Tetrahedron 70 (2014) 137e167

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Laporan Tetrahedron nomor 1023

Kemajuan terbaru dalam pengenalan molekul dalam air: artifireseptor

cial dan katalisis supramolekul
Evgeny A. Kataev *, Christoph Muller€
Institut Kimia, Fakultas Ilmu Pengetahuan Alam, Technische Universitat€ Chemnitz, 09107 Chemnitz, Jerman

articl ei nfo

Sejarah artikel:
Diterima 21 Agustus 2013
Diterima dalam bentuk revisi 11 Oktober 2013
Diterima 4 November 2013
Tersedia online 19 November 2013

Kata kunci:
Pengenalan molekul
air
Artifireseptor cial
Tuan rumahekimia tamu
Kimia supramolekul
Katalis supramolekul

Isi
1. Pengantar . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .............................................. 137

2. Reseptor untuk amina dan ion amonium. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... ........................................... 138

3. Reseptor untuk asam amino dan peptida. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. ............................................ 141
4. Reseptor untuk anion anorganik dan pasangan ion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .... .......................................... 146
4.1. Reseptor netral. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .............................................. 146
4.2. Reseptor yang dibebankan. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .............................................. 148
.
4.3. Reseptor untuk pasangan ion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .............................................. 153
5. Reseptor untuk molekul organik kecil. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .............................................. 154
6. Efek termodinamika. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .............................................. 158
7. Katalis supramolekul dalam air. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .............................................. 159
8. Kesimpulan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .............................................. 165
Ucapan Terima Kasih. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .............................................. 165
Referensi dan catatan. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .............................................. 165
Sketsa biografi. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .............................................. 167

dekade karena pemahaman yang lebih baik bagaimana interaksi non-kovalen

1. Perkenalan bekerja, seberapa kuat interaksi ini dan bagaimana mengaturnya di ruang
untuk mencapaifikesesuaian dan selektivitas untuk spesies sasaran. Jika kita
Pengenalan molekul oleh artifireseptor kial kini telah meluas ke sebagian membandingkan ef yang mengikatfiEfisiensi reseptor sintetis yang ada
besar kimia supramolekul. Sejumlah target untuk mengikat selektif telah dengan reseptor alami, yang alami masih jauh di depan. Namun, protein
meningkat secara dramatis baru-baru ini alamieInteraksi ligan masih penuh dengan misteri. Jadi, kami memiliki
masalah dengan banyak parameter dari'bawah' dan 'teratas'sisi dan tidak
masalah jika kita mendesain host untuk tamu, atau tamu untuk tuan rumah.
* Penulis yang sesuai. Alamat email:evgeny.kataev@chemie.tu-chemnitz.de (EA Kataev).
Kita tidak boleh lupa bahwa molekul
138 EA Kataev, C. Muller€ /
Tetrahedron 70 (2014) 137e167
0040-4020 / $e lihat materi depan 2013 Elsevier Ltd. Semua hak dilindungi undang-
undang. http://dx.doi.org/10.1016/j.tet.2013.11.010
pengakuan dalam sistem alami melibatkan tidak hanya dua pemaind 'tuan
rumah' dan 'tamu'dbukan tiga 'tuan rumah', 'tamu', dan 'air'. Whitesides pada
tahun 2005 menulis dalam ulasannya tentang masalah de-penandatanganan Stabilitas kompleks yang terbentuk tinggi dan kurang dari 1 equiv N-
ligan untuk mengikat erat protein:“orang mungkin harus menyederhanakan metilpirolidin yang digunakan dalam reaksi dengan inang masih mengarah
pertanyaan, dan bertanya - Apa perbedaannya?fipemujaan - jawaban pada pembentukan kompleks homodimer yang terprotonasi (1 $Tamu).
1
singkatnya adalah - air”. Seperti yang akan kita lihat di bawah dalam ulasan Kompleks heterodimer juga dibentuk dan dideteksi dengan teknik analitik
ini, air memainkan hampir peran utama dalam menentukan energi dari proses standar. Kompleksasi campuran N-metilpirolidin dan N-isopropilaziridin
pengikatan. Namun, berbicara tentang kontribusi energetik dari berbagai dengan inang mengarah ke kompleks dengan dua molekul berbeda di dalam
parameter host, tamu, dan air kita dapat sampai pada kesimpulan bahwa'itu 1
rongga inang, seperti yang terungkap dari Spektrum H NMR. Asal usul
adalah masalah yang memiliki perasaan menampar nyamuk: bunuh satu, dan
1 selektivitas yang menarik ini tidak jelas dan tampaknya, lebih banyak data
masih banyak yang tampaknya tidak ada bedanya'. Oleh karena itu, untuk
harus dikumpulkan untuk memahami aturan selektivitas untuk host ini.
memahami pengakuan molekuler dalam air, the 'dari bawah ke
Perhitungan kimia kuantum dilakukan untuk menilai kontribusi energik dari
atas'pendekatannya terlihat agak layak. Dalam ulasan ini, kami fokus pada
artifireseptor yang spesifikfidirancang secara khusus atau dipelajari untuk ikatan. Perhitungan ini meramalkan bahwa pembentukan homodimer amina
mengikat tamu dalam solusi air. Pada bagian terakhir dari peninjauan kami terikat-proton sangat menguntungkan secara entalikal, bila dibandingkan
membahas reseptor yang tidak hanya dapat mengikat dalam air tetapi juga dengan aduk pelarut amina terprotonasi.
untuk melakukan sintesis supramolekul atau kalkalisis. Literatur yang
dikumpulkan diterbitkan antara 2008 dan 2013. Untuk pekerjaan sebelumnya
kami merujuk pembaca kefiulasan pertama 'Kimia Su-pramolekul dalam Air',
2
diterbitkan pada 2007 oleh Oshovsky, Reinhoudt, dan Verboom. Literatur
yang disajikan di sini disusun berdasarkan jenis tamu, untuk mana artifituan HAI
rumah yang dirancang. Dibawah'artifituan rumah' atau 'reseptor', kami Ga3+
memahami molekul yang mengikat tamu melalui interaksi non-kovalen dan H HAI
biasanya menyediakan koordinasi multivalen, yaitu kombinasi dari beberapa AI NH
interaksi non-kovalen. Kami juga menyertakan contoh, di mana selain logam
N
interaksi non-kovalenekoordinasi tamu hadir. Transportasi molekuler dengan
artifituan rumah tidak termasuk karena topik ini baru-baru ini ditinjau oleh
3 3+
Gale. Beberapa publikasi yang menyentuh pengakuan dalam media berair HH Ga
4,5 6 HN H N
telah muncul baru-baru ini; mereka termasuk pengakuan fosfat, amina, HAI HAI
7 8 9 11,5 12 14
katekolamin, pasangan ion, gula, e mengikat anion umum, e Ga3+
15,16 HAI
pengakuan oleh cucurbiturils, pengakuan oleh molekul wadah yang larut 3+
17,18 19 Ga
dalam air, dan mekanisme pengikatan dalam kimia supramolekul.
1 Tamu

2. Reseptor untuk amina dan ion amonium
Pengakuan ion amonium menarik perhatian yang cukup besar dalam kimia
supramolekul karena sejumlah amina mengambilfifungsi c dalam sistem
kehidupan. Rentang target untuk pengikatan dan penginderaan selektif dengan
artifireseptor tetap tetap selama 10 tahun terakhir pada dasarnya sama.
Kelompok yang diminati adalah ace-tylcholine dan turunannya, amina alifatik
terprotonasi, peptida kaya amina, amina biogenik, yaitu produk dekarboksilasi
6 sinyal tamu bergeser
asam amino. Sp€ath dan Konig€ menerbitkan tinjauan ulang komprehensif
tentang pengakuan amina dan ion amonium dan kami merujuk pembaca ke
artikel ini untuk informasi lebih lanjut. Perhatian khusus kami difokuskan
pada reseptor yang mengikat ion amonium dalam larutan berair. Pengakuan
ion amonium dalam pengertian klasik biasanya dikaitkan dengan kompleks
logam transisi amonium-mahkota eter atau amina. Kompleks ini adalah suffi-
sangat kuat dalam air tetapi sering kurang selektivitas antara anggota baku
amina yang diinginkan. Dari literatur terbaru, pergeseran ke kapsul molekul
sebagai reseptor untuk ion amonium terlihat jelas. Reseptor-reseptor tersebut
memberikan tambahan interaksi hidrofobik dengan residu alkil amina dan
memiliki konstanta pengikatan yang tinggi dalam air karena melindungi tamu
dari lingkungan kutub.
Ribka dan rekan kerja mengambil strategi lain untuk mengakses ikatan
dalam air, yaitu mereka telah memfungsikan cavitand dengan kelompok
21
karboksilat. Cavitand tiga dinding2 dan 3 ikat tamu yang lebih besar dari
22
analog empat dinding yang dijelaskan sebelumnya. Reseptor baru mengikat
amina alifatik dan aromatik yang besar dalam kloroform jenuh dengan D 2O.
Namun, cavitand yang larut dalam air 3hanya mengikat 1-adamantanol.
Hanya tamu ini yang benarfill kavitas hidrofobik inang dan menstabilkan
konformasi terlipat dalam air, yang dibentuk oleh ikatan hidrogen
1
intramolekul. Seperti yang disimpulkan dari Dengan pengukuran NMR,
ke atasfiSelain enkapsulasi, agregat host rusak, dan
sinyal menjadi lebih tajam. Sebagai strategi alternatif untuk memberikan
kelarutan dalam air pada rentang pH yang luas, disarankan untuk
23
memfungsikan cavitand dengan kelompok PEG (4). Cavitand yang
dilaporkan sebelumnya larut dalam larutan organik ditunjukkan untuk
mengikat berbagai kation ammo-nium dalam kloroform jenuh dengan air.
Cavitand baru4 larut dalam kisaran milimolar pada D2O di pD 1e12.
Spektrum NMR dari inang agak luas, tetapi menjadi tajam setelah
penambahan 2-adamantane amina atau tamu lain. Sinyal tamu muncul di
kejauhanfiwilayah tua karena anisotropi besar yang diberikan oleh delapan
cincin aromatik. Konstanta pengikat untuk amina yang diselidiki berada di
2 1
kisaran 10e10 M. , seperti yang disimpulkan dari spektrum NMR.
Menariknya, tuan rumah tidak mengikat rantai panjang amina alifatik kecuali
dodecylsulfate. Data termodinamik dari pengikatan 2-aminoadamantane
1 1
menunjukkan pengikatan secara fa-vaskular yang entropis: DS¼55 mol K ,

Sebuah contoh yang bagus dari sangkar molekuler yang mengikat ion DH¼20 kJ mol 1. Fakta ini dijelaskan dalam hal pelepasan pelarut pada
amonium dalam air disediakan oleh Bergman dan Raymond, yang proses enkapsulasi. Para penulis juga mendalilkan bahwa penalti enthalpik
menyelidiki sifat-sifat inang yang dapat larut dalam air yang dirakit sendiri. pada peristiwa pengikatan berasal dari pemisahan pasangan ion yang lebih
20 besar dari kompleks tamu. Sang penyelenggaraestruktur tamu agak kaku
1. Tuan rumah ini dapat merangkum homodimer yang terikat proton dari N- karena kinetik distabilkan melalui ikatan-H intramolekul yang ada dalam
alkylaziridine, azetidine, pyrrolidine, dan piperidine. Proses en-capsulation struktur host. Dengan bantuan eksperimen EXSY, dimungkinkan untuk
1 1
dari dimer terprotonasi ditemukan setelah analisis H NMR spektrum inang memperoleh penghalang 17,6 kkal mol untuk proses disosiasi tamu dari
dengan N-metilpirolidin. rongga tuan rumah.
EA Kataev, C. Muller€ /
Tetrahedron 70 (2014)
137e167
NNH HN N
H HAI
R'OOC COOR
HAI
COOR H OH
H
HAI H N NH AI
H
 H OOOH [4] resorsinarena difungsikan dengan L.-proline (7), L.-pipeco-linic acid (8),
AI
HAI dan asam lainnya. Yang menarik, reseptor ini mengikat sejumlah tamu
R R R
aromatik yang berbeda termasuk amina, asam, dan asam amino. Menurut
R pengukuran NMR, reseptor dapat mengadopsi konformasi konus dalam air
atau mereka berada dalam pertukaran cepat antara konformasi yang saling
2 R = C11H23, R '= Et bertentangan dan konfigurations. Host sintetik mengikat senyawa aromatik
3 R = Et, R '= Na yang larut dalam air seperti cincin naftil tersubstitusi 2,3 dan 1,8, cincin fenil
yang disubstitusi mono atau orto. Misalnya, konstanta asosiasi reseptor
HAI HN HAI
HAI HN berbasis proline7 dengan triptofan dan asam naftalena-2,3-dikarboksilat
H 1
N
N adalah 127 dan 169 M masing-masing. Setelah mengikat substrat kiral,
HAI HAI
H 1
HAI diskriminasi kiral diamati di Spektrum H NMR. Reseptor mengandungL.-
HAI HAI
R R
picolinic acid (8) menunjukkan diskriminasi enansiomer superior dari 24
substrat yang diperiksa. Diusulkan bahwa pembentukan tuan
R rumahekompleks tamu melibatkan enkapsulasi bagian aromatik dalam rongga
R
HAI
HAI reseptor dan gugus fungsional (amina dan asam) berinteraksi dengan
HAI
H pinggiran kerucut.
HAI HAI
N
N
H N
NH HAI HO
HAI
R R R R
HAI OH HO
R= HAI
OH HO OH
HO HO OH
4
H H H H
4

Dua reseptor cyclophane 5 dan 6 untuk relevan secara biologis + - + -

24 Na Na HAI3S +
amina dilaporkan oleh Velazquez. Cyclophanes ini mengandung empat BEGITU3 -Na
HAI3S BEGITU -Na+
gugus karboksilat dan dengan demikian, membuat molekul bermuatan negatif 3
dalam rentang pH yang luas. Ikatan amina berikut diselidiki: histamin, R= N COOH N COOH
tryptamine, tyramine, phenethyl-amine, imidazole, histidine, phenylalanine,
dan asam 4-aminobenzoic. Konstanta pengikat ditentukan dengan
1
menggunakan Misi NMR dalam D2O pada pD 9. Kondisi titrasi ini dipilih
karena molekul inang dan bintang hadir pada pD 9 terutama sebagai spesies
4
tunggal: inang hadir sebagai M dan amina terprotonasi hadir sebagai
þ 7 8
M masing-masing. Data eksperimental jelas menunjukkan bahwa interaksi
elektrostatik adalah kekuatan utama yang menstabilkan kompleks. Karena Ada sejumlah peputide alami dan bioaktif yang memiliki beberapa gugus
penyelidikan sebelumnya menunjukkan bahwa cincin fenil dalam siklophan amino yang terpapar. Konig€ dan rekan kerja menggabungkan dua dan tiga
berorientasi sejajar satu sama lain, interaksi antara cincin aromatik amina dan eter mahkota (9 dan 10) melalui penghubung untuk mengikat ion amonium
siklopana melaluihalehalinteraksi susun bisa menjadi kekuatan penstabilan 27
1 peptida secara kooperatif. Reseptor berbasis multi-mahkota disintesis oleh
tambahan. Af tertinggifinity diamati untuk 5 dengan histamin (63 M ) dan koneksi bertahap eter mahkota dan sifat mengikat dianalisis dengan bantuan
1
tryptamine (24 M ) menunjukkan karakter hidrofobik dari inangeinteraksi flspektroskopi uoresensi. Akibatnya, reseptor yang mengandung dua atau tiga
tamu. eter mahkota yang terhubung dengan hubungan kovalen menunjukkan af
sedangfinity untuk lisin metil ester (satu kelompok amonium) dalam metanol
(log K¼4.5) dan tidak ada affinity dalam larutan air (50 mM HEPES, pH 7.5).
Ketika studi mengikat dilakukan dengan oligopeptida yang terdiri dari lisin
(K) dan glisin (G) HKKGeNH2, HKKeYa Tuhan, HKGKGeNH 2,
HKGGKeNH 2, sehingga peptida membawa dua atau tiga gugus amino
terprotonasi, pembentukan inangekompleks tamu terdeteksi dalam metanol
dan dalam larutan air (misalnya, log K untuk reseptor 9adalah 4,6 dalam
metanol dan 2,6 dalam larutan berair, masing-masing). Pengamatan ini
membuat penulis menyimpulkan bahwa peningkatan jumlah situs pengikatan
tidak mengarah pada efek kooperatif, kemungkinan karena
tingginyaflfleksibilitas molekul host dan guest.

Strategi serupa direalisasikan untuk kaliks larut air [4]

25,26
narasi 7 dan 8, yang diselidiki sebagai pelarut NMR kiral
reagen dalam D2O. Untuk mengikat ion amonium kiral dalam kaliber air
140 EA Kataev, C. Muller€ / Tetrahedron 70 (2014) 137e167
Kelompok Reinaud baru-baru ini melaporkan kalin yang larut dalam air
[6] 11, yang effimengikat kedua amina alifatik dan aromatik dengan adanya
 28 dengan substituen yang berbeda. Tujuan dari pekerjaan ini adalah untuk
seng (II) nitrat. Untuk mencapai kelarutan dalam air disarankan untuk
memahami efek substituen pada selektivitas dan affiJumlah host untuk
memfungsikan tepi atas kaliks [6] aren dengan gugus amonium bermuatan
berbagai tamu amonium. Analisis terperinci tentang properti yang mengikat
positif yang terhubung melalui penghubung. Tanpa linker, komplek itu tidak 1
stabil karena kedekatan jarak dari tiga muatan positif, seperti yang disarankan oleh H NMR dan pemodelan perhitungan menunjukkan bahwa jumlah luas
oleh penulis. Kaliber baru [6] arene menawarkan properti langka untuk permukaan hidrofobik yang tersedia untuk pengikatan berperan pentingfitidak
mengikat amina lipofilik primer karena amina ini, dan khususnya bentuk bisa berperan dalam pengakuan efektif tamu hidrofobik. Misalnya, reseptor13
protonasinya, berbedafikultus untuk mengekstrak dari air. Properti ini berbeda memiliki selektivitas untuk NPr4Cl dan NBu4Cl dengan affinegara 1100 dan
dengan Raymond'inang sintetis (1) yang mengikat amina sekunder istimewa. 1
7060 M , masing-masing (40 mM buffer fosfat dalam D2O, pD 7.4).
Menariknya, keberadaan ketiga komponen dalam larutan, kation Zn (II), Reseptor14 dengan donor dan substituen metoksi polar memiliki af yang
reseptor, dan amina mengarah pada pembentukan kompleks terner. Jika salah 1
satu komponen tidak ada, tidak ada af mengikatfiNitas reseptor, baik untuk lebih rendahficocok untuk tamu ammonium: 60 dan 90 M untuk NPr4Cl dan
kation Zn (II) maupun untuk amina, terdeteksi. Kompleks ternary sensitif NBu4Cl, masing-masing. Bahkan posisi gugus karboksilat (reseptor15 dan
terhadap pH dan stabilitas maksimum dengan amina dicapai pada pH 7,8. 16) sangat penting untuk ikatan tamu yang kuat. Reseptor16 adalah pengikat
0 1 1 terlemah dan mengkoordinir tamu ammonium dengan konstanta asosiasi
Formasi kompleks dalam air digerakkan secara entropis ( DS ¼103 mol K , 1
0 1 20e50 M. .
DH ¼10,2 kJ mol ). Diusulkan agar kation amina dan Zn (II) sangat terlarut.
Berbeda dengan larutan berair, kompleksasi dalam larutan organik didorong
secara entalpi karena sifat eksotermik dari koordinasi seng. Sistem
menampilkan selektivitas untuk amina primer dan hidrofobik, seperti
dimethyldopamine, tyramine, dan
H HAI HAI H HA
AI AI I
LiO P
HAI LiO P HAI HAI
P OLi
HAI
tryptamine, dengan konstanta stabilitas relatif (Krel¼Kamine tamu/ e
1
Kheptylamine) dari 1 hingga 6 M . Koordinasi tidak terdeteksi untuk amina
hidrofobik, seperti histamin, n-propilamin, sperma, dan 5-aminobutanol. 12

R
N X

N
R
X X

R
N

-
13 R = 3-CH2CH2MENDEKUT , X = H
14 R = 3-CH2CH2MENDEKUT-, X = OCH3
15 R = 3-COO-, X = H
-
16 R = 2-COO , X = H

Cucurbiturils dengan berbagai ukuran terus dieksplorasi untuk mengikat

Pengakuan asetilkolin masih menarik perhatian banyak ilmuwan karena
implikasinya pada gangguan saraf, seperti Alz-heimer'penyakit. Gosse dan
Bibal disintesis untukfipertama kali flcyclotriveratrilene uorescent 12, yang
29
mengikat asetilkolin dalam suatu media berair. Reseptor 12memancarkan
cahaya di bawah eksitasi menjadi penyebab keberadaan kedua-substituen
donor-elektron dan gugus fosfat akseptor-elektron. Dalam D murni 2O
1 Data konsisten dengan host yang dilaporkan sebelumnyaekompleks tamu,
mengikat setelahfinitas inang terhadap asetilkolin adalah 76 M , seperti yang
disimpulkan dari NMR percobaan titrasi. Difltitrasi uoresensi peningkatan
intensitas diamati, dimana analisis data memberikan konstanta pengikatan
1 32
KSebuah¼63 M . Jikafltitrasi uoresensi dilakukan dalam media fisiologis
yang digunakan untuk kultur neuron pada pH 7,6, maka konstanta pengikatan
1
hanya 23 M , tetapi flkenaikan uoresensi lebih besar dari yang diamati dalam
air murni. Properti ini menarik untuk desain masa depan asetilkolinflsensor
uorescent bekerja di air.
Inang bermuatan negatif berbasis indole diselidiki oleh Hof untuk
30
mengikat kation amonium dalam larutan berair. Tuan rumah 13e16
memiliki struktur tripod dan cincin aromatik difungsikan
tamu yang berbeda, terutama ion amonium. Host su-pramolekul ini adalah
salah satu dari beberapa molekul sintetik yang dapat mengikat mono dan
poliamina alifatik terprotonasi. Inoue dan rekan kerja menyelidiki uril
cucurbit [6]17 difungsikan dengan siklo-heksana di sisi ekuator untuk
31
pengikatan ion amonium sederhana. Fungsionalisasi ini memungkinkan
penulis untuk mencapai kelarutan cucurbituril yang sangat baik ini dalam air
murni. Sebelumnya, kelarutan yang baik untuk CB6 hanya mungkin dicapai
dengan adanya asam atau natrium klorida. Konstanta pengikat reseptor baru
untuk amina terproton adalah 2e3 urutan besarnya lebih tinggi dari CB6
klasik di 0,05 M NaCl. Konstanta pengikat tertinggi diamati untuk sperma
12 1
(kompleks 1: 1, KSebuah¼3.4 10 M. ). Analisis data termodinamika dari
proses pengikatan menunjukkan bahwa asal-usul ini tinggifinity adalah tidak
adanya ion yang mengganggu (asam atau garam) yang dapat bersaing dengan
tamu. Tuan rumahekomplek tamu diisolasi dan dikarakterisasi dengan analisis
kristal tunggal sinar-X untuk semua diamina yang mengandung 4e8 karbon.
yang melibatkan interaksi kelompok amonium dengan oksigen mobil-bonyl
dan menempatkan rantai alifatik di kantong hidrofobik dari 17. Pengaturan
serupa dari tamu yang mengandung ammonium di CB7 (18) ditemukan oleh
Macartney dan rekan kerja. Inang yang lebih besar mengikat inhibitor
asetilkolinesterase dicationic, seperti suc-cinylcholine, BW248c51, dan
Sebuah,kamu-bis (trialkylammonium) alkana. Sang
penyelenggaraekompleks tamu (18 $Tamu) memiliki struktur
pseudorotaxane, sehingga rantai alkil diulir melalui rongga inang. Di
EA Kataev, C. Muller€ /
Tetrahedron 70 (2014)
137e167
karya lain kelompok yang sama menyelidiki kompleks kolin dan kolon
33 1
fosfonium oleh CB7. Konstanta pengikat diukur dengan bantuan H dan
31
Titrasi P dalam larutan berair buffer pada nilai pD berbeda tergantung pada
tamu. Proton kelompok akhir tamu bergeser ke atasfibidang kompleks.
Konstanta pengikat asetilkolin dan tamu serupa berada dalam kisaran 10 e10
1 7
M. dan menurun pada baris berikut: butyrylcholine (2 10
1 5 1 5 1 þ
)>acetylcholine (7 10 M. )>choline (6.5 10 M. )>NMe 4 (1.2 10 M. ).
þ HN
Analog garam phos-phonium (mis. PMe 4) terikat ke CB7 sedikit lebih baik
daripada tamu amonium. Jika tamu memiliki gugus quinuclidinium atau
benzyl alih-alih tetramethylammonium, maka konstanta pengikat tumbuh
9 10 1
menjadi 10 e10 M. . Pengamatan ini sesuai dengan yang
sebelumnyafimenemukan bahwa lebih banyak tamu hidrofobik lebih terikat
dengan CB7.
HAI
N N * 3. Reseptor untuk asam amino dan peptida
N N 6
*
HAI
17
N 36,37
HA
I
HAI
H pengikatan yang mengandung logam dengan situs pengikatan lainnya yang
AI
HAI
CB7
N
18 tamu
Af yang kuatfinitas cucurbituril untuk tamu amonium dalam air berhasil
34
digunakan dalam merasakan aktivitas enzimatik. Nau dan rekan kerja
mengembangkan pewarna yang mengandung gugus amino gratis untuk
memantau aktivitas enzim lisin dekarboksilase. Setelah mengikat amina ke
rongga CB6 (19) kuat flpeningkatan uoresensi (100 kali lipat) diamati.
Sebagaimana ditentukan darifltitrasi uoresen pada nilai pH yang berbeda acara
pengikatan disertai dengan pK yang kuatSebuah
(DpKSebuah¼4.5). Jadi, pewarna mulai menarik proton yang sudah pada pH
11 dan diprotonasi pada kisaran pH yang lebih luas daripada pewarna bebas.
Sebagai aplikasi dari properti yang menarik ini penulis menguji Dye
kompleks$CB6 sebagai sensor baru untuk memantau dekarboksilasi enzim
lisin, yang mengkonversi L.-lysine menjadi cadaverine. Pengujian ini bekerja
dengan sangat baik karena ca-daverine berikatan dengan CB6 dengan 2 orde
magnitudo lebih tinggifitidak seperti pewarna, sehingga menggantikan
pewarna dari kompleks. L.-Lisin mengikat ke CB6 dengan af jauh lebih
1 Percobaan transfer saturasi NMR digunakan untuk mengukurfikonstanta laju orde
rendahfinity (870 M ) dan tidak dapat menghilangkan pewarna (Fig. 1).
Amina yang secara struktural mirip adalah senyawa yang menantang
untuk deteksi di lingkungan berair bahkan dengan berbagai sensor. Garcia dan
rekan kerjanya menggunakan properti siklodekstrin dan cucurbituril untuk
mengikat ion amonium dan membangun susunan penginderaan yang
membedakan amina primer, sekunder, tersier alifatik dan aromatik. Susunan
terdiri dari enam pewarna dasar dan tujuh kapsul organik yang tersedia secara
komersial: Sebuah-, b-, g-CD dan CB5, CB6, CB7, CB8. Sinyal analitik
dikumpulkan dari perubahan UVevis spectra. Setiap amina menghasilkan
jenis tertentufiGambar c karena memindahkan pewarna atau berinteraksi
dengan host dengan caranya sendiri. Itu
air). Karena ester amino aromatik menunjukkan ees yang jauh lebih tinggi,
data menunjukkan bahwa interaksi penumpukan antara porfirin dan cincin
fenil kuat dalam kloroform tetapi lemah dalam air.
N NH N
NH
5 6
HN
NH + NH
M.
NH
5 1
19•Kadaverin HN
19•Pewarna
non-fluorescnet berpendar
Fig. 1. Indikator perpindahan displai dengan cucurbit [6] uril (CB6, 19) dan fluorescent
pewarna dikembangkan untuk memantau aktivitas enzimatik dari dekarboksilase lisin.
kalibrasi array memungkinkan seseorang untuk mengidentifikasi struktur
amina dengan presisi tinggi.
Pengalaman hebat telah dikumpulkan selama dekade terakhir dalam
memahami prinsip-prinsip pengakuan asam amino dalam pelarut yang
berbeda. Beberapa artikel ulasan telah dipublikasikan baru-baru ini yang
menyentuh topik pengenalan asam amino. Ulasan-ulasan ini menjelaskan
sensor untuk asam amino, prinsip umum chromo-genic dan flsensor
38 39
uorogenik, enantioselektif flsensor uoresensi, dan pengakuan oleh
16
cucurbiturils. Interaksi paling kuat dalam media polar seperti air, metanol,
atau DMSO adalah logamekarboksilat dan logameinteraksi amina. Sebuah
tanda modular reseptor untuk asam amino biasanya menggabungkan situs
masing-masing mengenali gugus amino dan residu alkil. Tugasnya adalah
untuk mengatur situs pengikatan ini pada jarak spasial yang tepat dan
mengatur sebelumnya struktur keseluruhan host untuk pengikatan.
Pendekatan baru yang kami bahas di bawah ini mengeksplorasi interaksi
hidrofobik dengan rantai samping asam amino, ikatan hidrogen
danhalehalinteraksi. DarifiSekilas interaksi ini lemah tetapi menentukan
dalam menentukan selektivitas reseptor. Sebagai contoh, kompleks porfirin
kobalt (II) mengikat asam amino yang berbeda pada pH 9 dalam larutan berair
sesuai dengan UVevis dan CD spektroskopi tetapi tidak memiliki selektivitas
40
antara para tamu. Kompleks asimetris tembaga (II) yang mengandung dua
lengan antrasena tidak dapat membedakannya L.- dan D-isomer meskipun itu
mengikat L.- Anion mandelate dalam larutan berair 15 kali lipat lebih kuat dari D-
41
mandelate. Berbeda dengan contoh-contoh ini Simonneaux dan rekan kerja
memfungsikan inti por-phyrin dari kompleks ruthenium (II) (20, 21) dengan
substituen kiral yang besar dan menggunakan kompleks untuk mengikat amina
dalam pelarut or-ganic dan asam amino dalam air dengan selektivitas enantio-
pergeseran amina
42
selektivitas hingga 60%. Ligan porfirin membawa empat fragmen kiral dalam
posisi meso, baik hidrofobik untuk melakukan pengakuan dalam pelarut or-ganik
atau hidrofilik untuk mengikat dalam air. Para penulis mengusulkan bahwa
penyelidikan ini dapat membantu mengungkap sifat kekuatan pengikat yang
terlibat dalam pengenalan asam amino kiral karena ini merupakan langkah kunci
dalam sintesis protein. Ketika kompleks ruthenium mengkoordinasikan amina atau
asam amino, melindungi sinyal NMR harus dilakukan berkat efek cincin saat ini
dari cincin porfirin. Pusat logam menunjukkan kinetika pertukaran ligan aksial
lambat, yang merupakan alasan untuk enansioselektivitas tinggi kompleks.
pertama dalam reaksi reversibel. Hasilnya dalam perjanjian yang baik dengan hasil
1
yang diperoleh dari integrasi sederhana Spektrum H NMR kompleks terbentuk atas
penambahan substrat ke inang. Ikatan amina dan ester asam amino diukur dalam
CHCl3 dan CH3Larutan OH, sementara pengikatan asam amino diukur dalam air.
Akibatnya, pengakuan asam amino dalam air sebanding dengan pengakuan ester
asam amino dalam pelarut organik. Perbedaan utama mengalami turunan phe-
35 nylalanine (60% ee dalam kloroform dan hanya 28% ee dalam
142 EA Kataev, C. Muller€ /
Tetrahedron 70 (2014) 137e167
 HN HAI
HAI NH
S S
HAI
HAI
HAI H HAI HAI
AI
Sc
HAI H HAI
AI
S HAI
HN HAI NH
NaO S HAI

H
AI
23
HN HAI H HN
AI
Dalla Cort dan rekan kerja menjelajahi bagian dalamflPengaruh ikatan
43
hidrogen pada pengikatan enansioselektif asam amino dalam air murni.
Desain reseptor 22terdiri dari kompleks Zn (II) -salophen dengan unit gula H HAI S S HAI
AI
yang melekat secara kovalen. Konstanta pengikat dengan karboksilat berbeda HAI HA HAI
ditentukan dari UVevis titrasi. Af tertinggifinity diamati untuk formiate dan I
6 1 Sc
asetat dengan KSebuahca. 10 M. . Eksperimen dengan alanin, valin,
H HA HAI
fenilalanin, leusin, prolin, dan triptofan mengungkapkan bahwa konstanta AI I
3 1 S HAI
pengikatan untuk asam amino ini mencapai nilai 10 M. dan faktor NH HAI HAI HN
NaO
diskriminasi 9,8 antara L.- dan D-para tamu Selektivitas ini adalah salah satu S
yang tertinggi ditemukan untuk pengenalan asam amino kiral dalam air. HA
I
Sebagai aturan, konstanta pengikat turun dengan peningkatan hambatan sterik
asam amino. Untuk memahami enansioselektivitas tinggi pengakuan 24
perhitungan kimia kuantum dilakukan. Hasilnya jelas menunjukkan reseptor
itu22 menyediakan dua-titik interaksi: ikatan seng (II) -karboksilat dan
hidrogen antara gugus am-monium asam amino dan atom oksigen molekul Gagasan untuk menggabungkan dua situs yang mengikatdZn (II)-situs
gula. untuk pengikatan gugus karboksilat dan situs eter mahkota untuk pengikatan
45
residu amonium asam amino disarankan oleh Kwong dan Lee. Kompleks
25 dipelajari dalam larutan air / DMF (1: 3 v / v) yang disangga dengan 10
mM HEPES pada pH 7,4 menggunakan UVevis dan fltitrasi uori-metrik.
Kompleks menunjukkan af tinggifikasih sayang untuk L.-aspartate
4 1 4 1
(KSebuah¼4.5 10 M. ) dan L.-cysteine (KSebuah¼2.5 10 M. ). Af inifini-
N N
ties adalah 18e79 kali lebih tinggi daripada asam amino lain yang
HO OH HO OH
mengandung rantai samping alkil atau aril dan 180 kali lebih tinggi dari itu
Zn
untuk kationik L.-Enithine. Tren pengikatan berikut untuk situs Zn (II)
HAI HAI
HAI HAI HAI HAI terungkap tergantung pada rantai samping asam amino: car-
HO OH HO OH boxylate>tiol>amida>hidroksil>amonium. Reseptor dapat membedakanL.-
22 dan D-berbagai asam amino. Enansioselektivitas terbaik diamati untuk
mengikat fenilglikin (KD/ KL.¼3.0). Tidak ada enantioselektivitas dapat
dideteksi untuk mengikatL.-aspartate, mungkin karena specifikota koordinasi
asam amino pada situs pengikatan Zn (II). Para penulis membandingkan
Metode presipitasi yang tidak biasa dilaporkan oleh Hayashi untuk kompleks Zn (II) tanpa bagian mahkota eter untuk membuktikan fakta bahwa
44 kedua situs yang mengikat diperlukan untukfipengakuan terhadap L.-mulai.
effipengakuan dan ekstraksi asam amino dari air. Reseptor didasarkan pada
kompleks skandium (III) dengan ligan organik yang mengandung gugus
sulfonat (23 dan 24). Dalam kompleks ini satu gugus sulfonat bebas dan
menyediakan interaksi elektrostatik dengan gugus amonium dari asam amino.
Pusat skandium (III) menawarkan interaksi yang kuat dengan kelompok
karboksilat. Affinitas dan selektivitas reseptor ditentukan dengan
mencampurkan reseptor dengan asam amino, filtrasi kompleks yang N
diperoleh, diikuti oleh integrasi sinyal dalam spektrum NMR, yang N N
memberikan hasil dan rasio pemindahan. Menariknya, reseptor23 dan 24 Zn
adalah yang paling efficient untuk menghilangkan asam amino dengan
HAI
kelompok guanidinium (Arg), imidazolinium (His), dan ammonium (Lys). HAI

Terbukti, selektivitas ini dijelaskan oleh interaksi yang kuat antara gugus
sulfonat bebas dari reseptor dan kelompok asam amino bermuatan positif. O H
Rasio penghilangan untuk asam amino ini lebih tinggi dari 70%, sedangkan
AI OO
untuk sebagian besar asam amino lainnya, bahkan termasuk yang dengan
cincin aromatik, rasio penghilangan tidak mencapai 10%. 25
H HAI HA
N I
H N H H
AI AI
N Cu
R N
HAI HAI
R HAI HAI
HAI
H HAI HAI HAI H
AI HAI NH3 HAI AI

HAI N NH
HAI

26
 EA Kataev, C. Muller€ / 137e167
Tetrahedron 70 (2014)
48
sifat dari kapsul molekul berbasis cyclotriveratrylene 36. Sebagai calon
Prinsip desain yang sama diwujudkan oleh Konig€ dan rekan kerja, yang tamu, asam amino yang relevan secara biologis adalah cho-sen: b-alanine,
46
mengembangkan reseptor peptida 26. Reseptor terdiri dari dua situs yang GABA, taurine, dan homotaurine. Reseptor yang sebelumnya disintesis35
mengikat: situs Cu (II) untuk koordinasi glisinebagian histidin dari peptida menunjukkan af sedangficocok untuk para tamu yang belajar dalam campuran
dan situs mahkota eter untuk koordinasi kelompok terminal amonium dari 49
air / asetonitril 10%. Reseptor baru 36 menampilkan 3 orde besarnya lebih
peptida a. Desainnya didasarkan pada kompleks Cu (II) yang diketahui tinggi affinity daripada reseptor 35, bahkan dalam larutan dengan porsi air
dengan urutan Gly-His dan Gly-Gly-His. Nitrilotriacetato NTAeKompleks Cu lebih tinggi (20%) dalam asetonitril. Ini af tinggifinity dari 36 untuk asam
(II) hanya menempati empat tempat koordinasi pada Cu (II) dan menyisakan amino dikaitkan oleh penulis dengan kekuatan interaksi tambahan di
dua tempat gratis untuk mengikat molekul tamu. Sudah diketahui bahwa hostekomplek tamu, yaitu kationehal interaksi antara fragmen cyclo-
NTAeKompleks Cu (II) banyak digunakan untuk puri proteinfitujuan kation, triveratrylene dan anionehal interaksi antara kelompok an-ion dan halCincin
itulah sebabnya reseptor kuateintervensi peptida diharapkan. Percobaan 1
aromatik asid. Menurut Titrasi H NMR, sinyal molekul tamu digeser ke
pengikatan dalam 50 mM HEPES buffer (pH 7,5) menunjukkan bahwa
atasfisetelah bercampur dengan tuan rumah. Konstanta pengikat yang dihitung
reseptor memiliki hampir milimolar af-ficocok untuk peptida dan 5 1
spesifisfiCally mengakui konsekuensi GHG dan GGH dengan affinities (log adalah setinggi 10 M. dengan selektivitas untuk taurin. Pentingnya ion
KSebuah) 5.7 dan 5.8, masing-masing. Grup amonium N-terminal memiliki lemahehal interaksi dalam stabilisasi hostekompleks tamu juga dibuktikan
dengan perhitungan DFT.
peran penting dalam pengakuan dan memicu perubahan emisi pada
pengikatan peptida, memungkinkanflpenginderaan uorescent peptida di bawah
pH fisiologis. Sama kelompok riset berusaha menggunakan kelompok
47
guanidinium sebagai situs pengenalan car-boxylate alih-alih situs Cu (II).
Seri reseptor ditopik yang dikembangkan menunjukkan konstanta hubungan
sedang dalam larutan air. Tujuan utama dari pekerjaan ini adalah untuk
mengikat secara selektifg-aminobutyric acid (GABA), neurotransmitter, yang HAI HA
I
HA
I
H
HA AI
memainkan peran penting dalam organisme hidup. Difluence dari beberapa I HAI
parameter struktural reseptor pada kemampuan mengikat dan selektivitas HAI

mengikat diselidiki: struktur residu bermuatan positif dan penghubung antara HAI HAI

eter mahkota dan fragmen bermuatan. Sejumlah asam amino yang berbeda HN
dengan semua jenis polaritas, muatan, kebasaan, dan keasaman diuji. Studi
HAI
mengikat dilakukan dengan menggunakanfluoresensi dan UVevis NH N NH
spektroskopi serapan. Menurut konstanta pengikat yang diukur senyawa HAI HAI
dengan etilena pendek (27e30) dan xylene kaku (31e33) dan triazole linker
1 35
(34) memiliki af mengikat sedang sampai baikfinities (100e500 M. ) dan HAI HAI HAI HAI
selektivitas. Reseptor ini bahkan dapat membedakan GABA dari prekursor
fisiologisnya, glisin dan asam glikamat. Menariknya, senyawa31 dan 32
menunjukkan selektivitas untuk tripeptida, yang memiliki karboksilat pada
salah satu ujungnya dan ion amoniumnya pada jarak yang tepat dari gugus HAI
HAI HAI
karboksilat. H
AI
HA HN HN
I
NH
HAI NH
HN NH

H H
AI AI
36

HA HAI
Tamu
I
HAI
HAI
HAI HAI H2N H2 N taurin
HAI HAI NR β alanin
COOH BEGITU3H
HAI HAI
H H H H H2 N H2 N
GABA homotaurine
COOH BEGITU3H

N N
R= NH N N
27 NH
31
H H HN H H HN Arena kaliks [4] difungsikan dengan gugus asam fosfonat dan diselidiki
1
untuk mengikat asam amino dengan cara H NMR dalam buffer fosfat yang
N N 28 32
N N 50
NH HAI NH HAI dideuterasi pada pD 7,3 dan 22 C. Dalam contoh ini, penulis
H H H H menggabungkan kaliks [4] arena dan gugus fosfonat bermuatan negatif
sehingga residu amonium asam amino dapat berinteraksi dengan gugus asam,
N N N N
sedangkan ekor hidrofobik akan mengikat di dalam rongga kaliks [4] arena.
NH HAI 29 NH O 33 Pergeseran NMR memberikan bukti untuk proses enkapsulasi oleh reseptor37
N N sa N saya
dan 38. Af tertinggifinegara menunjukkan reseptor 38untuk ester metil asam
ya amino dasar seperti arginin dan lisin. Reseptor kaku37 memiliki af yang lebih
N N N N rendahficocok untuk ester asam amino dibandingkan flreseptor fleksibel 38.
N
Stoikiometri campuran 1: 2 dan 2: 1 diamati dalam titrasi Percobaan,
30 34 menunjukkan bahwa interaksi elektrostatik antara anion fosfonat dan gugus
amonium asam amino memiliki dampak besar pada pengenalan.
144 EA Kataev, C. Muller€ /
Tetrahedron 70 (2014) 137e167
Tantangan untuk mengikat GABA secara selektif dalam air menarik
perhatian Martinez dan rekan kerja, yang menyelidiki hal tersebut
 residu lisin, yang ditemukan di situs pintu masuk kofaktor. Menurut data
OH eksperimental koordinasi reseptor41 memiliki efek yang jauh lebih kuat pada
OH
OHOO HAI
HAI
HAI
HAI
P aktivitas enzim daripada reseptor 40. Interaksi dengan41disertai dengan
P HAI P P HAI
perubahan konformasi reversibel dari struktur protein, seperti disimpulkan
HO
dari spektroskopi CD (spektroskopi dichroism lingkaran). Host kunci yang
diusulkanestruktur tamu ditunjukkan pada Fig. 2.
OO HAI HAI
Baru-baru ini, inti reseptor aktif 41 dikombinasikan dengan situs
HAI H 53
A pengikatan karboksilat untuk mengenali asam amino dalam urutan peptida.
I Desain reseptor ini didasarkan pada penyelidikan sebelumnya dengan
37 54
bifosfonatekonjugasi pirol guanidiniocarbonyl. Sayangnya, reseptor yang
HAI OH OH
dijelaskan sebelumnya ini memiliki
HAIHO a preferensi untuk asosiasi diri dan karena itu af rendahfinity untuk molekul
O target. Reseptor baru42 dan 43 tidak memiliki masalah ini dan menggunakan
dua lengan untuk mengikat arginineglisinepeptida yang mengandung aspartat
OO
HAI (RGD). Peptida ini sangat penting karena mereka ada di banyak seleprotein
P OP PO P
HO
dan seleacara komunikasi sel. Reseptor42 dan 43 ikat asam amino ionik
dalam peptida yang mengandung RGD linier dan siklik dalam larutan berair
buffer dengan Kd¼20e30 mM. Reseptor 42 menunjukkan af tinggifinitas dan
HAI OO HAI selektivitas untuk peptida yang mengandung RGD siklik dengan K d¼15e30
HH H H mM.
38
Sebuah uji tandem supramolekul yang menarik disarankan oleh Nau dan
rekan kerja, di mana penulis mengubah ikatan macrocycles yang tidak selektif
Schmuck dan rekan kerjanya mengembangkan artifisymporter resmi 39, 55
menjadi penginderaan asam amino yang sangat selektif. Idenya didasarkan
yang mampu melakukan transpor aktif asam amino terasilasi N dengan pada fakta bahwa cucurbit [7] uril (CB7) hampir tidak dapat mengikat asam
51 amino, tetapi sangat mengoordinasikan amina terprotonasi dalam air. Amina
menggunakan gradien pH sebagai tenaga penggerak. Untuk desain
transporter ini guanidiniocarbonyleMotif pengikat pirol digunakan sebagai ini dihasilkan dari asam amino yang sesuai dengan menggunakan
struktur inti, yang difungsikan dengan rantai alifatik panjang untuk memiliki dekarboksilase. Sebagai contoh, histidin memiliki konstanta pengikatan
1
kelarutan yang baik dalam pelarut organik. Dalam percobaan transpor laju dengan CB7 400 M , tetapi histamin berikatan dengan CB7 dengan affinity of
transpor asam amino melalui fase organik ditentukan oleh pelepasan substrat 4 1
3.2 10 M. (menurut pengukuran ITC dalam 10 mM buffer natrium fosfat,
dari inang yang sesuai.ekompleks tamu. Dengan demikian, asam amino yang
pH 7,5 pada 30 C). Juga ditemukan bahwa pewarna dapoxyl membentuk
terikat pada yang terlemah diangkut paling cepat. Perilaku terbalik ditemukan
kompleks dengan CB7 dan memancarkan cahaya 200 kali lebih kuat daripada
untuk asam-asam amino yang terikat terkuat, mereka diangkut paling lambat.
dalam bentuk bebas. Properti ini menawarkan onlineflpemantauan uores-cent
Menurut percobaan kompetisi reseptor memiliki selektivitas untuk asam
dari perpindahan pewarna pada kompleksasi CB7 dengan amina terprotonasi.
amino aromatik karena kation tambahanehal interaksi hadir di tuan Sebagai target untuk penyelidikan ini, au-thor memilih histidin, arginin, lisin,
rumahekompleks tamu. Tarif transportasi berada di urutan paling effiarti tirosin, dan dekarboksilase yang sesuai. Dalam pengujian, asam amino
cientfitransporter resmi yang dikenal sejauh ini. Dengan memanfaatkan didekarbilasi dengan spesifisitas tinggi yang sesuaifienzim c. Kemudian amina
gradien pH (100 mM BIS-TRIS pH 6 dan pH 8, kloroform digunakan sebagai yang dihasilkan berikatan dengan CB7 dalam bentuk terprotonasi dan
fase organik) dimungkinkan untuk mewujudkan transpor aktif asam amino. menggantikan pewarna dapoxyl. Karena pewarna dapoxyl dipindahkan
selama reaksi enzimatik, orang dapat mengikuti onlineflpendinginan
uorescence. Metode ini dipindahkan ke format pelat mikrotiter, yang
menunjukkan sensitivitas terbatas untuk mendeteksi asam amino 2,4 nmol per
sumur. Metode ini juga diterapkan untuk de-terminasi ee (kelebihan
enantiomerik) dariD-amino acid-stating akurasi akurasi nilai yang dihitung
hingga 99,98% ee. Properti ini tersedia karena laju awal percakapan
enzimatikL.-isomer memiliki hubungan linier dengan konsentrasi awal L.-
Bagian dalam campuran dengan D-isomer.

Ahli biokimia biasanya menggunakan reaksi kovalen dengan residu asam
amino yang dapat diakses pada permukaan protein untuk memodulasi
aktivitas protein. Schrader mencoba menyelesaikan tugas ini dengan
menggunakan interaksi non-kovalen, yang terbentuk di antara
maknafireseptorial 40, 41 dan alkohol dehidrogenase. Reseptor dapat
52
menentukanfimengikat ke kofaktor atau ke bagian protein yang dapat diakses
dan masukflmemengaruhi aktivitas enzimatik. Alkohol dehidrogenase (ADH)
þ dengan CB8 (log K¼7e8). Diusulkan bahwa selektivitas triptofan,
adalah NAD Enzim -de-pendent, yang menampilkan beberapa lisin dan
arginin pada permukaannya. Seperti yang disimpulkan dari data eksperimen,
reseptor40 dan 41memiliki mekanisme penghambatan yang berbeda dari
þ kompleks yang diusulkan dengan residu triptofan ditunjukkan dalamFig. 3.
aktivitas enzim. Reseptor40 mengeluarkan NAD dari situs pengikatannya
dan dengan demikian menghabiskan tingkat kofaktor di bawah ambang kritis,
yang mengarah ke denaturasi yang tidak dapat diubah. Reseptor41 memiliki
preferensi untuk mengikat
Berbeda dengan CB7, uril cucurbit [8] (CB8, 44) mengikat asam amino
alami dalam 10 mM dapar natrium fosfat pada pH 7,0 dengan kadar yang
56
baik.finity. Pengukuran ITC dan NMR menunjukkan bahwa CB8 dan
kompleks antara CB8 dan metil viologen (CB8$MV) secara selektif hanya
mengikat asam amino aromatik dengan urutan sebagai berikut: Trp>Phe>Tyr
[Nya. CB8 juga mampu mengikat tripeptida, yang mengandung aromatik
asam amino, misalnya, Trp-Gly-Gly atau Phe-Gly-Gly. Stoikiometri
pengikatan adalah 1: 1 untuk CB8 kompleks$MV dan 1: 2 untuk CB8 gratis.
Menariknya, konstanta pengikatan untuk CB8 kompleks$MV dengan metil
viologen adalah 3e4 urutan besarnya lebih rendah (log K¼3e4) dibandingkan
fenilalanin, dan tirosin berasal dari pencocokan beberapa parameter asam
amino: hidrofobisitas, ukuran, dan permukaan yang terpapar pelarut. Struktur
Para penulis menganalisis hubungan antara area permukaan yang terpapar
dengan energi transfer asam amino dari sikloheksana ke air. Itu
EA Kataev, C. Muller€ / Tetrahedron 70 (2014) 137e167 145
 HAI N N
N
N N *
NH
N N 8
HAI * N
NH N
N N HAI
H HN

44 MV 44•MV•Peptida

45
Fig. 2. Struktur reseptor 40e43. Reseptor 40 dan 41 ditampilkan sebagai kompleks dengan
þ
NAD dan residu lisin dari protein.
Fig. 3. Struktur kompleks diperoleh di hadapan uril cucurbit [8] dengan asam amino aromatik.
MV-metil viologen.

59
pengakuan selektif dan replikasi informasi. Sebagai model sistem penulis
Tampaknya Trp, Phe, dan Tyr adalah asam amino hidrofobik dan memiliki mempelajari pengikatan oligomer siklodekstrin 47e50 ke untai peptida asam
permukaan yang relatif besar. Fakta ini sesuai dengan selektivitas yang amino aromatik. Total enam pep-pasang diuji dalam pengikatan siklodekstrin:
diamati untuk asam amino ini. FGGGFGGGF, FGGGYGGGF, FGGGNa1GGGF, FGGGWGGGF,
Kompleksasi supramolekul antara CB8, metil viologen (MV), dan Trp FGGFGGF, GGGF, di mana F, G, W, dan Na1 adalah fenilalanin, gliserin,
dalam air kemudian diimplementasikan oleh Urbach dalam ikatan multivalen glikol, t gugup, gan - (2-naphtylmethyl) glisin. Masalah kelarutan sampel
57 peptida tidak memungkinkan mereka untuk melakukan pengalaman yang
dari dua molekul rantai linier. Satu rantai mengandung satu, dua atau tiga
molekul MV dan rantai lainnya adalah peptida dengan pengulangan satu, dua mengikat dengan menggunakan ITC. Dengan demikian, penulis beralih ke
atau tiga asam amino triptofan. Di hadapan CB8 dua rantai membentuk resonansi permukaan plas-mon (SPR), yang memungkinkan seseorang untuk
kompleks yang distabilkan oleh ikatan non-kovalen (kompleks45, Fig. 3). mengikuti pembentukan real-time kompleks pada permukaan sensor. Peptida
Terlihat bahwa rantai peptida saling mengikat secara multivalen. Studi itufipertama diimobilisasi pada permukaan dengan metode kopling amina
mengikat ITC confirmed bahwa affikeuntungan nasional adalah 31e280 kali standar. Seperti yang disimpulkan dari data percobaan, semua siklodekstrin
lipat karena multivalensi. Namun, tidak ada kooperatif yang ditemukan dalam mengikat peptida GGGF dengan af yang serupafinity. Reseptor trimerik
sistem ini dan entalpi pengikat adalah aditif. Dalam pekerjaan selanjutnya mengikat hepta- dan nonapeptida, tetapi affinity berada dalam urutan yang
58 3 1
strukturehubungan aktivitas diselidiki untuk sistem CB7efenilalanin. Asam sama besarnya dengan GGGF (K Sebuah¼10 M. ). Pengamatan ini
amino difungsikan dengan substituen yang berbeda di tiga posisi: gugus mengarahkan penulis untuk menyarankan a'melingkar' hipotesis untuk peptida
karboksilat, gugus amino, dan dalam posisi 4 cincin benzena, dan stabilitas yang lebih panjang, yang membantu menjelaskan af yang mengikat hampir
kompleks dengan CB7 diukur. Af terkuatfiditemukan untuk turunan 4- samafinegara. Peptida kecil memiliki satu gugus fenil tunggal, sedangkan
aminometil (AM) dari fenilalanin dalam tripeptide AMePhe-Gly-Gly, yang hepta- dan nonapeptida'melingkar' dan karenanya tidak memiliki residu fenil
merupakan peningkatan 500 kali lipat dari affiperbandingan dengan yang dapat diakses.
fenilalanin (Kd¼0,95 nM). Ini adalahficontoh pertama dari af tinggifinity dan
situs-spesifikfic pengenalan peptida yang difungsikan dengan reseptor sintetis.
Menurut data termodinamika pengikatan yang kuat didukung oleh empat
N
interaksi utama koaksi terhadap CB7: rantai samping aromatik, gugus amino- N
metil rantai samping, tulang punggung peptida, dan gugus amonium berujung N N
N (kompleks)46, Fig. 3). Af tinggifinity dalam air membuka perspektif untuk HAI
HAI N N
menggunakan host iniesistem tamu sebagai affitag protein. Sifat koperasi
mengikuti dari analisisDDG dari proses pengikatan antara turunan yang
berbeda. Modifikation pada gugus karbonil dan pemasukan sub-stituen X Y X
1
aminometil dengan jumlah menghasilkan 3,8 kkal mol ; Namun, pada
1
kenyataannya nilai yang diukur adalah 5,5 kkal mol . 47 X= ,Y=
48 X= ,Y=
49 X =, Y =
50 X= ,Y=

Fujita menunjukkan bahwa bahkan penggunaan arti hidrofobik yang tidak

Penggunaan hanya interaksi hidrofobik untuk mengikat peptida dengan selektiffikantong molekul cial memberikan ikatan peptida kuat yang
residu aromatik telah terbukti menjadi pendekatan yang berhasil untuk 60
pengakuan dalam air. Bol dan rekan kerja tertarik pada persaingan sifat-sifat membawa asam amino aromatik. Selain itu, peptida kecil yang mengandung
molekul DNA, yaitu secara berurutan asam amino Trp dan Phe dalam i, iþ4 dan aku, akuþ7 posisi mengadopsi
konformasi heliks. Misalnya, kantong molekuler51 mengikat senyawa
aromatik yang kaya elektron berkat
146 EA Kataev, C. Muller€ /
Tetrahedron 70 (2014) 137e167
N 12+
N
aromatikeinteraksi aromatik dengan electron-defifragmen tri-azine cient. N N N N
Konstanta pengikat diukur dalam buffer fosfat pada pH 7,0 dengan bantuan N NN NN
N
Pt
4 1 Pt N N NN
UVevis titrasi. Nilainya ada pada 10 M. memesan hexapeptides dengan N N 12 TIDAK3 -
residu triptofan tunggal. Konstanta pengikat peptida dengan dua residu HN
N N HN
5 1
aromatik ada di urutan 10 M. . Peptida dengan i, iþ4 posisi unit aromatik Pt N Pt
memiliki sekitar dua kali lipat konstanta pengikatan yang lebih tinggi 51 Peptida
daripada yang dengan i, iþ7 posisi. Struktur yang diusulkan dari en-kapulasi
residu indol di rongga inang ditunjukkan dalam kompleks51 $Peptida.
Dengan demikian, karya ini menggarisbawahi sekali lagi bahwa interaksi
hidrofobik dan posisi cincin aromatik dalam peptida sangat penting untuk 50
pengenalan asam amino dalam air.
 Dicarboxylate adalah target yang menarik untuk hostekimia tamu dalam kuat antara unit anion dan tiourea dari reseptor, sehingga interaksi ini
air karena dicarboxylate memainkan peran penting dalam proses biokimia menempatkan pewarna dalam larutan per-pendikuler satu sama lain, sehingga
yang berbeda, misalnya, dalam siklus Krebs. Perwakilan utama dari proses FRET tidak menguntungkan.
dicarboxylate alami adalah malonat, oksalat, adipat, dan glutarate. Costero
dan rekan kerja mensintesis dua turunan tiourea yang terhubungfluorescein
65
(53) dan rhodamin B (54) untuk merasakan asam dikarboksilat. Karena COOEt
reseptor membentuk pasangan FRET, campuran reseptor equimolar digunakan OH H
untuk mendeteksi garam trimetilammonium dari asam dikarboksilat dalam N
COOEt
larutan buffer 100 mM MES / DMSO (1: 2). Pendinginan FRET diamati pada NH

interaksi reseptor dengan anion dengan selektivitas untuk malonat. Diusulkan S HAI
HAI
bahwa tanpa malonat dua pewarna effiberinteraksi dengan satu sama lain dan
mengaktifkan proses FRET. Penambahan malonat menginduksi interaksi yang HO HAI OH
53
4. Reseptor untuk anion anorganik dan pasangan ion EtOOC
OH H
N

Penelitian di fibidang pengakuan anion adalah refldipengaruhi oleh

N
sejumlah ulasan yang diterbitkan di bidang ini, yang membahas kemajuan H
12 8 COOEt
terbaru tentang artifireseptor anionial, reseptor untuk pasangan ion, dan S
61,4 COOH
spesifikfipengakuan fosfat. Sementara sebagian besar reseptor non-logam
sintetis tidak bekerja di media berair, reseptor berbasis logam biasanya
bekerja di air dan mengikat anion melalui koordinasi dan interaksi N HAI N
elektrostatik. Dalam bagian dari tinjauan ulang ini, kami tidak melaporkan Cl
reseptor berbasis logam murni karena baru-baru ini ditinjau oleh beberapa
62,63 54
kelompok penelitian.

Sensor berbasis logam-salophen secara ekstensif dieksplorasi di fibidang

4.1. Reseptor netral 14
pengakuan anion. Dalla Cort dan rekan kerja belajar kompleks uranium 55
difungsikan dengan bagian gula, yang memberikan kelarutan kompleks ini
Bakker dan rekan kerja melaporkan sensor untuk klorida dalam air, yang 66
64 dalam air. Studi pengikatan anion menunjukkan bahwa ikatan itu kompleks
bekerja secara terbalik di bawah fotoaktivasi. Sensor optode terdiri dari 1
plastik PVC film dengan turunan spiropiran lipofilik 53, ionofor selektif flanion uorida dengan KSebuah¼115 M dalam buffer MOPS pada pH 7,5.
þ Kompleks ini juga dapat mengikat anion lain seperti ortofosfat, ADP, dan ATP
klorida 52 dan penukar anion (R Cl). Sensor bekerja pada peristiwa kimia 1 4 1
berikut. Di bawah normal cahaya tampak spiropyran ada dalam bentuk cincin- dengan konstanta pengikat 480 M dan lebih dari 10 M. untuk nukleotida,
masing-masing. Karya ini membuktikan bahwa kompleks uranium mampu
tertutup yang stabil dengan kebasaan yang sangat rendah (pK Sebuah¼2,3 0,1),
membentuk asam Lewiseinteraksi dasar bahkan dalam media polar.
tetapi di bawah sinar UV itu berubah bentuk menjadi bentuk cincin-terbuka
berwarna dengan kebasaan jauh lebih tinggi; jika bentuk cincin-terbuka hadir
þ
mulai mengekstrak H bersama dengan Cl. Pronasi bentuk cincin-terbuka OH
menyebabkan perubahan warna dan membuatnya
HO
HAI
mungkin untuk memvisualisasikan proses co-ekstraksi. Namun, cahaya OH

tampak membalikkan proses kembali dan menginduksi ionflmasuk dan keluar

dari
HAI
sensor. Selektivitas sensor ini tinggi; menurut data ex-eksperimental hanya OH

SCN yang menunjukkan signifitidak bisa ikut campur. N

HAI
N UO
HAI

HO HAI
TID
N HAI HO
AK2 OH
C H HAI 55
12 25
HG HO
HG Vis UV
TIDAK2

HG Jolliffe dan rekan kerja mensintesis reseptor selektif untuk sul-nasib

N HO 67
berdasarkan siklopeptida yang difungsikan dengan lengan tiourea. Studi
52 C H
12 25
sebelumnya menunjukkan reseptor itu 56 memiliki selektivitas yang sangat
Ionofor selektif baik untuk sulfat dalam CDCl3. Sekarang penulis menguji serangkaian
53 EA Kataev, C. Muller€ /
Spiropyran Tetrahedron 70 (2014)
137e167
4 1
residu hidrofobik. Kedua reseptor menunjukkanfinity >10 M. dalam
reseptor yang difungsikan 56e61dalam larutan air yang terdiri dari DMSO 25% air dalam DMSO.
dan hingga 25% bagian air. Bagian air yang digunakan untuk menyiapkan
larutan dibatasi oleh kelarutan reseptor. Menariknya, proses pertukaran antara
anion bebas dan enkapsulasi agak lambat pada skala waktu NMR di DMSO
S
R'
yang hanya mengandung 0,5% H2O, tetapi menjadi lebih cepat dengan HAI N N
H
meningkatnya porsi air. Reseptor dengan situs pengikatan tiourea dekat R N nHHAI
dengan tulang belakang siklik memiliki af tertinggifinity. Fakta ini dikaitkan H N R
dengan yang baikfit antara situs ikatan hidrogen dan geometri sulfat. Reseptor HAI N
H H HAI
59 dan 61disintesis baik dengan tujuan untuk mencapai kelarutan yang lebih N HN
baik atau untuk melindungi situs pengikatan dari molekul pelarut dengan N n NH
S N H H
N
 HAI HA
R I
56 n = 3, R = Me, R '= p-tBuPh
57 n = 2, R = H, R '= p-tBuPh
58 n=1, R=H, R'=p-tBuPh
59 n=3, R=Me, R'=p-CF3Ph
60 n=3, R=H, R'=p-tBuPhCH2
61 n=1, R=H, R'=p-tBuPhCH2
n N binding properties for sulfate, iodide, and selenate with binding constants
S between 4.75 and 8.67 logarithmic units. Replacement of the proline fragment
in the cyclopeptide with triazole ring led to an interesting behavior of the
69
resulting receptor in an aqueous methanol solution. New receptor 67 is well
preorganized and has slightly smaller inner binding cavity than the original
1
cyclopeptide 66. H NMR titrations in a 1:2 (v/v) D 2O/CD3OD mixture
showed that only CH-groups on stereogenic centers are sensitive to the
binding of sodium sulfate and remarkable downfield shifts (0.66 ppm) were
detected. Interestingly, the comparison of binding properties of original
cyclopeptide 66 and new pseudopeptide 67 clearly indicates that the latter
receptor has less ability to form 2:1 complex in aqueous solution: K 11 and
1 1 1 1
K12 are 360 M and 26,000 M for 66 and 1010 M and 9650 M for 67,
respectively. The authors proposed that 67 is less hydrophobic and thus hy-
drophobic stabilization in the 2:1 complex and solvent isolation is weaker
than in the original cyclopeptide. However, 67 provides better affinity for
sulfate because of better preorganization.

Gale and co-workers investigated neutral receptors bearing only

X 70
O OH hydrogen-bond-donor sites for anion coordination. Association constants
N N N 62X= SS for these receptors were determined in 0.5% and 10% water-DMSO with the
N O O N 1
HN O help of H NMR. Receptors 68e70 bind sulfate in DMSO with high binding
O NH N N 63X= SS
constants in a 1:1 stoichiometry. For example, receptor 69 binds sulfate with
N N HN SS 4 1
affinity >10 M . Detailed analysis of binding properties of receptors 68 and
O 64X=
O NH
69 showed that equilibria are more complex for these receptors at high
O O
N N N N concentra-tions of sulfate. The presence of 10% water in DMSO cancels
N O
65X= SS multiple binding events and only a corresponding 1:1 binding is observed.
H O Selective binding in the presence of 10% water is favored for the acetate
X
1
anion; the calculated association constants are 600 and 690 M for 68 and
69, respectively. Receptors 68 and 70 were crystalized from the solution
(10% water in DMSO) in the presence of tetrabutylammonium sulfate and
form X-ray suitable crystals. According to the X-ray single crystal analysis,
Kubik and Otto continued the studies on neutral cyclopeptide receptors all the oxygen atoms are involved in coordination in the hosteguest
68 complexes.
that selectively bind sulfate. In the recent work they reported on
combination of two cyclopeptides into macrobicyclic receptors 62e65, which
show extraordinary affinity (log K¼8.67) for sulfate in solution containing
67% of acetonitrile in water. Two cyclopeptides were connected via different
linkers during the template reaction at high dilution. The disulfide exchange
reaction between the cyclic precursor and the linker functionalized with thiol
residues is reversible and amplifies those products that bind the template with
the highest affinity. Sulfate, iodide, and selenate showed best amplifications O N
for bicyclic receptors indicating that N
N
OH N
N O N O
HN HN
SS O NH O NH
SS N N NN N

O O N
N
S S N N N
N
N N N
H O H O
66 67

N N
H H
NH HN
O O
NH HN
R R

NH
NH
68 70
these receptors bind templates with a considerable affinity.
According to the ITC measurements, all receptors have excellent 69
148
(2014) 137e167
Addition of Cl or F to a solution of 71 induces strong downfield shifts of
Selective binding of chloride and fluoride in a 20% water/DMSO mixture pyrrolic CH- and NH-signals. The exchange equi-librium was slow and
71 allowed the authors to determine binding constants by simple integration.
was studied by Sessler in the presence of ‘strapped’ calix[4] pyrrole 71.
 4
Calculations show that the receptor binds halide anions with affinity >10 M molecules. The same results were obtained after analysis of pK a2 of these
1
, when sodium or tetra-butylammonium cations were used as counterions. complexes: the higher the acidity of the imidazolyl NH (e.g., pK a2¼8.75 for
The NMR in-tegration method was suggested as an analytical tool for the 73), the higher the binding affinity for cya-nide. Simultaneously, the binding
detection of chloride. The method was successfully realized for high-ion sport process to NH protons co-operates with the binding to acidic CH-protons.
drinks to determine the chloride level with a good precision. This fact was unambiguously proved by synthesizing the receptor without the
CH-proton. For the first time the authors conducted time-resolved
measurements of fluorescence of hosteguest com-plexes and showed that
O hosteguest complexes live shorter time than free hosts.
O
N
O
H O
Appropriately designed urea-based receptors can also bind an-ions in an
N 73
H aqueous solution. This fact was proved by Yang and co-workers with
NH H HN receptor 74. According to the X-ray single crystal analysis, binding of
N phosphate results in the formation of a 2:1 li-gand/phosphate complex.
Solution measurements were conducted in a DMSO/25% water mixture with
1
the help of H NMR and UVevis titrations. The determined binding constants
1 1
for receptor 74 were low but still detectable: K11¼5 M and K21¼12 M for
1
TBAH2PO4 and K11¼4.73 M for TBAHSO4.

71
O
N N
H H
O NH HN O
Ye and co-workers reported ruthenium complexes 72 and 73, which can NH HN
72
bind cyanide anion in water (20 mM HEPES buffer, pH 7.0). This is an O2 N NO2
exceptionally interesting example of anion co-ordination in water. Binding of
cyanide is relatively efficient for water as a solvent, e.g., association constants
1
74
for 72 and 73 are 345 and 878 M , respectively. According to fluorescence
titra-tions, coordination of cyanide quenches the original fluorescence of
ruthenium(II) complexes, enabling detection of the anion. Receptors possess
high selectivity for cyanide over a range of inorganic anions. The detection
limit of cyanide is 5 mM. The cyanide anion is presumably exchanged with 4.2. Charged receptors
1
one perchlorate anion. As inferred from H NMR, COSY, and HMBC
The majority of classical charged receptors for anions are based on
measurements, both NH- and CH-donor binding sites participate in
13 polyammonium or guanidinium binding sites. In re-cent developments, water
coordination of cyanide. It was also possible to follow changes in C NMR
is used more often as a solvent for binding studies and new designs are
spectrum of cyanide anion upon mixing with the complexes. These changes
explored for stronger and more selective recognition. Particular attention is
were explained in terms of deprotonation of host
paid to cavitand-like structures synthesized by covalent synthesis or self-
assembly.

Fundamental investigation on the interaction between anions and triamine

74
was recently published by Bianchi and co-workers. This is a very important
investigation for understanding anion co-ordination in an aqueous solution by
H polyammonium receptors. Simple tren ligand 75 was selected for studies
N H because, in spite of often use in the design of anion receptors, its binding
N
properties were not fully investigated in water. The authors gathered complete
N N 2ClO4- thermodynamic and structural information about the hosteguest formation in
24 47
aqueous solution with the following anions: NO 3 ; SO ; TsO ; P2O ; and
510
N N
P3O . Interestingly, the tridentate binding mode was the most typical for
Ru2+ 3þ
H3L receptor according to the X-ray crystal structure. The complexation
N N
process was mainly entropically favorable, which is in accordance with
72 general elec-trostatic interaction model. However, some deviations for this
rule were observed, for example, the coordination of tosylate and phosphate to
a double-charged tren ligand. More favorable enthalpic effect for tosylate in
N N
comparison with other anions was explained in terms of less degree of
solvation, i.e., more freedom is lost after the formation of the hosteguest
complex. Binding of phosphate was also enthalpically favorable and
N N N H N N N entropically un-favorable. The authors suggested that phosphate binds to tren
H H þ
N 2+ N N 2+ li-gand by two types of hydrogen bonds O/NH and HO/N, resulting in
Ru Ru N
protonation of the amino group and deprotonation of hydrogen phosphate.
N N N N E.A. Kataev, C. Muller€ /
2ClO4- 2ClO4-
Tetrahedron 70 (2014)
137e167

73
HN
H H
O
H O H 2+
HN P O H 75H HPO42-
H N
O N H
 N receptors are polyamine cryptands, which are protonated at neu-tral and acidic
O
pH and thus offer several positively charged binding sites inside their cavity.
O The binding constants were determined with the help of potentiometry for a
range of dicarboxylates found in Nature. The authors plotted effective
HN
association constants versus pH; from this graph it was clear that highest
COOH
selectivity is achieved at pH 4.5 with the following preference: oxala-
te>fumarate>malonate>maleate>succinate>glutarate. The com-plexation
1
HO O O
process was also successfully observed in H NMR spectra, which indicated
fast receptoresubstrate exchange on the NMR time scale. Generally, receptor
76 79 binds dicarboxylates better than receptor 78, e.g., log Ka of receptors 78
and 79 for fumarate are 3.89 and 6.06, respectively. Experimental data show
that al-though receptor 79 has higher affinity for anions than 78, selec-tivities
for both receptors are similar. Higher affinity for oxalate was explained by the
authors in terms of higher anion charge density, rigidity of the anion, and
Pure electrostatic interactions for selective recognition of chloride by possible coordination of two carboxylate units to only one head unit of the
75 receptors. This fact was supported by the solid-state structure of the complex
receptors 76 were used by Tang and co-workers. The ratiometric probe for
chloride do not involve specific recognition principles but it is very sensitive be-tween 78 and oxalate.
for chloride anion in biological media thanks to selective quenching of
quinoline dye by chloride. Electrostatic interaction between anions and
commercially available PAMAM dendrimers was investigated by Anslyn and
co-workers. The absorption of fluorescein and carboxyfluorescein by the
dendrimers was followed with the help of fluorescence spectroscopy.
Extrapolation of absorption isotherm was used to calculate anion capacities of
76
the dendrimer.
N
NH HN HN
High selectivity for sulfate was achieved within the octahedral
arrangement of the binding sites of receptor 77 in an aqueous so-lution at pH
77 1
2.1. Binding of sulfate was followed in D 2O with the help of H NMR
spectroscopy and in the presence of the fully protonated receptor (with p-
HN
toluenesulfonic acid) receptor. The methylene and methyl protons shifted NH
downfield during the en-capsulation process. The encapsulation was also NH
evident in the solid phase and the hosteguest complex was characterized with
the X-ray diffraction analysis. The highest binding constants 3600 and 120 M
1
were detected at pH 2.1 for sulfate and nitrate anions, respectively. Other
anions were bound to the receptor with much less affinity. 78

N
NH HN HN

HN
NH HN

79
N
NH HN

The same group reported another polyamine cryptand re-ceptor 80 that

binds different inorganic anions in a MeOH/H 2O 1:1 (v/v) mixture at ionic
79
strength 0.1 M (potassium tosylate). Association constants (log Ka) range
NH HN from ca. 2 to 4 with the preference for sulfate, phosphate, and arsenate.
N
Although dihy-drogen phosphate has less charge than sulfate, receptor 80
binds phosphate selectively over a wide pH range. The maximum se-lectivity
is achieved at pH 7 according to the potentiometric ti-trations. High
77 selectivity was attributed to the presence of both donor (ammonium groups)
and acceptor binding sites in the receptor structure. This fact was additionally
proved by the in-vestigation of the receptors with phenyl rings instead of
pyridine rings.
150 E.A. Kataev, C. Muller€ /
Tetrahedron 70 (2014) 137e167
Delgado and co-workers developed two synthetic receptors that show
78
selectivity for fumarate over maleate in water. The
HN
NH
N
HN
N
 HN N increased up to 5.8 times and a new emission band appeared. This property
NH allows the utilization of the receptors as a fluorescent sensor for halide anions.
HN

Fu and co-workers developed the first sensor for sulfite anion that works in
84
aqueous solution (90% 10 mM TRIS buffer/DMSO, pH 7.2). Sensor 84
consists of a fluorescent guanidiniocarbonyl pyr-role moiety and an
80 anthracene residue. Thus, the receptor has two fluorescent dyes that form an
FRET in a single molecule. Binding studies show that in a sensoresulfite
mixture the anthracene moiety undergoes the intermolecular [4þ4]
photodimerization upon irradiation (Fig. 4). This reaction results in a
A receptor for pertechnetate anion that works in an aqueous solution was cancellation of FRET effect and enables ratiometric sensing of the anion. This
80
reported by Amendola and co-workers. According to the ITC in-teresting behavior makes the sensor highly selective for sulfite over the
measurements, the complexation of receptor 79 with the anion occurs in a 1:2 24 24 47
range of anions: F , Cl , Br , I , CH 3COO , SO ; HCO3 ; HPO ; P2O ;
0 0 1
fashion with DH ¼ 11 kcal/mol and TDS ¼3.35 kcal mol . The hosteguest NO3 ; NO2 . The calculated associa-tion constant for sulfite is 104 M and the
1
99
complex was additionally characterized in solution with Tc NMR and in the Job’s plot indicates a 1:1 stoichiometry of binding. The most competing anion
solid phase with the X-ray crystal structure analysis. Both methods provide an 1
is NO2 with the association constant 35 M . Additional experiments in pure
evi-dence of coordination of one anion in the cavity and the second anion out DMSO proved that the sensor dimerizes at room temperature un-der
of the cavity. irradiation, but this process is very slow. Addition of strongly coordinating
sulfite accelerates the process of dimerization. As inferred from the
Detailed studies on recognition of herbicide glyphosate were conducted by
81
experimental data the rate of dimerization de-pends on the sulfite
Tripier and co-workers. They synthesized a series of polyammonium-based 4
concentration, this allows sensing of sulfite with a detection limit 7.8 10 M
receptors and investigated recognition of different phosphates and 1
carboxylates with similar structures. Fluorescent derivative 81 showed .
82
excellent selectivity for glyphosate and ATP. Receptor 81 strongly interacts
1
with glyphosate in the pH range 6e11. According to H NMR measurements,
hosteguest interactions involve the interaction between the ammonium site of Great selectivity for sulfate in an EtOH/H 2O (v/v 9:1) solution was
glyphosate and nitrogen atoms of the linker in the receptor. For the interaction reported for squaramide-based receptor 85 in an indicator displacement assay
85
of 81 with ATP, the presence of pep interactions at basic pH was evident. with cresol red (CR) and bromocresol green (BG). The aqueous solution
was buffered with 10 mM TRIS buffer at pH 8.9. The dyes are displaced
selectively by sulfate and phos-phate from complex 85$CR and only by
sulfate from complex 85$BG. Such high selectivity allowed the authors to
H construct cal-ibration curves and detect sulfate content even in water well or
N
NH2 H2N NH spring water. The results were in a good agreement with the results obtained
from standard ionic chromatography. The authors also suggested a method
HN N NH
that allows one to determine a ratio of sulfate and phosphate anions in one
N N experiment by using two sensing complexes at the same time.
H H

N
81
O O
NH HN
O O
NH HN
N N
X X

N N N(CH3)4 (H3C)4N

I I

85
82 X = Br
O O
83X=I

New generation of receptors 82 and 83 for binding of halide anions was SO3
83
developed by Beer and co-workers. Coordination of anions occurs through a
so-called halogen bonding (XB). This class of receptors strongly interacts
with halide anions in organic media and even in a methanol/water 9:1 Cresol Red (CR)
mixture. Only Br- and I-con-taining receptors in the form of salts with PF 6 Br Br
O O
counteranion are
able to bind Br and I anions. For example, Br-containing receptor Br Br
82 binds Br and I anions with association constants SO3
2.88 104 M 1 and 6.31 5 1
10 M , respectively. Interestingly, upon
formation of hosteguest complexes, the fluorescence intensity was
Bromocresol Green (BG)

Another sulfate selective sensor based on similar binding motifs was

86
developed by Costa and García-Espana~. The receptor
E.A. Kataev, C. Muller€ /
Tetrahedron 70 (2014)
137e167
 FRET O N O NH2 O N

O O NH H HN NH H
NH O NH2
N NH2 SO32- 2- 2 hν HN
H
NH HN SO3
NH2
NH2
SO32-
SO32- 2-
H NH2 SO3
NH HN NH
N NH2
O OH O H NH2
HN
NH2
84 N O

Fig. 4. Photodimerization process of receptor 84 induced by sulfite.

for anions. According to the potentiometric measurements in two different

moieties are grafted on the surface of boehmite ( g-AlO(OH)) or silica coated
boehmite nanoparticles (structure 86). Sensing of anions is realized by means
of the indicator displacement assay (IDA) with bromocresol green (BG) as a
dye, which changes its color from yellow to blue upon displacement from
nanoparticles as a result of a protonation event. The sensor system works at
pH 3.4 in acetate buffer and binds sulfate anion with affinity log Ka¼4.89,
which is 30-fold higher than the most competing phosphate anion (log
Ka¼3.33). All functional groups are working together to bind sulfate anion
with good selectivity. Neither the squaramide func-tion nor the ammonium
group alone is efficient to bind the anion in pure water. To explain the
selectivity of the sensor the authors suggested that sulfate exists as a dianion
at pH 3.4, but phosphate exists as a monoanion at this pH value. Different
mono-, di-, and tri-carboxylates were tested to displace BG dye to understand
the dependence of the charge. Although all carboxylates exist as near
monoanions at pH 3.4, tricarboxylates were able to displace the dye. This
means that surface charges of anions and surface effects generated by the
colloidal particles should be taken into consid-eration to find an explanation
for such behavior.
(H3C)3N
NH2
O
NH
O
NH
Si
OO
HO O
ionic media, 0.15 M NMe4NO3 and NMe4Cl, the association constant
between Cu(II) and the ligand is 3.4 logarithmic units higher in NMe4Cl than
in NMe4NO3 solution (13.63 vs 10.28 loga-rithmic units, respectively). On
the basis of these data it was hy-pothesized that the obtained value is the
2þ
affinity of chloride to [CuL] complex. UVevis titrations conducted in 0.05
M MES buffer at pH 6.1 were in a good agreement, e.g., log Ka for F , Cl ,
and Br are 4.8, 3.9, and 2.7, respectively. The pH of solution for binding
studies was chosen from potentiometric titrations of the ligand in the presence
2þ
of Cu(II). The titrations show that at pH 6.1 the [CuL] is virtually the only
existing species. At higher pH values weak or no binding was detected
because the only coordination place on Cu(II) was occupied by a hydroxide
anion.
In the next publication binding properties of free ligand 87 and its Zn(II)
complex were studied in detail for the following anions: chloride, bromide,
iodide, nitrate, perchlorate, sulfate, phosphate, and pyrophosphate.
88
Association constants were determined by potentiometric titrations in aqueous
0.15 M NaClO4 solution. In-terestingly, the ligand shows high selectivity for
24
phosphate over other inorganic anions: log K a for SO ; H2PO4 ; and
27
H2P2O are 2.96, 4.04, and 2.56, respectively. The authors suggested
analyzing the selectivity of the ligand by plotting a distribution species of
equilibria for all anions in the same graph as a function of pH. From this
graph it was clearly seen that selectivity for phosphate is high in the range
1
4<pH<10.5 with a peak of selectivity at physiologically important pH 7.4. H
NMR titrations revealed that NMR is not very sensitive method in water
because the guest to be bound replaces the water molecules solvating the
binding site and this process does not strongly change the magnetic
surrounding of the host. The Zn(II) complex of the li-gand showed binding
properties toward halides and is able to bind Cl and F in aqueous solution.
þ
Unfortunately, the formation of complex [ZnLOH] over a broad pH range
limits the ability of the complex to bind anions. Thus, the previously studied
Cu(II) complex is a better anion receptor than the analogues Zn(II) complex.

Morey and co-workers also used squaramide units in the design of tripodal
86 receptors 88 and 89 for recognition of folic acid in 0.25 M TRIS buffer at pH
O 89
O 9.0. The affinity of the receptors for folate-related anions was higher (ca.
NHHN 3 4 1 2 1
10 e10 M ) than for the gluta-mate anion (6 10 M ). It was suggested on
O O
the basis of quantum chemical calculations that the reason for the selectivity
HN
NH for folate-related anions is additional hydrogen bonds formed between OH
group of the pterin ring and squaramide moieties. Additionally, a cationep
N N
N
interaction was proposed for the interaction of pteroic acid with the receptor.
With the help of the indicator displacement assay in the presence of 5-
N carboxyfluorescein the receptors can detect folic acid in commercial samples.
In the next work, func-tional squaramide arms were attached to the surface of
90
87 magnetic nanoparticles. This material was able to detect mono- and
dicarboxylates in an aqueous solution with good selectivity against
tricarboxylates and inorganic anions. For example, the binding constants for
An interesting design for anion receptors was suggested by Fusi and 5 1 2 1
citrate and glutamate were 1.1 10 M , and 2.8 10 M , respectively. Similar
Michenoni. They combined two binding sites in a cryptand like receptor strategy was used to detect
87 152 E.A. Kataev, C. Muller€ /
(87)dmetal binding site and hydrogen-binding site. With this design it was
Tetrahedron 70 (2014) 137e167
possible to bind fluoride selectively and override strong solvation in water.
The binding chain contains two squaramide units, which offer rigid and
preorganized binding sites

orthophosphate in a CH3CN/H2O 4:1 (v/v, pH 6.5 10 mM TRIS buffer)

91
solution with pyridinium-based receptor 90 attached to a Merri-field resin.
The material showed good selectivity and was tested on blood serum samples
to measure the phosphate level.
 An interesting approach for construction of selective receptors for
biologically important compounds was suggested by Matsui and co-
92
workers. They synthesized different peptides and selected the best one that
can coordinate ATP with high affinity and selectivity in an aqueous solution
(complex 92). A random selection, rational design, and molecular imprinting
were used to discover a new structure of a selective receptor. Taking into
consideration the structure of the active site of biotincarboxylase for binding
of ATP, the authors started with a conventional split-and-mix procedure to
generate a sequence to bind ATP. Among the selected peptides, Resin-Lys-
Gly-Arg-Gly-Lys-Gly-Val-Gly-Lys-NHAc was chosen as an initial precursor
for muta-tion. Arg and Lys residues in this structure provide electrostatic in-
teraction to bind ATP. It was found that replacing Val-Gly with Glu-Lys-Tyr-
Leu increases the affinity for ATP because of the additional pep stacking
interaction between the tyrosine residue and the ade-nine base. The resulting
sequence was further subjected to cross-linking in the presence of ATP as a
template with the help of di-methyl adipimidate (DMA) and dimethyl suberimidate
(DMS). The first modification appeared to lead to a superior affinity polymer, which
is about 5.3 times higher than the open chain precursor. Ratios of binding constants
KATP/KADP and KATP/KGTP were increased in this case from 2.4 to 19 and from
0.8 to 10, respectively.

O H O
NH2 N
HN N O NH
H O
O OH HN O
N O
H O
HN N H NH
N OH H3N O O
O N H OH O O
O HN NH
H2N HH P OH
N OO
NH2 O OP O
H N
HN P O 2
O O- N NH
H2N
O HN NH H
H O
Steed and co-workers explored a concept of anion encapsulation with the N
70 HN
help of zwitterionic receptors. The authors prepared receptor 91 that binds Resin
92 ATP
bromide by forming a capsular complex in a 2:1 ligand/bromide
stoichiometry, where the bromide anion is encapsulated between two
receptors. Experiments to prepare a sample of completely free receptor
1 Water-soluble receptor 93 was developed by Schmuck and Kuchelmeister
unfortunately failed. However, addition of AgPF 6 reveals some shifts in H
93
NMR spectrum in-dicating the formation of the free host. This work shows to bind AMP nucleotide. The receptor has a twee-zers-like structure with
that electrostatic interactions used for self-assembly are very effective even in two guanidinium groups on the ends. Binding constants for nucleotides were
a highly competitive medium such as water. measured in a buffered aqueous solution. The association constants are in the
5 6 1
range of 10 e10 M . The receptor is selective for AMP over ADP and ATP
but binds cAMP, CMP, UMP, and GMP with the same affinity as AMP.
According to the NMR investigations and molecular modeling such an
efficient coordination is achieved thanks to a combination of electrostatic and
pep stacking interactions.
N

O
NH
N NH
2PF6-
O
N

90

O O
N

O
N O

91
E.A. Kataev, C. Muller€ / Tetrahedron 70 (2014) 137e167 153

solution. The enhancement of selectivity was explained in terms of high

Two positively charged pyrrole-based receptors 94 and 95 were reported hydration energies of basic F and H2PO4 .
by the groups of Sessler, Lee, and Hay. Receptor 94 is a calix [4]pyrrole
94
functionalized molecule with two pyridinium groups. This host binds
7 1
pyrophosphate (Ka¼2.55 10 M ), fluoride, dihy-drogen phosphate, and
acetate in acetonitrile with high affinity. The complex of the host with a
coumarine dye works as a ‘turn-on’ fluorescence sensor, in which binding of
an anion leads to the dis-placement of the dye. Interestingly, when water is
added in the amount of 30% the binding constant for pyrophosphate is ca. 1/7
of the value obtained in pure acetonitrile. Affinities for fluoride and
dihydrogen phosphate were reduced even stronger (ca. 1/276 and 1/ 240 fold),
respectively. Thus, the selectivity for pyrophosphate is higher in an aqueous
 N N

N N

-
4Br
N N

N N

Excellent binding properties in an acetone/water mixture showed receptor 96

95. The host consists of a neutral pyrrole and positively charged triazolium
95
binding sites for anion coordination. Detailed analysis of binding constants
in acetonitrile, methanol and in an acetone/water (2:3, v/v, pH 7.2 HEPES
buffer) mixture shows that association constants are lower in aqueous medium
4 5 1 bind cations and anions simultaneously in a water/acetonitile (2:98, v/v)
by 1e2 orders (10 e10 M ) of magnitude but selectivity for sulfate is
retained. Crystal structures of 95 with pyrophosphate and dihy-drogen
phosphate emphasize that acidic NH, CH, and neutral aro-matic CH protons
are involved in coordination with the anion. Since the host consists of binding
sites of different nature, the authors analyzed each contribution in different
solvents with the help of quantum chemical calculation. The results support an
þ
interesting conclusion that (CH) eanion interactions in water as a solvent are
less important than neutral CHeanion interactions.
Yoon investigated the receptor that binds myo-inositol phos-phates (IP n,
where n¼1e6) by receptor 96 in DMSO/HEPES buffer (1:9, v/v, 0.02 M
96
HEPES, pH 7.4). The most interesting target for recognition and sensing is
2þ
D-myo-inositol 1,4,5-triphosphate (IP3) because it controls cellular Ca
concentrations. A series of phos-phates were tested to understand binding
preferences of the host. According to the fluorescence measurements, addition
of guests to a solution of the host induces a decrease in the excimer band in
the pH range between 5 and 8.5. The most efficient quenching was induced by
IP3, which indicates the preference of the receptor to bind this analyte. The
7 1
calculated association constant is 2.31 10 M , which corresponds to a 1:1
stoichiometry. NMR studies provided an evidence that both benzylic CH 2-
and imidazole CH-fragments are involved in hydrogen bonds with oxygen
atoms of the phosphate residues.
4.3. Receptors for ion-pairs
Beer and co-workers synthesized several heterotopic receptors, which
97
mixture. Receptors 97 and 98 consist of calix[4]diqui-none part for binding
cations and hydrogen-bond-donor sites for anion coordination. Detailed
1
binding studies were performed with the help of UVevis and H NMR
spectroscopy to understand how strong these receptors bind cations, anions,
and ion-pairs. Coopera-tivity and simultaneous binding of cations and anions
were evident from the association constants for PF 6 salts of cations in the
absence and in the presence of tetrabutylammonium (TBA) salts of anions.
þ þ þ 4 1
For example, receptor 98 binds Na , K , and NH 4 with K11>10 M in the
presence of chloride in solution, while in the presence of bromide the binding
3 1 98
constants are in the order of 10 M . Interestingly, addition of
tetrabutylammonium chloride to a solution without a cation in-duces no
changes indicating that binding is very weak. When the linker was changed to
triazole linker (receptor 99), it was possible to detect affinity of the receptor
for single ions. For example, association constants of 99 with NaPF6 and
1
TBACl are 460 and 178 M , re-spectively; however, if the titrations are
carried out in the presence of TBACl with NaPF6, the observed association
1
constant is 1000 M .
OO
OOO O

O O

NH HN

97 R = t-Bu
98 R=NO2

O O
O O O
O

N N
N N
N N

NH HN

O O

99
154 E.A. Kataev, C. Muller€ /
Tetrahedron 70 (2014) 137e167
 The goal of selective anion recognition is often a practical ap-plication, for O O
O H O
example, a detection of concentrations of target an-ions in solution. Several NO
publications are dealing with the detection of anions in water, wherein a low- H
N
selective binding is converted to a highly selective recognition with the help O
of additional physical of chemical events. For example, cross-reactive sensors O O O O
99 HO OH
often possess high selectivity in different solvents including water. Anzen- O OH
HO O
bacher and co-workers were interested in sensing and discrimi-nation of ion-
pairs in water. This goal they achieved by using an array sensor composed of
0 0 100
six ‘off-the-shell’ pH-indicators (fluo-rescein, auramine, ethyl eosin, 4 ,5 -
0 0 OH
dibromofluorescenin, 2 ,7 -dichlorofluorescein, and an urea derivative of HO O
O
100
fluorescein) doped into polyethereurethane matrix. Polyethylene oxide O
OH O
NO
chain pro-vides coordination of cations, while urethane amides bind anions H
through amides hydrogen bonding. There were 35 inorganic salts tested NO

þ þ
þ þ O
consisting of five cations (Li , Na , K , NH 4, and tetrabuty-lammonium) O O
O
and seven anions (F , Cl , Br , I , CH 3COO , NO3 ; H2PO4 ). Cross-validation O
O
of the array sensor was carried out with the help of fluorescence and UVevis HO HO O
spectroscopy at different pH values. The assessment of individual contributors
is very diffi-cult for sensor arrays. It was clear that pH indicators feel local pH 101
changes in the material. The ions penetrate the uppermost polymer layers and O O
þ O O
influence the H /OH balance. The system possesses an excellent O O O O
discrimination capacity and recognition accuracy ( 93%).

HO OH
O OH
HO O
5. Receptors for small organic molecules 102
OH
Recognition and sensing of bioactive lipids might be very useful for
biochemical research. Glass and co-workers synthesized and in-vestigated a O HO O
new class of tube-like compounds, which can encap-sulate linear and O O O
101
branched lipids and produce a selective fluorescent signal. For the design O
O O O
of these receptors, naphthalene rings were used because they are known as
environment-sensitive fluorophores in order to detect recognition with the
help of fluorescence spec-troscopy. Four receptors (100e103) were
O O
synthesized and in-vestigated in a buffered (20 mM HEPES) aqueous solution HO HO O
1
at pH 8.4. According to the UVevis and H NMR titration, the changes in
spectra induced by addition of lipids to receptors were too small to calculate 103
association constants. Therefore, the only reliable method for the detection of
binding event was fluorescence spectroscopy. Hydrophobic guests show in
general higher association constants. Receptors 100 and 101 show different Pillar[n]arenes are supramolecular hosts that show excellent binding
fluorescence changes during titration with guests. Fluorescence decrease was properties to a range of different guests in an aqueous solution. Ogoshi
detected for 100, while receptor 101 induced in general a fluorescence reported for the first time the synthesis of water-soluble pillar[5]arene
increase; however, quenching was observed for short and branched lipids. 102
(105). He determined the binding con-stant of the host with paraquat,
This difference in fluorescence response is explained in terms of confor-
4 1
mational lability of the receptors. It is suggested that 100 exists in aqueous which is 8.2 10 M in D2O. UVevis titrations allowed the authors to observe
solution in a collapsed form and upon binding of short or branched lipids the the complex formation by appearing of a new charge-transfer band thanks to
receptor does not change its conformation and thus small fluorescence close interaction of two aromatic compounds. Huang and co-workers
increase is observed. However, binding of longer lipids leads to threading the investigated the hosteguest complex in water between pillar[6]arene 104 and
cavity of the host and this causes the receptor to adopt open conformation, paraquats 1 and 2. The stability of the complex is high and comparable to the
1 stability of cucurbiturils and cyclodextrin complexes with organic
which leads to a fluores-cence decrease. This hypothesis was supported by H 103
NMR binding studies, in which small shifts of aromatic signals were molecules. The only dif-ference from the known hosts is the fact that
observed. Receptors 102 and 103 bind lipids much stronger, thanks to a more pillar[6]arene bears carboxylate groups and thus, a negative charge at neutral
hydrophobic cavity. Binding events for these receptors are accom-panied with 8 1
pH in water. The association constant with paraquat 1 is 10 M according to
a fluorescence increase (Table 1). fluorescence titrations. This is 4 orders of magnitude higher than the
association constant between paraquat and pillar [5]arene 105 because of the
102 1
better geometrical fit. H NMR in-vestigations prove the fact that paraquat
threads the cycle and the stabilization of the hosteguest complexes is achieved
Table 1
through pep stacking interactions. If the pH of the solution is changed to
1
Selected binding constants (Ka, M ) for different acids
acidic, decomplexation was observed by UVevis spectroscopy. Thus, the
process of threading and dethreading is reversible and can be controlled by
100 101 102 103 changing the pH of solution. Binding studies were also conducted with
Hexanoic acid 100 72 800 d amphiphile paraquat 2, which induces vesicle formation at pH>7 and micelles
Decanoic acid 3500 3800 180,000 120,000 at pH<7. This reversible trans-formation was utilized to control the release of
Dodecanoic acid 18,000 27,000 520,000 320,000 water-soluble dye calcein, a hydrophilic fluorescent guest. Additionally, the
Heptylamine 16,000 16,000 980,000 3,100,000 authors
1-Heptanol 4900 6700 430,000 230,000 E.A. Kataev, C. Muller€ /
Tetrahedron 70 (2014)
137e167
principle of the controlled release of guests from micelles was also realized by
demonstrated that the formation of the hosteguest complex be-tween paraquat 104
Huang employing crown ether based receptors instead of pillar[6]arene.
and pillar[6]arene decreases significantly the tox-icity of paraquat in cells. The
OR

RO
 varies from 0.18 to 1.41 for different guests. Thus, the rule suggested by
RO RO Rebek that the best binding would be when the volume of a guest is ca. 55%
RO
OR

OR 106
of the inner cavity of a host, is not applicable for this zinc-cage. Relative
affinities of the host for guest molecules were determined by a competition
RO OR OR
experiment, namely by the rate of displacement of adamantane with other
OR guests. Thus, the strongest binding was observed for cis-decaline. The authors
RO explained this observation by flexibility of the host molecules and ability to
adjust its conformation to the shape of a guest. Another interesting rule was
104 suggested on the basis of experimental data. The order of stability of the
hosteguest complexes is parallel to the order of the solvent accessible surface
RO area (SASA) of the guest, the host and the hosteguest complex. The DSASA
OR values are calculated as DSASA¼SASAGþSASAH SASAHG. All the
1
RO RO complexes were char-acterized with H NMR spectroscopy in an aqueous
OR solution and for some of them X-ray single crystal data were collected.
RO
OR OR
OR
The influence of the presence of water on the formation of hosteguest
RO
107
complexes was investigated by Szumna. The work describes the synthesis
105 of capsule-like molecule 107, which forms a dimer held by hydrophobic
108
interactions. The interaction of this receptor with a-hydroxy acids was
studied in toluene or in a toluene/ water mixture. The complexation of the
N dimeric host with 2-hydroxysuccinic acid in toluene proceeds with a 1:2
N
stoichiometry. However, the presence of water changes the stoichiometry to a
1
2Br
-
2Br
- 1:1 ratio. H NMR studies demonstrate that the symmetry of hosteguest
complexes is different in toluene and in a toluene/water mixture. The authors
N N
proposed that water could be encapsulated in the cavity of the host instead of
C H
a-hydroxy acids and can influence the stoichi-ometry of binding and
11 23 symmetry of the hosteguest complexes. Al-though the dimeric host has good
discrimination ability between different enantiomers of acids in toluene, this
property was sup-pressed by the presence of water. Probably, the higher
flexibility and lower stability of the dimer are the reasons for this observation.

Paraquat 1 Paraquat 2

Aoki investigated a cuboctahedral molecular cage as a receptor for

105
hydrocarbons and related compounds in water at neutral pH. The cage is
kinetically stable and consists of a tris-Zn(II) cyclen-complex and
trithiocyanuric acid building blocks, which are con-nected with each other in a
4:4 ratio through ZneS bonds (Fig. 5, 106). Binding studies in water show
that efficient coordination is present for hydrocarbons C2H2 nþ2 (n¼1e10),
adamantane, cis- and trans-decaline, cyclododecane and (R,R)-bis( a-
methylbenzyl) amine. Interestingly, n-butane and n-octane are quantitatively
en-capsulated in the cage, while negligible inclusion was observed for n-
dodecane. Some other alkanes, like n-nonane and n-decane were only partially
encapsulated, ca. 20% and 8%, respectively. The van
3
der Waals volume of the inner cavity of the cage is 160 A . Sur-prisingly, it
appeared that the cage is able to encapsulate guests with larger volumes. For
example, the volume ratio Vguest/Vinner host
S
NH NH HN NH

Zn S N S
N NH H TCA
NH NH hydrocarbon
NH Zn + -3H
N water, pH 7.0
N S
NH
N N
Zn
NH
NH S N S 106 Yoshiziwa developed new bowl-shaped organic host 108 for recognition
109
TCA of aromatic compounds in an aqueous solution. This host consists of
anthracene moieties connected through positively charged pyridinium
fragments. X-ray crystallographic analysis of the host revealed the presence of
acetone molecules in the inner
Fig. 5. Self-assembly and structure of cuboctahedral molecular cage 106. 156 E.A. Kataev, C. Muller€ /
Tetrahedron 70 (2014) 137e167
1
For-mation of complexes was followed by H NMR spectroscopy, wherein
cavity. The receptor forms an open-ended hydrophobic cavity, wherein the aromatic signals of the guest shift from 7 to 5 ppm.
pyridinium Lewis acidic centers are bound to oxygens of the encapsulated
acetone. Thus, the authors investigated binding properties of the receptor
Loeb and co-workers succeeded in synthesis of a rotaxane, in which a
toward different aromatic guests con-taining carbonyl groups. For example,
wheel and axle interact with each other through several non-covalent forces:
the host quantitatively en-capsulates benzoin in a 1:1 stoichiometry in D 2O. 110
ionedipole, pep stacking, and significant electrostatic interactions. The
However, smaller polycyclic guests are encapsulated with a 1:2 stoichiometry.
presence of electrostatic interaction allowed the authors to transfer the
complexation process in an aqueous solution. Namely, a crown ether was þ
cofactors. The proposed mode of coordination of NAD is similar to that
functionalized with sulfonate groups (109) to carry a negative charge and to proposed by Schrader for his receptor.
52
interact with 1,2-bis(pyridinium)ethanes (110e113). Stability constants of the
hosteguest complexes are relatively high in such solvents as meth-anol and
1
acetonitrile (Ka>100 M ). Binding is also sufficiently strong to be detected O O O O
-
SO3- n SO3
1
even in a mixture of 50% CD 3OD, 40% D2O, and 10% DMSO (v/v) by H +
4Na
NMR spectroscopy. The corresponding con-stants for complexes of the crown
1
ether (109) with guests 110e113 are 0.5, 3.7, 0.5, and 7.7 M , respectively.
SO3- SO3-
The energy impact of the ioneion interactions was reported as D(DG)¼ 5.1 O O O O
1
kJ mol , according to the double-mutant cycle. X-ray single crystal structures n
of the hosteguest complexes support strong stacking interactions between the
components. 114 n=1
115 n=2

O Guests for 114 and 115

X
O S
O N R
O
N
O O
-
R N 2Br
O O
N 116 R=H
O O

S
O 117 R=CH3
X O 118 R=CH2CH2CH3
O
109 Guest
119 N Br
-

Guests for 114

110 X= 4-COOEt
111 X=3-COOEt A number of artificial receptors were developed by Otto and co-workers
112
by using the dynamic combinatorial approach. The au-thors showed that
112 X=
N even with a large number of members in the library it is possible to reveal the
best binder for a molecule of in-terest. A library of 9000 compounds generated
113 X= 113
from 8 compounds was used to develop a new receptor for ephedrine. The
N
library was generated from building blocks, which react with each other
reversibly through the disulfide bond. When all starting com-pounds mixed in
one pot, a library is generated. Addition of a target molecule shifts the
114
equilibrium to the best binder. With this approach two best binders for
ephedrine were identified with the help of LCeMS. These compounds have
structures (120)2(121)2 and (120)(121)3 and bind ephedrine in a 50 mM
4 4 1
borate buffer at pH 8.0 with affinities 1.3 10 and 1.5 10 M , respectively.

Crown ethers usually can coordinate cations in water with affinity

5 1
reaching 10 M . Liu and co-workers developed tetrasulfonated hybrid crown
ethers 114 and 115, which bind bipyridinium cations with association
7 1 111
constants as high as 10 M in water. The as-sociation of receptors 114
þ
and 115 was investigated with guests 116e119 and with cofactors NAD and
1
NADH by H NMR spectros-copy and isothermal titration calorimetry (ITC). While ephedrine bears several hydrophilic groups, nicotine, another target
The binding process is strongly enthalpically favored, especially for receptor for finding an artificial receptor, is rather hydro-phobic molecule (log D¼0.41
114. Binding of guest 119 is 2 orders of magnitude weaker than binding of at pH 7.4). Two building blocks were prepared to generate a library of cross-
guests 116e118. X-ray crystal structure analysis of hosteguest complexes 115
reactive macrocyclic com-pounds in an aqueous solution. The building
indicates the presence of strong pep stacking interactions between aromatic
rings of the host and the guest. The average distance in the blocks are designed taking in mind that they should interact with nicotine
through pep and cationep interactions. As inferred from LCeMS spectra, the
1 presence of nicotine in the library strongly amplifies the formation of
face-to-face stacking between aromatic rings is 3.4e4.0 A. According to H
NMR studies, the complexation induces upfield shifts of both signals heterodimer 122. A detailed analysis of binding properties in 50 mM borate
þ buffer at pH 8.4 by isothermal titration calorimetry (ITC) revealed that the
belonging to the host and to the guest. Only NAD can bind to receptors with
3 1
relatively good affinity 2.21 10 M , while no binding could be detected for receptor binds nicotine with affinity
E.A. Kataev, C. Muller€ /
NADH. The present results open a perspective of an application of crown
Tetrahedron 70 (2014)
ethers in recognition of 137e167
O NH
HN O
3 1
1.81 10 M . At pH 6.9 and 9.3 the affinity was in the same order of O O
magnitude, indicating that the cationep interaction is not present and the OH S S OH
major contribution to the binding originates from pep stacking and
hydrophobic interactions. S S
HO O

O O
S
S
122

A series of guest-binding investigations were conducted with organic
116,17
capsules 123 and 124 by Gibb and co-workers. These
organic capsules are prone to form dimer complexes in the presence of guest
molecule, especially hydrophobic guests like alkanes. In-terestingly, these
types of guests possess nonmonotonic assembly in the raw of alkanes with
117
increasing chain length. Thus, receptor 123 binds ethane in a 1:1
stoichiometry, while binding of larger guests starting from propane induces
dimerization of a receptor together with encapsulation of the alkane in an
aqueous solution. Receptor 124 bearing methyl groups forms in most cases
118
1:1 com-plexes, while n-pentane triggers the formation of a 2:2 complex. If
the assembly process is carried out in the presence of both receptors 123 and
119
124 and a guest, then a heterodimer complex is formed as a major product.
A capsule-like molecule was also obtained by covalent linkage of two
receptors producing a receptor with high affinity for alkanes with length up to
C26. According to analytical investigations, long guests adopt different
120
packing conforma-tions. Interestingly, receptor 123 can also bind
hydrophobic an-ions in 10 mM phosphate buffer solution at pH 11.3. The
authors were able to measure the affinity of the host for sodium perchlorate by
displacing adamantane carboxylic acid with the salt. Association constant K a
1 1 121
for NaClO4 is 95 M , as determined from direct H NMR titrations.
Among the binding studies, the dynamics of the en-capsulation process was
also investigated. It was shown that the dissociation of the complex of pyrene
encapsulated in the dimer 1232 is 5 orders slower than the opening and
122
closing process of the dimer. A property to bind hydrophobic guests was
further in-vestigated in the kinetic resolution of isomers of esters during the
123
hydrolysis. Thus, it was possible to show that those guests that
126
remained almost the same. New receptor 130 binds all-equatorial
monosaccharides with selectivity for D-glucose and methyl b-D-glu-coside.
The new structure offers fluorescent sensing of glucose in blood samples. In
the recent publication, Davis and co-workers found that receptor 127 has
excellent affinities for all-equatorial di-saccharides under biomimetic
conditions. This finding suggests that ‘induced fit’ or ‘conformational
selection’ can be superior than rigid preorganization in carbohydrate
127
recognition.
6. Thermodynamic effects
Binding of organic molecules in water by artificial receptors is governed
by similar rules as binding by natural enzymes and an-tibodies. Several
common features between natural binding events
and those observed for synthetic receptors were described by Houk and co-
128,129
workers in their review article. One can divide all the
classes of host molecules according to their binding affinities into three major
3 1 6 1
groups: association constants of 10 M , 10 M and higher. This order
corresponds to interactions in synthetic or nat-ural receptoreguest complexes,
enzymeeinhibitor, and enzyme-transition state complexes, respectively.
Interestingly, association of synthetic hosts with guests, like cyclodextrins, is
almost the same order of magnitude in water as in enzymeesubstrate com-
strongly bind to the dimer are more difficult to hydrolyze because more guest
molecules are encapsulated than present in solution. Interesting binding
properties in water were obtained by Brotin, Buffeteau and co-workers for a
cryptophane, composed of two cyclotriveratrylene units. This host previously
was shown to co-ordinate strongly xenon in organic solvents and in an
160
aqueous so-lution. Later, the authors demonstrated efficient binding of
halomethanes and even enantioselective encapsulation of pro-pylene oxide,
epichlorohydrin, and 1,2-epoxybutane in basic
D2O.161e164
HOOC
X X
O O
O O
R R
HOOC COOH
R R
O O
O O
X X
R = CH2CH2COOH
COOH
123X=H
124 X = CH3
Recognition of carbohydrates in aqueous solution is extensively studied
124
by Davis and co-workers. Receptors 125 and 126 were studied in different
solvents to show that the affinity of these re-ceptors for glucose decreases
5 1 1
from 3 10 M in chloroform to 9.2 M in water. The binding process is
largely enthalpy-driven (e.g., binding of cellobiose by 126 DH¼ 3.22 kcal
1 1
mol , TDS¼0.62 kcal mol ) albeit the major contribution to the binding
comes from hydrophobic forces. This energetical profile is seen by the authors
as a nonclassical hydrophobic effect. The binding con-stants of the receptors
are low but it should be kept in mind that lectinemonosaccharide affinities are
3 1
often less than 10 M . The studies on receptor properties of 125 showed that
it is unusually
selective for b-N-acetyl-D-glucosaminyl (128), which is a monomer building
125
block for chitin. The affinity of the receptor for 128 and its
1
methylated derivative 129 is relatively high in water, 56 and 630 M ,
respectively. NOESY experiments clearly show the encapsulation of the
sugars in the cavity. In the later work, the structure of the re-ceptor was
considerably simplified albeit the affinity and selectivity
158 E.A. Kataev, C. Muller€ /
Tetrahedron 70 (2014) 137e167
3 1
plexes (10 M ). This fact indicates that there is a common feature between
natural and synthetic hosteguest complexes. Recent in-vestigations on the
hosteguest interactions in water provide more and more evidence that this
common feature is simply water.
Already in 1994 Gilli and co-workers during the analysis of the linear
relationship between DH and TDS (enthalpyeentropy com-pensation) for
biological receptors realized that the binding en-thalpy is mainly determined
by the ‘energetic balance of the hydrogen bonds formed by the reaction
partners before and after the binding event’, and the binding entropy ‘is
130
essentially a re-distribution of hydrogen bonds’ between water molecules.
Thus, Baron and Setny stated a question ‘is water a passive player, only
embedding cavityeligand recognition or a driving player?’ To an-swer this
question the authors used a straightforward computa-tional approach and
described complete thermodynamic parameters of the cavityeligand
recognition. Seven systems were investigated with different physicochemical
properties of the cavity and the ligand. Surprisingly, despite the simplicity of
the system, this model generated data close to the observed values for enzy-
meesubstrate interactions. The results suggest that waterewater interactions
determine the energy profile of the binding event. Therefore, water plays a key
role in the binding process. Due to this effect, the overall free energy is of
similar magnitude for hydro-phobic- and electrostatic-driven binding
131
events.

Cucurbiturils do not fall in the range of molecular hosts with average
binding affinity. These hosts have exceptionally high af-finities for a number
of different guests in water. De Simone and co-workers proposed an idea of
‘high-energy water release’ based on quantum calculations that explain
132
extraordinary properties of cucurbiturils. Following the calculation of
potential energy of water release from the cavity maximum was reached for
CB7 (if compared with CB6 and CB8) because the cavity of CB7 does not
allow water molecules to arrange in an energetically stable hy-drogen bond
network. This explains the experimental fact that CB7 possess highest affinity
in water.
To assess the energy of complexation, changes in the surface accessible
area of the guest or host are often taken into consider-ation. It was Connors,
who analyzed binding constants of cyclo-dextrins for different guests and
could predict 95% of 569 binding events by using DSAHSAdchanges in
133
surface accessible hydro-phobic surface area of the host. This idea
originates from the observation of the hydrophobic effect for hydrocarbons,
which spontaneously aggregate to minimize the exposed solvent
accessible surface in an aqueous solution. The process of aggrega-tion is
entropically favorable because water has less order in bulk solution than in
vicinity of a hydrophobic surface, where water forms so-called ‘icebergs’.
Houk and co-workers also analyzed the relationship between average binding
constants and average sur-face areas buried upon binding for natural
129
complexes. The au-thors found a clear trend between these two parameters
and
calculated that by burying 67 A of accessible surface area of a guest one
1
generates 1 kcal mol of binding energy.
For example, calculations of solvent exposed surface area of guests helped
Urbach and co-workers to understand the preference of cucurbit[8]uril to bind
56
Phe, Trp, and Tyr amino acids. It is appeared that these guests expose the
largest volume of water and at the same time are most hydrophobic ones
among other amino acids. Another interesting investigation on elucidation of
134
solvent effect was conducted by Raymond and co-workers. The authors
attempted to understanddwhat kind of driving forces control the encapsulation
process in an aqueous environment. As a target re-ceptor they investigated
cage molecule 1 (Na12[Ga4L6]), which en-capsulates iridium complexes
bearing alkyl residues. The studies were carried out in three different solvents:
water, methanol, and dimethylsulfoxide (DMSO). Guest molecules were
i
chosen so that they have different sizes (Me, Et, Pr, and Pr substituents) and
dif-ferent hydrophobicity (perfluoroalkyl residues). Although the host binds
3 4 1
many different guests with relatively high binding constant (ca. 10 e10 M
in water), there were a number of strange prop-erties. First, most of the guests
that bind with high affinity are monocationic; however, the host is highly
anionic and should bind dicationic and tricationic guests better because of the
stronger electrostatic interactions between the host and the guest. Second, the
host binds neutral guests too, suggesting that there are other forces involved in
þ þ
binding. Third, strongly solvated monocations such as Li and Na are not
encapsulated.

After the first analysis of the thermodynamic data in Table 2 it is clear that
in water or methanol large and hydrophobic guests are bound enthalpically
favorable but entropically unfavorable. The trend in DMSO is
oppositedbinding of the larger guests is enthalpically unfavorable and
entropically favorable, which is close to the classical hydrophobic effect. The
135
analysis of thermodynamic data according to Krug’s rule showed that
enthalpyeentropy correlation in protic solvent is a true chemical phenomena
but the same correlation in DMSO leads to the conclusion that it is an artifact
from the initial van’t Hoff study. The analysis of the data was also conducted
136
by using the method describe by Inoue, which involves plotting DH versus
TDS for different guests. The linear character and the fact that at DH¼0 the
entropy is positive, led to the conclusion that solvent molecules are released
from the host cavity and this is the driving force for the encapsulation. The
analysis of the thermodynamic data in terms of pure solvation effect proved to
be convincing. In this view, the larger

Table 2
Thermodynamic parameter for the encapsulation of iridium complexes by host 1 in 100 mM
TRIS/DOTf at pD 8.0, CD3OD, and DMSO-d6
Guest Solvent DH0 DS0 K
a

D2 O 4.3 3 17

R=Me

R¼iPr D2 O 11 20 5.9

R¼ PrF D2O 17 44 0.16

R¼Me CD3OD 12 23 5.9
R¼Pr CD3OD 16 38 2.7
R¼Me DMSO-d6 8 6 36
R¼Pr DMSO-d6 3.3 1 0.44
E.A. Kataev, C. Muller€ /
Tetrahedron 70 (2014)
137e167
of more hydrogen bonds leads to a decrease in both enthalpy and entropy of
the guest the more solvent molecules (water or methanol) are ex-posed and encapsulation (Table 2).
the more hydrogen bonds between solvent molecules are build. Thus, building

7. Supramolecular catalysis in water
In this chapter, we discuss recent literature on supramolecular catalysis,
which we consider in a classical sense defined by Hosseini and Lehn:
“Supramolecular catalysis, the chemical transformation of a bound substrate,
137
for which complexation and recognition steps are prerequisites”. We also
touch reports on supramolecular synthesis, which involve recognition
processes and chemical transformation. It is well-known that most enzymatic
reactions work in water at ambient pH value. Water is a very cheap, in-
expensive, nontoxic, and easy to handle solvent, which can be set free into
nature after cleansing. Therefore, supramolecular catalysis will be, certainly, a
part of ‘green chemistry’ in near future. Su-pramolecular catalysis and
synthesis is nowadays limited mostly to four classes of water-soluble cage-
like compounds shown in Fig. 6. These compounds encapsulate various
organic compounds in aqueous solution thanks to their hydrophobic cavities.
By this property they mimic enzymatic hydrophobic cavities and often
function as ‘molecular flasks’, namely promote transformation of organic
molecules in an aqueous solution. As one can see below, in most cases size,
shape, and charge of the cavity play major role in promoting various reactions
and in determining structures of products.
Fig. 6. Selected cavities that perform supramolecular synthesis and catalysis in water.
The synthesis of a wide variety of oxindoles with the help of cyclodextrins
was described by Rao and co-workers, as oxindoles are of high interest for the
synthesis of many bioactive compounds, such as antibacterial, anti-
138
inflammatory, and laxative compounds, to mention a few. This is the
example of a supramolecular syn-thesis, not a catalysis, because b-CD is used
in an equimolar amount relative to the reagents. All of these reactions use
isatin-derivates and dimedone as starting compounds. In the absence or in the
presence of catalytic amounts of b-CD the reaction yields only 15e25% of the
product (Fig. 7). However, in the presence of 1 equiv of b-CD the reaction
leads to a single product with a high yield of 91%. Thus, b-CD works as a
reagent that activates isatin by encap-sulation. The authors showed by NMR
experiments that isatin is encapsulated into the b-CD cavity. After addition of
indole to isatineb-CD complex, one molecule of indole enters the primary
side of b-CD and the reaction takes place inside the cavity as shown in Fig. 7.
In a following article the authors described an elegant supra-molecular
139
synthesis of spirooxindoles (Fig. 8). Again, b-CD works as an activating
reagent, namely it encapsulates isatine and acti-vates the keto-group by
forming hydrogen bonds with it. The resulting spirooxindoles could be
obtained after 4e6 h of reaction time at 60 C in good yields (84e91%).
Another synthesis for spirooxindoles using b-cyclodextrin as a catalyst in
140
water was reported by Singh and co-workers. This reaction involves urea
and thiourea instead of malononitrile as in the previous example. (Fig. 9). The
product is not formed in the absence of b-CD, while 1 equiv of b-CD yields
91% of spirooxindole. Interestingly, this reaction can be catalyzed by catalytic
amounts of cyclodextrin (10%) producing 80% of the product. Among tested
solvents, the best catalytic efficiency was observed in water. The authors
suggested the same mechanism of the cyclodextrin action as described above,
which is an activation of keto-groups of indole through the formation of
hydrogen bonds inside the cavity.
Nageswar and co-workers investigated a series of reactions in water in the
1
presence of cyclodextrins. They showed that bi-ologically active a -oxindole-
a-hydroxyphosphonates can be pre-pared with high yields at room
141
temperature. Isatine reacts with dialkyl- and trialkyl-phosphites in water in
the presence of an equimolar amount of b-CD. A range of products were
obtained in up to 94% yield (Fig. 10). Cyclodextrin was reused in the reaction
sev-eral times. After four cycles only a 10% decrease in yields was ob-served
(81%). In the other work, catalytic amounts (10%) of b-CD promoted the
formation of 2-aryl-2,3-dihydroquinazolin-4(1H)-ones in water at elevated
142
temperature. In this reaction isatoic anhydride reacts with different
aldehydes and ammonium acetate or anilines (Fig. 11). This approach was
also used in the synthesis of substituted pyrroles by reaction of phenacyl
bromide and pentane-2,4-dione with a variety of substituted anilines, benzyl
143
amines or even ammonium acetate as shown in Fig. 12. The authors pro-
vided NMR evidence that complexation of phenacyl bromide inside b-CD
cavity occurs before the condensation step. In the cavity of the cyclodextrin the
keto-groups are activated through hydrogen bonding with the cyclodextrin OH-
groups. A series of other pyrrole derivatives were obtained from phenacyl bromide
and dimethyl or diethyl acetylenediacetate and a substituted aniline or simply
144
ammonium acetate (Fig. 13).
Luo and Cheng reported a thorough investigation of supramo-lecular
145
catalysis by amine-functionalized cyclodextrins. The idea of the work was
to combine the ability of chiral primary amines to catalyze aldol reaction with
supramolecular recognition by cyclo-dextrins. Systematic studies of the
catalytic reaction revealed sev-eral features that resemble enzyme catalysis:
substrate binding, conformational changes of the host upon binding, and
stereo-control by the host. Among the investigated catalysts, the best re-sults
were obtained for compounds 133 and 134. The catalytic
160 E.A. Kataev, C. Muller€ /
Tetrahedron 70 (2014) 137e167
 Fig. 7. Synthesis of oxindoles inside b-CD. The proposed activation pathway by OH-residues
of cyclodextrin inside the cavity is also shown.
Fig. 8. Synthesis of spirooxindoles inside b-CD.

R=
susbt.
phenyl-
and
benzyl
groups or
ammoniu
m acetate

Fig. 12. Synthesis of substituted pyrroles using b-CD.

Fig. 9. Synthesis of spirooxindoles from dimedone and urea.

Fig. 13. Synthesis of substituted pyrroles using b-CD.

1
Fig. 10. Synthesis of a -oxindole-a-hydroxyphosphonates in the presence of equi-
molar amounts of b-CD.
reaction is pH-dependent and maximum enantioselectivity was observed at
pH 4.8 with 97% ee. For example, catalyst 133 follows MichaeliseMenten
3 1
O CHO O kinetics with Km¼6.31 mM and kcat¼6.07 10 min . Organocatalysts 135
O + β−CD, H2O NH and 136 can also cata-lyze the reaction but much slower with lower yields
+ NH4OAc
R1 60-65°C
N and stereo-selectivity. As inferred from the substrate screening, it is the
1
N O H R cyclodextrin core that determines the stereochemistry of the re-action, not the
H
1 appended amine. The catalysts are highly sensitive for aldol donors. The
R = H, F, Br, NO2, Me, OMe, OH, Allyloxy
O CHO O 2
reaction performs well only with small ke-tones, such as acetone, butanone,
NH2 R
and cyclopentanone. In-terestingly, association constants of catalysts with
2 1
substrates and products are in the same order (ca. 10 M ). The authors con-
O β−CD, H2O N
+ + ducted a detailed analysis of conformational changes upon com-plexation.
N R1 R2 60-65°C N
O 1
The cyclohexane fragment slightly enters the cavity of cyclodextrin. If a
H H R substrate is added, it pushes the cyclohexyl ring out to some extent and
1
R = H, F, Br, Me, OMe, OH generates sufficient space to accept
2
R = H, Me, OEt E.A. Kataev, C. Muller€ / Tetrahedron 70 (2014) 137e167 161

Fig. 11. Synthesis of 2-aryl-2,3-dihydroquinazolin-4(1H)-ones catalyzed by b-CD.

Fig. 14. Model reaction, supramolecular- and organocatalysts tested in enantioselective aldol
reaction. The proposed catalytic cycle is also shown.
a ketone. On this basis, a catalytic cycle for the reaction was pro-posed ( Fig.
14). According to the measurements of kinetic isotope effect, the rate-limiting
step in this catalytic reaction is the imine bond formation. This is in contrast
to enzymatic aldol reactions, where CeC bond formation is usually a limiting
step. This work provides interesting insight into enzymatic catalysis and gives
a lot of information for future design of supramolecular catalysts.
Interesting concept of photoswitchable supramolecular catalysis with
cyclodextrins was reported by Zhao and co-workers. The au-thors were able
II
to realize a catalyst for ester hydrolysis by using a Zn -complex with
appended b-CDs (Fig.15), which was immobilized on to gold-nanoparticles
146
functionalized with azobenzene units. It is
switched to cis-form under UV light, then the catalyst enters the solution and
starts to perform hydrolysis. The release of the catalyst is accomplished with
30-fold increase in the rate of hydrolysis.
Cucurbiturils have been extensively investigated in recent years as
supramolecular catalysts for stereoselective photodimerization reactions,
oxidation, hydrolysis and even as inhibitors of undesired chemical
transformations. This literature has been recently reviewed by Sivaguru and
147
co-workers, therefore we refer the reader to this review for more details.
Bergman, Raymond and co-workers reported a series of catalytic reactions
promoted by the cage-like complex formed between 1,5-bis(2,3-
dihydroxybenzoylamino)naphthalene and trivalent metal-

Fig. 15. Switching of the catalytic activity of the Zn(II)-based catalyst by light.
3 þ 3þ 3þ
ions (Al , Fe , Ga ). Since part of their work was already reviewed
17
3 recently, we present here only recent achievements. The important feature
well-documented that trans-azobenzene is bound to b-CD with af-finity 10 3þ
of complex 1 (M¼Ga ) is the hydrophobic cavity and anionic character,
1
M , while cis-isomer has much lower affinity. Thus, the Zn-catalyst bearing which makes the molecule an ideal
cyclodextrin arms is bound to gold-nanoparticle unless azobenzene is in trans- 162 E.A. Kataev, C. Muller€ /
configuration. If the isomer is Tetrahedron 70 (2014) 137e167
for the formation of pulegoles under mild conditions (pH 7.50 and 60 C).
host for neutral and cationic organic guests. The authors in-vestigated a series
of reactions, in which intermediates are usually cationic species and they are A concept of the encapsulation of an active catalyst in the cavity of
efficiently encapsulated in the cavity of the catalyst.
148
For example, complex molecular host 1 was demonstrated to work in an aqueous so-lution. The gold
1 is able to accelerate Nazarov cyclization with ca. one-million fold based catalyst Me3PAuCl converts enyne 137 to product 139 with high
enhancement in comparison with the reaction conducted in the absence of the selectivity (Fig. 18). If the catalyst is encap-sulated in the cavity of 1, the
catalyst. 3,4,5-Trimethylhepta-2,5-dien-4-ol (mixture of possible selectivity is changed favoring product
stereoisomers) can be completely transformed into Nazarov prod-ucts in
aqueous media at pH 11.0 and 50 C during 12 h (Fig. 16). The reaction can be Catalyst, O O
H2O OH
þ O
+
shut down by the presence of 1.1 equiv of NEt 4da guest that is strongly
5% DMSO,

bound to the catalyst. Kinetic in-vestigations in D 2O/DMSO-d6 mixture 20h

137 138 139
(50%) of the reaction in the presence of 7 mol % of the catalyst show that the
reaction begins with a constant rate, which decreases with time. The decrease Catalyst: <1% 85%
in reaction rate was attributed to product inhibition. Stronger binding affinity
was found for cyclopentadiene-products, as compared with the starting
Me3PAuCl
materials. To prevent inhibition of the catalysis by the product the authors +l 60% 40%
Me3PAu @SA
used maleimide to start the subsequent Diel-seAlder reaction. The resulting
compound is large enough to be Fig. 18. Demonstration of changing of selectivity by encapsulation of Me 3PAuCl in host 1.
 Fig. 16. Nazarov cyclization of 3,4,5-trimethylhepta-2,5-dien-4-oles and the proposed mechanism occurring in the cavity of host 1.
pushed out of the cavity. The structure of the diene has also an in fluence on
the reactivity because U-shaped dienes are ideal for the cyclization. Thus,
Z,Z-isomer reacts with the lowest rate. The high efficiency of the catalyst in
this reaction was attributed by the authors to the increase of basicity of the
alcohol group and strong binding of positively charged transition state. The
proposed mechanism is shown in Fig. 16.
Successful results with Nazarov cyclization led the authors to investigate
another cyclization, which involves a proton-mediated transformation of
149
citronellal to cyclic products (Fig. 17). Complex 1 works as a functional
model of natural terpene syn-thase and directs the monoterpene toward
deprotonation instead of nucleophilic attack by water. When citronellal is
treated under acidic conditions without the catalyst, p-methane-3,8-diols
138. This simple experiment demonstrates that exclusion of water from the
hydrophobic cavity of the catalyst favors the formation of 138 instead of 139.
This observation additionally proves the fact that hydrophobic cavity of
catalyst 1 prevents carbocation from capturing by water in the reaction of
terpene synthesis.
The same idea for catalysis in the cavity of molecular host 1 was realized
with the help of half-sandwich complex [RuCp(PMe 3) (MeCN)2PF6], which
150
is known to catalyze the allyl alcohol-isomeri-zation (Fig. 19). The hosted
þ
catalyst [RuCp(PMe3)(MeCN)2] @1 appeared to be very stable in an
aqueous solution and can be stored for days, while free catalyst [RuCp(PMe 3)
(MeCN)2PF6] decomposes fast under the same conditions resulting in
catalytically inactive species. Moreover, the encapsulated complex has 1 order
of magni-tude higher solubility in water than the free one. Isomerization of

Fig. 17. Cyclization of citronellal catalyzed by complex 1.

are formed selectively. In the presence of 10 mol % of the catalyst the
pulegoles are the main products (70%) of the reaction with only trace amounts
of p-methane-3,8-diols. Treatment of p-methane-3,8-diols with 1 does not
show any conversion to pulegoles. This indicates that 1 is a highly selective
catalyst
catalyst with the encapsulated one reveals that the rate is slightly attenuated
1 1
from 44 to 16 M h . However, placing the catalyst in the hydrophobic
cavity results in higher stability of the catalyst with turn over number of ca.
1070. This is a higher turn over number than that demonstrated by the free
catalyst in organic solvents.
2 +
R [Ru(RMe3)(MeCN)2] @1 (2 mol%)
1 OH 1 O
R 100 mM DCO3- in D2O, pH 8 R
42 °C, 2h
allyl alcohol 140 and 3-buten-2-ol 141 occurs with good yields in the
presence of the catalyst; however, compounds 142 and 143 stays unchanged
even at 75 C. Detailed investigations show that the ac-tive catalyst is located
in the cavity and no exchange with the solu-tion is present. The comparison of
the catalytic activity of the free
E.A. Kataev, C. Muller€ /
Tetrahedron 70 (2014)
137e167
Cage 132 (Fig. 6) was found to adapt and stabilize the twisted conformer
151
of an overcrowded alkene. The twisted conformation of alkene 144 is not
stable under normal condition. However, upon complexation with cage 132
and microwave irradiation at 100 C for 1 h the conformation of 144 changes
to a twisted one (Fig. 20).
2 OH
R

140:R1=H, R2=H
141: R1 = H, R2 = Me
142: R1 = Me, R2 = H
143: R1 = H, R2 = Ph

Fig. 19. Isomerization of allyl alcohol catalyzed by the hosted ruthenium complex.

In contrast to the above described cage, Fujita and co-workers developed

positively charge molecular cages 131 and 132, which are built on the basis
of palladium(II) complexes. These cages are used in stoichiometrical or
catalytic amounts to perform supra-molecular synthesis in water. The
principle of action is similar to cyclodextrin or cucurbiturils; the hosts possess
a hydrophobic cavity and shield the reaction process from interaction with
18
water, namely they work as ‘molecular flasks’.
trapping of the intermediate is ascribed to both electronic and steric effects
provided by the host molecule.
Interesting results were obtained with insertion of water into alkyne in the
anti-Markovnikov manner under photoirradiation.
153
In this reaction the
authors provide an evidence for the fact that the cage mediates a guest-to-host
electron transfer. This process sub-sequently stabilizes a cation radical and
brings to a molecule new reactivity. The proposed mechanism of this
transformation is shown in Fig. 21.
Rather inert aromatic compounds, such as aceanthrylene 145 and 1H-
cyclopenta[l]phenanthrene 146, were tested in [2þ2] and [2þ4] cycloaddition
154
reactions with maleimide inside the cavity of molecular cage 131.
the previous example, the first step is the formation of a ternary complex
between 145 and maleimide 147 performed in suspension of starting
materials with cage 131 in water (Fig. 22). The resulting solution was heated
at 100 C for 1 h and quantitative conversion to the [2þ4] product was
observed. The structure of the product was unambiguously confirmed by X-
ray structure analysis of the cage-product complex. If irradiation is applied to
the same ter-nary complex the formation of the [2þ2] adduct is detected.
Remarkably, compound 146 appeared to be more reactive and DielseAlder
reaction in cage 131 proceeds at room temperature in 30 min, while in the
absence of the cage 146 does not react even at high temperatures. Irradiation
of ternary complex be-tween 146 and maleimide in the cage leads to the
[2þ2] adduct. Remarkable acceleration of cycloaddition reaction is attributed
As in again to the suitable orientation of substrates confined by the cavity.

O hν, 100°C O OH O O
70°C
HO OH HO OH HO OH HO OH

144

Fig. 20. Transformation of an alkene 144 inside cage 132.

O O O
N N hν N
The process is accompanied with a color change from yellow to deep purple. O O
O
This transformation was confirmed by NMR, UVevis spectroscopy and by
trapping the product with the help of bromi-nation reaction. The
transformation occurs, presumably, due to the adaptation of the guest to the
131•(145•147)
geometry of the host.
Stabilization of metastable species was found to be an effi-cient method to
152
perform interesting metalorganic trans-formations. Dinuclear ruthenium
O O
complex [Me4CpRu(CO)2]2 shows much higher photostability, when O N hν N
N O O
encapsulated in the cavity of cage 132. Under UV light the complex
undergoes a photosubstitution of CO ligand with an alkyne generating the
O

metastable species. When the resulting complex is ejected from the cavity of
the cage, CO molecule is inserted in alkyne and a new metalorganic
compound is generated. The efficient 131•(146•147)

Fig. 22. Cycloaddition reaction promoted by encapsulation in cage 131.

Fig. 21. Anti-Markovnikov water addition to alkynes encapsulated by host 132.

164 E.A. Kataev, C. Muller€ / Tetrahedron 70 (2014) 137e167
Fujita and co-workers realized recently a real catalytic conden-sation with
155
cage 131. This host catalyzes the Knoevenagel con-densation directly in
water. Taking into consideration the fact that during this reaction one water
molecule is produced, the discovered catalysis has the same features as
enzymes, which perform well in aqueous medium. In contrast to the previous
example, in this re-action, the product is released immediately after formation
because of its large size. Thus, only 1% of the catalyst is sufficient to obtain
products in high yields (up to 96%). Without the catalyst the reaction in water
proceeds only with maximum 26% yield. Even sterically crowded aldehydes
undergo efficient condensation. The cage prefers electron-rich aldehydes, such
as methoxy- and amino-substituted naphthaldehydes, because the cage is
positively charged. The pro-posed mechanism (Fig. 23) involves the
formation of negatively charged intermediate, which is stabilized by the
positively charged cage. Thus, the cage has analogy with the Bergman and
Raymond’s cages and mechanism of the catalytic action.
157
and subsequent disassembly of the dimer and the complex. Re-cently,
Kaifer and co-workers demonstrated that the excapsulated ferrocene molecule
in dimer 1232 undergoes electron transfer to a mediator, which is bound to the
capsule through strong electrostatic interactions.
158
The formed ferrocenium
cation is no more hydro-phobic enough to stabilize the dimer complex and
disassembly of the hosteguest complex is observed. This finding is
reminiscent of the properties of redox proteins, in which the redox active
center is par-tially or completely buried in the polypeptide framework.
Ramamurthy and Gibb investigated the effect of cage 1232 (di-mer) on
159
photochemical Norrish type I and type II reactions with ketones. These
reactions were compared with those carried out in the absence of the cage. It
was shown that a-alkyldibenzyl ke-tones formed complexes, which are
kinetically stable and allow one to investigate photochemistry inside the cage.
The authors divided all the reaction into three groups. The first group
consisted of a-hexyl, a-heptyl, and a-octyl dibenzyl ketones, which produced

Mechanism CHO

Model reaction 12+ Ar O

O
O O O (1% mol) O O O
 O
+ O O O O
H
Ar H O, rt, 6h

Aldehyde HO O O

CHO CHO CHO CHO

CHO O O O O
O O HO
O O
63%
96% 67% 38% O O

CHO CHO HO

MeO NMe HO HO O

96%
82% O O O O

O O O O

Fig. 23. Knoevenagel condensation catalyzed by cage 131 and the proposed mechanism.
A series of experiments were conducted by the research groups of Gibb,
Kaifer, and Ramamurthy in the hydrophobic cavity of so-called ‘octa-acid’
123. The authors found that ferrocene can be encapsulated in water by dimer
1232 and the reversible voltammetric response of ferrocene is completely
156
eliminated in comparison with that for free ferrocene. This behavior was
attributed to very slow electro-chemical kinetics for the oxidation in the
encapsulated state. Studies with the complexes between dimer 1232 and
viologen derivatives showed similar lowering of reduction rates in
comparison with the free viologen compounds. Similar results were obtained
for the complex between the dimer and tetrathiafulvalene (TTF). The first one-
electron oxidation of TTF was strongly hindered by encapsula-tion, while
second electron transfer led to destabilization of the host
Norrish type II products under irradiation of the ‘caged’ ketones, while free
ketones generated Norrish type I as major products. The second group
consisted of a-butyl and a-pentyl dibenzyl ketones, which yielded equimolar
amounts of two rearrangement products, while free starting material does not
undergo any reactions. The third group consisted of a-ethyl and a-propyl
dibenzyl ketones, which formed only one rearrangement products in low yield
and no reaction was detected without the cage. NMR experiments showed that
the aromatic rings occupy the two hemispheres of the capsule, if the
substituent is short. However, a long substituent leads to placing the ring in
the equatorial region. Thus, three pos-sible packing motifs (Fig. 24, structures
1e3) were observed and each of them leads to distinct photochemical
products.

R
OH
R

R hν O
hν + O
+ O O O
Type II Type I
O
O R

Structure 1 Structure 2 Structure 3

Fig. 24. Photochemical reaction occurring with ketones by irradiation. Three possible packing motifs found in hosteguest complexes between ketones with different lengths of R-substituent in the
cavity of receptor 123.
E.A. Kataev, C. Muller€ / Tetrahedron 70 (2014) 137e167 165

8. Conclusion References and notes

During the last five years (2008e2013) we have seen advances in
designing artificial hosts that bind guests in pure water or in mixtures with
organic solvents. The desire to bind guests stronger and more selective is
reflected in exploring new binding motifs, usage of strong electrostatic and
metaleguest interactions, iso-lation of binding sites from water by designing
new cavitands, cryptands, cage-like receptors, and self-assembled hosts.
Recogni-tion in water has enabled researchers to explore quite complex guests
and to be a step forward toward artificial recognition of bi-ologically and
clinically relevant substrates. We now see more understanding of
thermodynamic rules of binding in water and the role of water in binding.
Increasing interest in supramolecular synthesis and catalysis in water forms a
very perspective direction in supramolecular chemistry. We can anticipate
exciting discover-ies in the near future.
Acknowledgements
This work was financially supported by Fonds der Chemischen Industrie,
Deutsche Bundesstiftung Umwelt, Technische Universit€at Chemnitz, and
COST action ‘Supramolecular Chemistry in water’.
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 E.A. Kataev, C. Muller€ / Tetrahedron 70 (2014) 137e167 167

Biographical sketch

Christoph Muller€ (1986) received a Diploma in Chemistry from Technische Universit€at

Evgeny A. Kataev (1980) studied chemistry at Moscow State University (MSU), Russia, and Chemnitz, Germany, in 2013. He was awarded by Deutsche Bundesstiftung Umwelt (DBU)
graduated in 2003. He completed his Ph.D. degree in 2006, a joint program be-tween the with a fellowship to conduct a Ph.D. work under supervision of Dr. Evgeny Ka-taev. Currently,
University of Texas at Austin, USA and MSU under supervision of Prof. Jon-athan L. Sessler he is working on his dissertation work, which focuses on the develop-ment of selective
and Yuri A. Ustynyuk. In 2006/2007 he was awarded by the INTAS postdoctoral fellowship receptors and ion-exchangers for detection, separation, and recycling of environmentally
with Prof. Kay Severin (Ecole Polytechnique Federale de Lau-sanne, Switzerland). After relevant anions.
working as a group leader in 2007/2008 at A.N. Nesmeyanov Institute of Organoelement
Compounds and MSU he joined the group of Prof. Burkhard Konig€ at the University of
Regensburg, Germany as a Humboldt postdoctoral fellow. In fall 2011 he started as a Junior
Professor at Technische Universitat€ Chemnitz and leads the Laboratory of Supramolecular
Chemistry. His research interests are in the field of self-assembly, molecular recognition, and
molecular sensors.