Synthesis of Methyl Salicylate from Acetylsalicylic Acid Megumi K.B.

Woltermann 21 April, 2011 Chemistry 213 Section 102 TA: Daniel Moser

Introduction Esters are organic molecules containing a carbon with a dou le and sin!le ond to o"y!en# They !i$e %ruits and %lower their pleasin! aroma, and they are the main ut esters are essential in the Industrially

component in %at#1 &ot only are they made in nature,

pharmaceutical, polymer, clothin!, and a multitude o% other industries# produced esters include polyesters which can %a ric %or clothin!#2

e made into thermoplastics or synthetic

Esters are synthesized via an esterification reaction often from alcohols or carbo ylic acids. !ischer esterification is "hen a carbo ylic acid reacts "ith e cess alcohol and a strong acid to #roduce an ester.$ %he reaction is reversible& but the #roduction of ester is favored "ith a large #resence of alcohol.1 %his mechanism is a common method used to #roduce esters and is essential in #rocesses such as "ine aging. 'uring "ine aging& the organic acids and ethanol in "ine undergo !ischer Esterification to create esters that contribute to the final aroma and taste of the "ine.( In this reaction, the reactants under!o a transesteri%ication which is when an ester reacts with an alcohol to %orm a new ester# Transesteri%ication is a crucial mechanism in the %ormation o% $arious products such as iodiesel %uels which is an alternati$e %uel source# Animal %at or $e!eta le oil contains tri!lyceride, an ester, which under!o

transesteri%ication to %orm !lycerol, the y'product, and methyl ester#( %he synthesis of methyl salicylate from acetylsalicylic acid in$ol$es a

transesteri%ication and )ischer *steri%ication mechanism#+ Acetylsalicylic acid, more commonly ,nown as aspirin, is a widely accepted as an antipyretic and a mild anal!esic dru!#- Methyl salicylate is responsi le %or the e$er!reen scent and was ori!inally isolated

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%rom winter!reen lea$es# It is commonly made in industry %or its uses in %ood, per%umes and other eauty products#.

Scheme 1: Acid catalyzed transesteri%ication1 Acetylsalicylic acid)s ester grou# is #rotonated y sul%uric acid# Methanol attac,s the car onyl !roup, and a proton trans%er allows the ester to ecome a !ood lea$in! !roup# The lone pair on o"y!en creates a dou le ond and ,ic,s o%% the ester !roup remo$in! methyl acetate %rom the molecule#

Scheme 2: Acid catalyzed !ischer Esterification1

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*arbo ylic acid is #rotonated& and methanol attac+s the carbonyl grou#. A #roton transfer ma+es the alcohol into a good leaving grou#. %he lone #air on o ygen creates a double bond "ith carbon and +ic+s off a "ater grou## The car onyl is deprotonated lea$in! methyl salicylate# In this e"periment acetylsalicylic acid was synthesi/ed to methyl salicylate# Acetylsalicylic acid, sul%uric acid and methanol were re%lu"ed %or an hour and 20 minutes# T1C monitored the reaction2s pro!ress# Methyl salicylate was isolated y e"traction# I3, &M3, 4C and 4C'MS were used to analy/e the product# *"perimental !our aspirin ta lets, acetylsalicylic acid 51#30!, -#22mmol6, were !rinded and mi"ed with methanol 510#0 m16 %or one minute to %orm a cloudy colorless solution# The solution was %iltered y a 7irsch %unnel to remo$e the solid# Sul%uric acid 5#30 m16 and methanol 5(#0 m16 was added to the acetylsalicylic acid# The mi"ture was re%lu"ed %or one hour and 20 minutes, and T1C with a mo ile phase o% 2(8 *t9Ac:he"ane was ta,en e$ery 1( minutes to monitor the reaction# The reaction was cooled to room temperature# Sodium icar onate 5(#0 m16 was added to the solution in a separatory %unnel, and the solution e!an to %i//# Dichloromethane 5(#0 m1 " 36 was added, and the ottom dichloromethane layer was drained out o% the separatory %unnel# The or!anic layers were com ined and sodium icar onate 5(#0 m1 " 26 was added# The ottom or!anic layer was drained and dried o$er anhydrous sodium sul%ate then decanted %rom the solid# The solution smelled li,e e$er!reen# The dichloromethane was e$aporated o%% lea$in! a colorless oil, methyl salicylate 5#30 !, 1#;- mmol, 2-#3 8 yield6< ,- . /cm011 231.4& 345.$& 62$.4& 571.(& 5(6.5& 437.5& 17$2.2& 1756.2& 11$2.7& 1122.4& 1274.2& 12(5.1& 1$77.2& 1$24.2& 1((7.2& 1(52.1& 125(.2&

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1312.1& 136$.5& 242$.5& $15(.18 91 :M- /*'*l$& ##m1; $.4(2 /s& $.7791& 3.621 3.55$ 3.445 6.7$$ 6.237 6.$22 6.$2$ 6.(3( 6.374 6.624 6.653 6.541 /m& (.7791& 17.6(4 /s& .43918 <*=MS /m=z1 122.71& 1$3.6(& 114.46& 42.71& 42.45& 41.42& 32.45& 3(.46& 3(.77& 22.44. Data Ta le 1# ,- data of methyl salicylate ta+en on %hermo :icolet $57 !%0,- "ith A%- accessory. Significant Signal /cm011 1312.1& 125(.2& 1(52.1& 1((7.2 136$.5 $15(.1 >iterature Signal /cm011 4 1377& 1257& 1277& 1(27 1627 $277 Source Aromatic *?* stretches Ester @henol

Ta le 2# :M- data of methyl salicylate ta+en on Anasazi 37 M9z :M-s in d0chloroform. Signal /##m1 $.4(2 3.621 A 6.541 17.6(4 >iterature Signal /##m1 4 $.602 3.205.2 (.7 A 6.7 ,ntegration $.77 (.77 .43 S#litting S M S Assignment Methyl Aromatic Alcohol

Ta le 3# <*=MS data of methyl salicylate ta+en on %hermo <*=MS in '*M !ragment ,ons /Methyl Salicylate1 /*D20@henyl0 Alcohol1C /Aldehyde0@henyl0Alcohol1C /@henol1C /*?*0*?*0Alcohol1C 3esults As#irin "as crushed& mi ed "ith methanol& and ran through a 9irsch funnel via vacuum filtration to se#arate the #ill binders from acetylsalicylic acid. Methanol& acetylsalicylic acid and sulfuric acid "ere reflu ed "hich synthesized acetylsalicylic acid to methyl salicylate. %>* "as used to monitor the reaction. Sodium bicarbonate and '*M isolated the #roduct. <*& <*=MS& ,- and :M- confirmed the isolated #roduct "as methyl salicylate. Woltermann 2
C

M=B 122.71 1$3.6( 114.46 41.42& 42.45& 42.71 3(.77& 3(.46& 32.45

,n a !ischer Esterification reaction& a stronger acid #roduces a higher yield. ,n this case& concentrated sulfuric acid "as used. %his is a caustic chemical and e treme caution should be used "hen handling it. When monitoring the reaction& the %>* #lates sho"ed that there "as some starting material that remained in the flas+. 9o"ever& the reaction had already run for an e tended amount of time& so it "as sto##ed. salicylate as "ell as methyl acetate and "ater. %o isolate the #roduct& a se#aratory funnel "as used. Methyl salicylate and methyl acetate are both organic com#ounds& so sodium bicarbonate "as added to react "ith methyl acetate to form an aEueous com#ound. 9o"ever instead of using sodium bicarbonate& sodium chloride "as added to the mi ture. When the mista+e "as realized /after the '*M "as added1& the organic layer "as removed and #ro#erly "ashed "ith sodium bicarbonate. Sodium %he synthesis #roduced the #roduct methyl

bicarbonate reacted "ith the methyl acetate to create carbon dio ide& "ater and sodium acetate. Since carbon dio ide "as #roduced& the liEuid in the se#aratory funnel began to fizz. %he sto# coc+ "as left o#en "hen mi ing the #roduct "ith sodium bicarbonate to ensure carbon dio ide did not build u# in the funnel. '*M "as added to e tract out methyl salicylate& and the '*M "as eva#orated off leaving the #roduct. 9o"ever& the #roduct recovered "as not an oil but a solid soa+ed in liEuid. %he solid "as believed to be salt& so '*M "as added to e tract out the oil. When mi ed "ith '*M& the solid did not dissolve confirming that it "as a salt. %he mi ture "as vacuum filtered& and the '*M "as eva#orated off leaving the oil& methyl salicylate. %he ,- s#ectrum /!igure $1 sho"ed the a##ro#riate stretches for methyl salicylate. %he a##ro#riate four #ea+s for the carbon double bonds in the aromatic ring sho"ed u# at 1312.1 cm01& 125(.2 cm01& 1(52.1 cm01 and 1((7.2 cm01. %hese values corres#ond "ell to the literature values of 1377 cm01& 1257 cm01& 1277 cm01& and 1(27 cm01.4 An ester #ea+ sho"ed at 136$.5 cm01

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"hich is shifted a little to the right from the literature value of 1627 cm 01 due to conFugation "ith the benzene ring.4 %he alcohol grou# sho"ed u# as a #ea+ at $15(.1 cm 01 "hich is much lo"er than the literature value of $277 cm 01 "hich could be due to the ester grou#. 4 Esters are an electron "ithdra"ing grou# "hich "ea+ened the bond bet"een the alcohol grou# and benzene thus lo"ering the "avelength of the alcohol. %he :M- s#ectrum /!igure (1 further Fustified that the #roduct made "as methyl salicylate. A single #ea+ "ith an integration of $.77 ##m at $.4(2 ##m re#resented the methyl grou# attached to the ester "hich falls in the literature range of $.6 ##m A 2 ##m. 4 %he aromatic hydrogen)s sho"ed u# as a multi#let "ith an integration of (.77 in the 3.621 ##m A 6.541 ##m region. %his confirmed an aromatic ring "hich has a literature value of 3.2 ##m A 5.2 ##m. 4 %he alcohol hydrogen "as confirmed by a single #ea+ "ith an integration of .43 at 17.6(4 ##m "hich is higher than the literature value of (.7##m A 6.7 ##m. 4 %his "as most li+ely due to the ester being an electron "ithdra"ing grou# "hich further deshielded the hydrogen in the alcohol grou#. <* /!igure 11 confirmed the #roduct isolated "as #ure. %he multi#le #ea+s seen in the beginning of the s#ectrum "as the solvent. %here "as only one maFor #ea+ at 5.54 "hich "as methyl salicylate. Since there "ere no other maFor #ea+s& the <* sho"ed that the #roduct made "as #ure. <*=MS s#ectrum /!igure 21 "as an analysis tool that confirmed the #roduct "as methyl salicylate. %he #ea+ at m=z 122.71 re#resented the molecular ion M C. %he loss of a methyl grou# /0121 yielded the cation at m=z 1$3.6(. %he loss of an o ygen yielded the base #ea+ at m=z 114.46. %he #ea+s at m=z 41.42& m=z 42.45 and m=z 42.71 "ere isoto#es of the #henyl cation #roduced by the loss of *D /0251. %he #ea+s at m=z 32.45& m=z 3(.46 and m=z 3(.77 "ere isoto#es from the loss of a carbon double bond and t"o hydrogens /0231.

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%he yield from this reaction "as relatively lo" at 26.$G. 9o"ever "hen discussing "ith others& they #roduced methyl salicylate at about the same yield. Dne of the main reasons for this lo" yield is that !ischer Esterification is a reversible #rocess. %he #resence of alcohol drives the reaction to"ard methyl salicylate& but the #resence of "ater drives the reaction bac+"ard. Water "as not only #roduced in the reaction& but it "as #roduced "hen sodium bicarbonate reacted "ith methyl acetate. When saturated sodium chloride "as mi ed "ith the #roduct& even more "ater "as added to the #roduct. %his "ould drive the reaction bac+"ard "hich ultimately #roduced a lo"er yield. Also by having to add an e tra e traction ste# due to adding sodium chloride& some #roduct "as lost. Each #ill did not contain e actly $27 mg of acetylsalicylic acid. Some could have contained less "hich means the calculated yield "ould be lo"er than "hat the actual yield should be. %hough not a significant amount& #roduct "as still lost in transferring and handling the material. Conclusion %he synthesis of methyl salicylate from acetylsalicylic acid "as some"hat successful. %hough the yield "as lo"& it "as in the range that others in the class #roduced. A multitude of reasons contributed to the lo" yield. 9o"ever through :M-& ,-& <* and <*=MS& it "as clear the #roduct made "as methyl salicylate& and it "as #ure. Ester chemistry is of great im#ortance in the organic chemistry field. Methyl salicylate or evergreen oil is a com#onent in many #roducts because of its #leasant fragrances. %ransesterification and !ischer Esterification are crucial in the synthesis of some vital chemicals. %he chemicals and reactions involved here have great significance in a multitude of industries.

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3e%erences
1

Mcmury& Hohn. Organic Chemistry, 6. 2775; Broo+s=*ole& ##. 6420574. Bhou& 9.8 Iang& H.8 Ie& >.8 >in& 9.8 Iuan& I.& Effects of acidity and immiscibility of lactam0

based BrJnsted0acidic ionic liEuids on their catalytic #erformance for esterification. Green Chem. 2010& 12& 331A332
$

9artel& A.M.8 9anna& H.M.& @re#aration of Dil of Wintergreen from *ommercial As#irin %ablets.

J. of Chem. Ed. 200;& 86& (620(63.

(

-a##& A.8 Mandery& 9.& Wine Aroma. Cellular and Molec. Life ci. 1;.+& !2, 56$055( !u+uda& 9.8 Kondo& A.8 :oda& 9.& Biodiesel !uel @roduction by %ransesterification of Dils. J. of

"iosci. #nd "ioeng. 2001& $2& (720(13

3

htt#;==courses.chem.#su.edu=chem21$&K@re#aration of Methyl Salicylate from As#irin %ablets&

E #eriment 16.L
6

@iletta& @.8 @orchet& 9.*.8 'ayer& @.& *entral Analagesic Effect of Acetamino#hen but :ot of

As#rin. Clin. %harmacol. &heor. 1;;1& !$& $270$2(.

5

Sobel& M.8 Ballantine& '.S.8 -yzhov& M.& Nuantitation of @henol >evels in Dil of Wintergreen

Osing <as *hromatogra#hy0Mass S#ectometry "ith Selected ,on Monitoring. J. of Chem. Ed. 200(& 82& 371037$.
4

Minard& B.8 Bortiatyns+i& H.8 Masters& K.8 9almi& %.D.& Williamson& K.>. La' Guide for

Chemistry 21(& 2010'2011& ##. 262& 2($.

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)i!ure 3# )i!ure 0#

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