapan dan dikeringkan
- Diperoleh salisilat-karnosin berbentuk bubuk putih

- Dihitung rendemen
Hasil
IV. Hasil dan Pembahasan

Salisilat-karnosin (Sc) mempertahankan sifat farmakologi yang signifikan dari
asam asetil salisilat dan karnosin sambil mempertahankan aktivitas anti-virus
dan imun terhadap hidrolisis karnosin pada saat yang bersamaan.
162
Sintesis Aspirin
V. Hubungan dengan praktikum
Pada artikel menggunakan metode kondensasi sedangkan pada praktikum
menggunakan metode refluks dan distilasi.
163
Sintesis Aspirin
Environmental Pollution 268 (2021) 115737
Environmental Pollution
journal homepage: www.elsevier.com/locate/envpol
Free available chlorine initiated BaeyereVilliger oxidation: A key

mechanism for chloroform formation during aqueous chlorination of
benzophenone UV filters*
Xinyi Zhang a, b, Dongbin Wei a, b, *, Xuefeng Sun a, b, Chenzhong Bai a, b, Yuguo Du a, b
a
State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences,
Beijing, 100085, China
b
University of Chinese Academy of Sciences, Beijing, 100049, China
Article history: Chloroform, a regulated disinfection by-product in water, is often generated during chlorination disin-
Received 1 June 2020 fection treatment. However, the formation of chloroform is heavily dependent on the molecular struc-
Received in revised form tures of precursors. Moreover, compounds containing ketone moiety are ubiquitous in water
24 September 2020
environments. However, it is unclear if they can generate chloroform during chlorination. In this study,
Accepted 25 September 2020
Available online 28 September 2020
14 benzophenones (BPs), efficient and widely used UV filters, with different substituents were selected to
explore chloroform formation during chlorination. All 14 BPs generated chloroform, with yields
dependent on their molecular structures and operational conditions. Compounds 2,20 ,4,40 -tetrahydroxy-
Keywords:
Chloroform
BP and benzophenone produced the highest and lowest chloroform of 0.313 and 0.013 g/g, respectively,
BaeyereVilliger oxidation corresponding to the fastest and slowest formation rate constants of 1.41 101 and 2.71 102 min1.
Benzophenones Alkaline conditions and high chlorine dosages were favorable to chloroform formation. Three reactions
Formation mechanisms played key roles in chloroform formation from BPs: (1) chlorine initiated BaeyereVilliger oxidation
Kinetics converted ketone moieties of BP molecules into esters; (2) the esters further underwent hydrolysis and
formed phenolic and benzoic products; and (3) benzoic acids underwent decarboxylation and hydrolysis
to form phenolic products. Subsequently, these phenolic products could further generate chloroform in
the chlorination system. More importantly, BPs could generate chloroform in the ambient water matrices
during practical chlorination treatment. This work emphasized the critical role of BaeyereVilliger
oxidation for chloroform formation, implying that pollutants containing aromatic ketone moieties
generate chloroform during chlorination disinfection, and their potential risk should therefore be
reviewed.
© 2020 Elsevier Ltd. All rights reserved.
1. Introduction series of toxic disinfection byproducts (DBPs) (Alexandrou et al.,

2018). Trihalomethanes (THMs) were the first DBPs discovered in
Disinfection is a necessary process to guarantee the sanitary chlorinated drinking water in 1974 (Bellar et al., 1974; Rook, 1974)
safety of water. Chlorine is a commonly used disinfectant in water and were subsequently detected in various water matrices (such as
treatment processes as it can effectively kill pathogenic microor- swimming pool water and reclaimed water) (Du et al., 2017; Berg
ganisms (Sedlak and von Gunten, 2011; Sharma et al., 2017). et al., 2019). Considering potential threats to human health and
However, chlorine can also react with natural organic matter their ubiquitous occurrence in disinfected water, many countries
(NOM) or anthropogenic chemicals and unintentionally produce a and organizations regulate the permitted concentrations for THMs
in water quality standards.
To effectively control THMs, it is necessary to understand their
*
formation mechanisms. Boyce and Hornig (1983) clarified the
This paper has been recommended for acceptance by Charles Wong.
* Corresponding author. Research Center for Eco-Environmental Sciences, Chi-
conversion from 1,3-dihydroxyl aromatic precursors to chloroform
nese Academy of Sciences, No. 18 Shuangqing Road, Haidian District, Beijing, during chlorination through electrophilic substitution, addition,
100085, China. hydrolysis, decarboxylation, etc., and indicated that the carbon
E-mail address: weidb@rcees.ac.cn (D. Wei).
https://doi.org/10.1016/j.envpol.2020.115737
0269-7491/© 2020 Elsevier Ltd. All rights reserved.
X. Zhang, D. Wei, X. Sun et al. Environmental Pollution 268 (2021) 115737
atom between 2 hydroxyl groups on meta-positions was a primary 2.2. Chlorination procedure
reaction site. Sun et al. (2019) stated that haloacetonitriles could
generate THMs through continuous hydrolysis. Cao et al. (2019) Chlorination experiments were carried out in a 100-mL flask
explained that b-N-methylamino-l-alanine underwent chlorine under dark conditions. The reaction temperature was controlled at
substitution, decarboxylation, hydrolysis, rearrangement, and 30 C by water circulation from a thermostatic bath (Beijing
decomposition to finally form chloroform during chlorination Changfeng Instrument Co. Ltd., China). The initial concentration of
treatment. It can be concluded that chloroform can be generated each compound for chlorination was 80 mM. Considering the pH
from many kinds of compounds containing aromatic rings and ranges of the actual water samples (i.e. tap water, swimming pool
hydroxyl groups during chlorination. The ketone group is a com- water, wastewater), three different values (pH 6, 7, 8) were set.
mon and important moiety in organic compounds; however, it is Phosphate buffers were used to keep stable pH conditions; KH2PO4
unknown if pollutants containing ketone moieties can generate and Na2HPO4 were dissolved into ultrapure water and mixed at
chloroform during chlorination disinfection. different proportions to prepare desired pH buffer solutions. The
Benzophenones (BPs) are a class of widely used organic UV fil- initial dosages of FAC were set as 5, 10, and 15 molar equivalents for
ters, which have been frequently detected in surface water, each compound. Slightly excessive sodium sulfite (Na2SO3, 1.2
wastewater, sediments, and even human body fluid samples (He molar equivalent (equiv.) of sulfite to FAC) was spiked into the
et al., 2019; Liao and Kannan, 2019). The average concentrations chlorination systems to quench the reaction after 40 min. Chloro-
of 2-hydroxy-4-methoxy-5-sulfonic acid-BP (BP-4), 2-hydroxy-4- form was extracted with headspace-solid phase microextraction
methoxy-BP (BP-3), and 2,4-dihydroxy-BP (BP-1) were 38.2, 10.3, (HS-SPME) and then subjected to gas chromatography-mass spec-
and 4.70 ng/L, respectively, in the surface water of Shanghai (Wu trometer (GC-MS) analysis.
et al., 2017). The average concentration of BP-3 was 2086 ± 1027
and 153 ± 121 ng/L in the influent and effluent of a wastewater 2.3. Kinetics measurement
treatment plant (WWTP), respectively, in South Australia (Liu et al.,
2012). Although it has been proven that BPs could be transformed The kinetics experiments of chloroform formation were con-
into tens of by-products during chlorination disinfection treatment, ducted similarly. Two compounds, 10# (2,20 ,4,40 -tetrahydroxy-BP)
few studies have focused on THM formation. Duirk et al. (2013) and 1# (benzophenone) with the highest and lowest chloroform
measured the formation kinetics of chloroform during chlorina- production, respectively, were selected to compare the differences
tion of BP-3 and 2,20 -dihydroxy-4-methoxy-BP (BP-8). Yang et al. in formation rate constants. The selected compound (80 mM) was
(2018) explored the influence of pH and chlorine dosages on added into a buffer solution (pH 7) and FAC was spiked to initiate
chloroform formation during chlorination and chloramination the chlorination reaction. The FAC dosage was set as 5 molar equiv.
treatments of BP-3 and BP-4. However, the formation mechanisms for each compound. Chlorination reactions were quenched at 1, 3, 5,
of chloroform from BPs have not been investigated previously. The 10, and 40 min with excessive Na2SO3. The formed chloroform was
types of reactions involved in chloroform formation during chlo- extracted with SPME and analyzed with GC-MS.
rination and the influence of molecular structures of BPs on chlo-
roform production remain to be unknown. 2.4. HS-SPME extraction procedures
Therefore, in this study, 14 BPs were targeted to comprehen-
sively explore the formation characteristics of chloroform during An SPME device, including a holder and a replaceable fiber, was
chlorination. The formation mechanisms, influencing factors (pH purchased from Supelco (Bellefonte, PA, USA). Poly-
and chlorine dosage), and formation kinetics of chloroform were dimethylsiloxane fiber (100 mm) was conditioned prior to use by
discussed. Additionally, the formation characteristics of chloroform heating for 1 h at 280 C in a GC injection port. A chloroform so-
from BPs were evaluated in ambient water matrices. More impor- lution was prepared with the standard reference for optimizing
tantly, it was discovered that BaeyereVilliger oxidation initiated by parameters of extraction and detection. The flask containing the
free available chlorine (FAC) facilitated chloroform formation dur- chloroform solution was sealed with a Teflon stopper to avoid the
ing the chlorination of pollutants containing aromatic ketone volatilization loss of chloroform during the extraction period. The
moieties. SPME device was installed on a flask and the fiber was suspended at
1 cm above the solution. Based on the preliminary experiments, the
2. Materials and methods SPME operational conditions were optimized as follows: The
chloroform solution was maintained at 30 C and stirred at
2.1. Chemicals and reagents 100 rpm; extraction equilibrium was achieved within 5 min (SI
Fig. S1). The fiber was removed from the flask and immediately
Fourteen BPs (>97.5% purity) listed in Supporting Information inserted into the hot injector of the GC systems for chloroform
(SI) Table S1 and six model compounds, namely benzene, phenol, analysis. The extraction of the chloroform formed during chlori-
catechol, resorcinol, hydroquinone, and benzoic acid (>98% purity) nation was conducted in a similar manner.
were purchased from Sigma-Aldrich (Missouri, USA). Stock solu-
tions of BPs and model compounds were prepared in methanol at a 2.5. Analytical methods
concentration of 0.2 M separately and were kept at 4 C. A standard
reference of chloroform was acquired from Amresco (Solon, Ohio, Chloroform detection was performed with GC-MS (Agilent
USA). Methanol (HPLC grade) was obtained from Fisher Scientific 7890A/5975C, USA). Data were analyzed by Chemstation from
(Fair Lawn, NJ, USA). Analytical-grade salts for preparing buffer Agilent Technologies (MSD Chemstation E.02.00.493). Sample
solutions were obtained from Beijing Chemical Works. Sodium separation was performed with a DB-5 MS capillary column
hypochlorite (NaClO) was purchased from Wako Co. (Tokyo, Japan). (30 m 250 mm 0.25 mm, Agilent, USA). An electron ionization
The FAC concentration of the NaClO solution was standardized by source with an electron energy of 70 eV was adopted. Helium
an iodometric titration method (APHA, 2006). All chemicals were (99.999%) was used as carrier gas with a constant flow rate of
directly used without further purification. Ultrapure water gener- 0.6 mL/min. Samples were injected in splitless mode. The injector
ated from a Millipore Purification System (Massachusetts, USA) was temperature was 220 C and the auxiliary heating temperature was
used for all experiments. 250 C. The injector was equipped with Agilent Ultra Inert Inlet
2
Liners to accelerate chloroform volatilization. Ion source and According to chloroform production, BPs could be divided into 3
quadrupole temperatures were set as 230 C and 150 C, respec- clusters based on cluster analysis (SI Fig. S3). The first cluster only
tively. The oven temperature started at 40 C (kept for 1 min) and included compound 10# with the highest chloroform production of
increased at a rate of 10 C/min to 100 C (kept for 8 min). A mass 0.313 g/g. The second cluster included compounds 7# and 8# with a
spectrometer was used in selected ion monitoring mode and ions of chloroform production of approximately 0.237 g/g. The rest of the
m/z 118 and 83 were selected for chloroform quantification. BPs were part of the third cluster with the lowest chloroform
The chromatographic peak of chloroform (SI Fig. S2(a)) was well production ranging from 0.012 to 0.048 g/g.
separated and the measured mass spectrum and standard spec- Other than one BP, all of them contain hydroxyl groups. If judged
trum in the NIST Mass Spectral Library (2007) were consistent (SI by the number of hydroxyl groups in BP molecules, the compounds
Fig. S2(b)). To accurately quantify chloroform concentration, a with more hydroxyl groups produced more chloroform. One
standard curve was prepared by measuring a series of gradient exception was compound 9# with 3 hydroxyl groups, whose chlo-
solutions. Each sample was analyzed 6 times. The recovery for roform production was only 11.4% that of compound 7# with 2
chloroform was 97.4e104.6% and the limit of detection and limit of hydroxyl groups (Fig. 1(a)). Therefore, it was speculated that chlo-
quantitation were obtained at signal-noise ratios of 3 and 10, which roform production was also associated with the position of the
were calculated as 6.25 and 14.7 ng/L, respectively. All experiments hydroxyl group. Comparing chloroform production from com-
were conducted at least in duplicate and error bars in figures rep- pounds with the same number of hydroxyl groups at different
resented the relative standard deviation. positions, it was found that chloroform production from com-
pounds 5# and 6# was approximately 8.67% that of compound 7#,
3. Results and discussion indicating the effect of substitution positions. In addition, it was
observed that chloroform formation from compounds 7#, 11#, and
3.1. Chloroform formation during chlorination of 14 BPs 12# on the same substitution position with different substituents
was also different. Chloroform production from compound 7# was
As shown in Fig. 1(a), chloroform production was extremely 4.84 and 7.02 times higher than that of compounds 11# and 12#,
different for various BPs under the same chlorination conditions. respectively. Based on the above results, it can be concluded that
compounds containing meta-dihydroxyl groups on benzene rings
of BPs were beneficial to chloroform formation and that the hy-
droxyl group had a higher chloroform formation potential than
other groups on the same positions. These findings were consistent
with those of previous studies. Rook (1997) emphasized that the
substitution sites of hydroxyl groups determined chloroform pro-
duction. Gallard and von Gunten (2002a,b) showed that chloroform
yields were impacted by the types and positions of substituents.
To further confirm the effects of substituents on aromatic rings,
chloroform formation from six model compounds was investigated.
As shown in Fig. 1(b), the six model compounds exerted different
effects on chloroform production, which could be divided into two
clusters (SI Fig. S4). The first cluster only contained resorcinol with
the highest chloroform production of 0.627 g/g. The remaining five
compounds belonged to the second cluster whose production of
chloroform was 0.011e0.040 g/g.
3.2. Possible mechanisms of chloroform formation
Humic acid was first discovered as a precursor of chloroform

during the chlorination of natural water (Rook, 1976), among which
meta-dihydroxybenzene structures were responsible for chloro-
form formation (De Leer et al., 1985; Rook, 1997). Boyce and Hornig
(1983) specifically illustrated the transformation pathways from
meta-dihydroxybenzene to chloroform during chlorination. Elec-
trophilic substitution and the addition of chlorine led to the pro-
duction of chlorinated phenols and cyclohexenones as
intermediates. These intermediates were followed by a series of
hydrolysis and decarboxylation steps and finally generated chlo-
roform via carbonecarbon bond cleavage on the C2-site between 2
meta-positioned hydroxyl groups on the aromatic ring (SI Fig. S5).
Gallard and von Gunten (2002a,b) demonstrated that meta-
dihydroxybenzenes and monohydroxybenzenes were responsible
for fast and slow chloroform formation during the chlorination of
NOM, respectively. The formation rate of chloroform for meta-
dihydroxybenzenes was also greater than that for ortho- or para-
substituted counterparts (Gallard and von Gunten, 2002a,b). The
differences in chloroform formation can be explained by the
Fig. 1. Chloroform production during chlorination of (a) BPs and (b) model com-
different reactivity between compounds and FAC. Preferred sites for
pounds. ([BPs]0 ¼ 80 mM, [Model compounds]0 ¼ 80 mM, [FAC]0 ¼ 0.4 mM, pH ¼ 8, FAC substitution on the benzene ring depended on the combined
t ¼ 40 min). resonance and inductive effects of the substituents (Rebenne et al.,
3
1996). The activating effect of both hydroxyl groups on the ortho converting diphenyl ketone compounds to phenyl ester derivatives;
position could promote the reaction of meta-dihydroxybenzenes subsequent hydrolysis and decarboxylation caused the production
and FAC. Therefore, it could be concluded that phenolic com- of phenolic products, which were responsible for enhanced chlo-
pounds were primary precursors for chloroform formation, and roform formation. Therefore, the BaeyereVilliger reaction was the
meta-dihydroxybenzene was the optimal structure. However, as key mechanism for chloroform formation during the chlorination
BPs only have a diphenyl ketone skeleton, it was interesting to note of BPs and other aromatic compounds containing a ketone group.
that a large quantity of chloroform formed during the chlorination The effects of molecular structures on chloroform formation can
of BPs. be explained as follows. The 14 BPs first transformed into phenolic
During the chlorination of BPs, three types of chemical reactions products with different structures during chlorination, which
occurred and formed phenolic products (Scheme 1). The first re- directly affected chloroform production. For compounds 7#, 8#, and
action was BaeyereVilliger oxidation. More specifically, FAC con- 10#, the formed phenols kept the original moieties of meta-
verted ketone moieties of BPs to phenyl ester derivatives, as FAC dihydroxybenzenes. They underwent keto-enol tautomerisms and
displayed similar characteristics as peroxy acids in being both a ring cleavage, generating keto-carboxylic acids. The keto-carboxylic
weak acid and an oxidizing agent (Horton et al., 1969). The addition acids whose enol groups could be stabilized by carboxylate groups
of HOCl to the keto group to obtain esters was analogous to that were easily attacked by FAC (Rook, 1976; Larson and Rockwell,
accepted for peroxy acids in the BaeyereVillger reaction (Baeyer 1979), thus promoting chloroform formation. For compounds
and Villiger, 1899). Ester products were detected during the chlo- with only one or no hydroxyl groups on the aromatic ring, the
rination of BP-4, which confirmed the BaeyereVilliger oxidation formed phenols kept the structure of monohydroxybenzenes.
mechanism during the chlorination of BPs (Xiao et al., 2013). The Further ring cleavage occurred and only formed chlorinated ke-
second reaction was hydrolysis. The esters underwent nucleophilic tones, which showed a lower reactivity with FAC due to the lack of
hydrolysis and formed phenolic products and benzoic acid-like the stabilization of the carboxyl group (Gallard and von Gunten,
products. Hydrolysis reactions that formed ether products were 2002a,b), thus inhibiting chloroform formation.
observed during the chlorination of BP-4 and 4-
hydroxybenzophenone (Xiao et al., 2013; Liu et al., 2016). Jencks 3.3. Effects of chlorination conditions on chloroform formation
and Carriuolo (1960) proposed that the hydrolysis of esters could
easily occur in the presence of strong nucleophilic agents with the Besides the molecular structures of compounds, the operational
formation of phenolic products. The third reaction was decarbox- parameters of chlorination affect chloroform formation by influ-
ylation. Benzoic acid-like compounds underwent decarboxylation, encing the speciation of reactants, reaction types, and reaction
chlorine substitution, and further hydrolysis with regenerating extent. Compounds 1# and 10# with the lowest and highest chlo-
phenolic products. Similarly, Zhang et al. (2016) detected 2,4,6- roform production, respectively, were selected as targets to discuss
trichloro-3-methoxyphenol during the chlorination of BP-3. Li the influences of pH and chlorine dosages on chloroform formation.
et al. (2016) also found that 2,6-dichloro-3-methoxyphenol As shown in Figs. 2(a) and 3(a), for compounds 1# and 10#,
formed during the chlorination of 2,20 -dihydroxy-4,40 -dimethox- chloroform production under alkaline conditions were 3.17 and
ybenzophenone (BP-6). Larson and Rockwell (1979) found that 2.00 times higher, respectively, than that under acidic condition.
substituted benzoic acids could undergo decarboxylation and form Contrarily, the chloroform production for both compounds under
chlorophenols during chlorination. It is worth noting that the third neutral and alkaline conditions was similar. These results can be
reaction promoted the continuous formation of phenolic products. explained by the presence of different species of BPs at various pH
The increasing amount of phenolic products was conducive to values. BPs underwent deprotonation under neutral and alkaline
enhancing chloroform production. Among the three types of re- conditions, and the deprotonated phenolates of BPs had a higher
actions, FAC first initiated the BaeyereVilliger reaction by reactivity with FAC than molecular forms of BPs. Phenolate species
Scheme 1. Reaction pathways for conversion of compound 10# to chloroform.
4
Fig. 3. The chloroform production of compound 10# at different conditions. ((a):

Fig. 2. The chloroform production of compound 1# at different conditions. ((a):
[compound 10#]0 ¼ 80 mM, [FAC]0 ¼ 0.4 mM, t ¼ 40 min; (b): [compound
[compound 1#]0 ¼ 80 mM, [FAC]0 ¼ 0.4 mM, t ¼ 40 min; (b): [compound 1#]0 ¼ 80 mM,
10#]0 ¼ 80 mM, pH ¼ 8, t ¼ 40 min).
pH ¼ 8, t ¼ 40 min).
the reaction. Li et al. found that increasing the FAC dosage was
showed higher reactivity toward electrophilic oxidation/substitu-
beneficial to chloroform formation by promoting ring-opening and
tion (Rebenne et al., 1996). In addition, the decarboxylation of in-
substitution reactions (Hong et al., 2009; Li et al., 2019). These re-
termediate keto-carboxylic acids could easily occur under neutral
sults indicate that the FAC dosage is an important operational
and alkaline conditions, which is an important reaction for chlo-
parameter for controlling chloroform formation in disinfection
roform formation from dihydroxyl aromatic precursors (Boyce and
processes.
Hornig, 1983). Both reasons accounted for the higher chloroform
production under neutral and alkaline conditions. A similar pH
dependency was also reported in previous reports (Gallard and von 3.4. Formation kinetics of chloroform
Gunten, 2002a,b; Liang and Singer, 2003; Hansen et al., 2012; Yang
et al., 2018; Hu et al., 2019). As the formation of chloroform is greatly influenced by the
As shown in Fig. 2(b), an interesting observation was that the molecular structures of BPs and chlorination conditions, taking
chloroform production (around 0.013 g/g) of compound 1# showed compounds 10# and 1# with the highest and lowest chloroform
no obvious changes with the increase in FAC dosage. In other words, production as examples, the formation kinetics of chloroform were
chloroform production from compound 1# was the maximum at 5 studied.
molar equiv. of FAC, because the lower reactivity between the in- As depicted in Fig. 4, chloroform formation could be described
termediate ketone and FAC restricted the progress of the reaction. by first-order kinetics during chlorination. The rate constants of
However, increasing the FAC dosage significantly promoted the chloroform formation from compounds 10# and 1# had significant
chloroform production from compound 10# (Fig. 3(b)). Chloroform differences, and were determined to be 1.41 101 and 2.71 102
production at 5 molar equiv. of FAC was less than half of that at 10 min1, respectively. The rate constants in the present study were
molar equiv. and increased to 0.899 g/g at 15 molar equiv. as in- comparable to values reported in previous literature. For example,
termediate keto-carboxylic acid demonstrated higher reactivity the rate constant of chloroform formation during the chlorination
towards FAC and increasing the FAC dosage continuously promoted of raw river water was 1.1 102 min1 at pH 8 with 5 mg/L of FAC
5
Fig. 4. The kinetics of chloroform formation from compounds 1# and 10#.

([BPs]0 ¼ 80 mM, [FAC]0 ¼ 0.4 mM, pH ¼ 7).
(El-Dib and Ali, 1995). The rate constants of chloroform formation

from phenols were 1.00 102 min1 at pH 8 with 0.15 mM of
NaClO (Arnold et al., 2008), and 1.08 102 min1 at pH 7 with
0.5 mM of NaClO (Breide and Hunkeler, 2014). Additionally, Gallard
and von Gunten (2002a,b) observed that resorcinol and phenol
were the fastest and slowest chloroform precursors during chlori-
nation, respectively, proposing that the chlorination of ketones was
the rate-determining step for chloroform formation. In summary,
the kinetics results corroborated that chloroform production is
heavily dependent on the molecular structure of BPs during
chlorination.
3.5. Environmental significance
The above experiments were conducted in an ultrapure water

environment and it was necessary to ascertain whether chloroform Fig. 5. The chloroform formation of compounds 1# and 10# in different water samples
at (a)5-equiv., (b)10- equiv. of FAC. ([BPs]0 ¼ 80 mM, t ¼ 40 min).
could be continuously produced in real water matrices. Two
ambient water samples, tap water and an effluent of a secondary
treatment plant, were collected in Beijing, China. Their water
equiv., chloroform production was ranked as effluent > ultrapure
quality parameters are listed in SI Table S2. Compounds 1# and 10#
water z tap water. As shown in Fig. 5(b), the chloroform produc-
were spiked into the water samples, and no compounds were
tion of compound 1# in ultrapure water and tap water was 0.013
spiked in blank control.
and 0.019 g/g, respectively, while it was 0.028 g/g in the effluent
Fig. 5 showed chloroform production in different water matrices
matrix. Similarly, with the increasing of the FAC dosage to 10-equiv.,
at different FAC dosages. The patterns of chloroform production
the chloroform production of compound 10# increased from
were similar for the water matrices with increasing FAC dosage. For
0.414 g/g in ultrapure water and 0.437 g/g in tap water to 0.549 g/g
the blank control group, chloroform production increased by 0%,
in the effluent matrix. This was attributed to the different contents
62.6%, and 176% in ultrapure water, tap water, and effluent,
of organic matter in the 3 water matrices. As organic matter in the
respectively, when the FAC dosage increased from 5 molar equiv. to
effluent was abundant, it could consume FAC and form in-
10 molar equiv. It is suggested that organic matter in water matrices
termediates. When the FAC was at 5 molar equiv., there was not
contributed to chloroform formation. When compounds 1# or 10#
enough FAC to react with BPs, so chloroform formation was
were spiked in water matrices, chloroform production increased in
restricted. When the FAC dosage increased to 10 molar equiv., there
each water sample with the increasing FAC dosage.
was sufficient FAC to react with BPs, so chloroform formation
It was also found that the extent of increase in chloroform
increased.
production differed among the 3 water matrices by increasing the
In summary, chloroform can be produced during the chlorina-
FAC dosage. At 5 molar equiv. of FAC, chloroform production was
tion of BPs in real water matrices. It was reported that BP concen-
ranked as ultrapure water z tap water > effluent. As shown in
trations in WWTP influents ranged from ng/L to mg/L levels (Kim
Fig. 5(a), the chloroform production of compound 1# in ultrapure
and Choi, 2014). To evaluate the potential risks of chloroform for-
water and tap water was 0.013 and 0.012 g/g, respectively, and was
mation during chlorine disinfection, the corresponding chloroform
0.009 g/g in the effluent matrix. The chloroform production of
production could be estimated by adopting chloroform yields from
compound 10# displayed a similar trend, which decreased from
compounds 1# (1.94%) and 10# (64.6%) obtained in the present
0.234 g/g in ultrapure water and 0.244 g/g in tap water to 0.189 g/g
study. The calculated chloroform concentration was in the range of
in the effluent matrix. When the FAC dosage increased to 10 molar
6
several ng/L to several mg/L. Although the formed concentration functional groups responsible for chloroform formation during water chlori-
was lower than the recommended value 70 mg/L for chloroform in nation using compound specific isotope analysis. Environ. Sci. Technol. 42,
7778e7785. https://doi.org/10.1021/es800399a.
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and obvious toxicity effects of chloroform, it is necessary to control Dtsch. Chem. Ges. 32, 3625e3633 (in Ger.).
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Berg, A.P., Fang, T.A., Tang, H.L., 2019. Unlocked disinfection by-product formation
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4. Conclusions
Front. Environ. Sci. Eng. 13, 10. https://doi.org/10.1007/s11783-019-1098-3.
Boyce, S.D., Hornig, J.F., 1983. Reaction pathways of trihalomethane formation from
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constants of compounds 10# and 1# were 1.41 101 and Du, Y., Lv, X.T., Wu, Q.Y., Zhang, D.Y., Zhou, Y.T., Peng, L., Hu, H.Y., 2017. Formation
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j.jes.2017.01.013.
and decarboxylation. Moreover, alkaline conditions and high FAC Duirk, S.E., Bridenstine, D.R., Leslie, D.C., 2013. Reaction of benzophenone UV filters
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10.1016/S0043-1354(01)00187-7.
cated that BP-type UV filters and other aromatic compounds con- Gallard, H., von Gunten, U., 2002b. Chlorination of phenols: kinetics and formation
taining ketone groups could be readily converted into chloroform of chloroform. Environ. Sci. Technol. 36, 884e890. https://doi.org/10.1021/
during chlorination disinfection at various pH values and FAC es010076a.
Hansen, K.M.S., Willach, S., Antoniou, M.G., Mosbaek, H., Albrechtsen, H.-J.,
dosages, the potential risks of which should raise great concern. Andersen, H.R., 2012. Effect of pH on the formation of disinfection byproducts
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He, K., Hain, E., Timm, A., Tarnowski, M., Blaney, L., 2019. Occurrence of antibiotics,
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Chenzhong Bai: Methodology, Investigation. Yuguo Du: Resources, Contam. Toxicol. 56, 638e645. https://doi.org/10.1007/s00244-008-9216-4.
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Declaration of competing interest jo01263a033.
Hu, S.Y., Gong, T.T., Wang, J.J., Xian, Q.M., 2019. Trihalomethane yields from twelve
aromatic halogenated disinfection byproducts during chlor(am)ination. Che-
The authors declare that they have no known competing mosphere 228, 668e675. https://doi.org/10.1016/j.chemosphere.2019.04.167.
financial interests or personal relationships that could have Jencks, W.P., Carriuolo, J., 1960. Reactivity of nucleophilic reagents toward esters.
appeared to influence the work reported in this paper. J. Am. Chem. Soc. 82, 1778e1786. https://doi.org/10.1021/ja01492a058.
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Praktikum Kimia Organik II

Tahun Akademik 2020/2021

PRAKTIKUM KIMIA ORGANIK II

TAHUN AJARAN 2020/2021

JAM : 13.30 - 16.00

KOORDINATOR HARIAN : ANNISA RAHMI Z.J, S.Si

KOODINATOR UMUM : RAHMI VIKA ULIA, S.Si

FAKULTAS MATEMATIKA DAN ILMU PENGETAHUAN ALAM

Koordinator Harian Koordinator Umum

Annisa Rahmi Z.J, S.Si Rahmi Vika Ulia, S.Si

Dosen Pengampu Praktikum

Emil Salim, M.Sc.,M.Si

Objek I Objek II Objek III

Objek IV Objek V Objek VI

Martania Anggriany, S.Si Rifki Rinaldi, S.Si Rifki Rinaldi, S.Si

Bundelan Praktikum Kimia Organik II disusun dengan maksud untuk

Padang,28 Mei 2021

HALAMAN PENGESAHAN ................................................................................. i

HALAMAN PERSETUJUAN .............................................................................. ii

KATA PENGANTAR ........................................................................................... iii

DAFTAR ISI ......................................................................................................... iv

OBJEK I : SINTESIS ETIL ASETAT .................................................................. 1

OBJEK II : SINTESIS METIL SALISILAT ........................................................... 25

OBJEK III : ASETON ........................................................................................... 55

OBJEK V : SINTESIS ASETANILIDA ................................................................. 116

OBJEK VI : SINTESIS ASPIRIN.......................................................................... 144

ANNISA RAHMI Z.J, S.Si

SINTESIS ETIL ASETAT

3.1.2 Bahan dan Fungsi

- dimasukkan ke dalam labu distilasi

- direfluks selama 90 menit

- ditambahkan 2 gram natrium karbonat

- dicuci dengan 15 mL air dingin

b) Volume asam asetat

c) Volume asam sulfat

e) Mol asam asetat

Mol asam asetat = 30 g × 160molg = 0,5 mol

f) Mol asam sulfat

h) Massa etil asetat praktikum

Gambar 1. Spektrum FTIR Etil Asetat (CH3COOC2H5)

No. Bilangan Gelombang Gugus Fungsi

H3C C O H + H O S O H + H3C CH2 O H

H3C C O H + O S O H + H3C CH2 O H

H3C C O CH2 CH3 + H O H + H O S O H

No. Nama Senyawa Struktur Senyawa

2. Etil alkohol (Etanol) H

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Research Article OpenAccess

Kinetics and Mechanism of Ethyl Acetate Production Using Eco-Benign

J Phys Chem Biophys

C NaOH ×VNaOH 0.4

However, the percentage conversion of acetic acid was equally -0.2

k2 0.87 1.16 0.003 333.33

(AS) (B) k-2 (EH) (W) 0.75 1.34 0.0015 666.67

J Phys Chem Biophys

acid:alcohole mole ratio K1ρCA CC

1.5 For a plot of 1/Ro against concentration of acid at fixed alcohol

J Phys Chem Biophys

J Phys Chem Biophys

ANNISA RAHMI Z.J, S.Si

Sintesis Metil Salisilat 26

2.3 Metil Salisilat

Senyawa metil salisilat merupakan turunan dari ester asam salisilat.

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%? (3 *)" H %)

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