Acetylsalicylic Acid (Aspirin) Synthesis

Telow AJV
Sumicad, CJ, Tavanlar, EMMT, Chem 4!", #nstitute o$ Chemistry, %niversity o$
the &hilippines 'os (a)os
#! #ntroduction
*r+anic synthesis is the process where a desired or+anic compound is
constructed or prepared $rom commercially availa,le materials! The o,-ective o$
or+anic synthesis is to desi+n the simplest synthetic routes to a molecule!
Aspirin, also .nown as acetylsalicylic acid is as salicylate dru+ o$ten used
as anal+esic to relieve minor aches and pains, as an antipyretic to reduce $ever,
and as an anti/in0ammatory medication! The history o$ aspirin and its medical
use can ,e traced way ,ac. in the second millennium (CE! Medicines $rom
willow and other salicylate/rich plants appear in the E+yptian pharmacolo+y
papyri! 1urin+ 4 (CE in 2reece, 3ippocrates +ives women willow tree lea$ to
relieve the pain o$ child,irth! 3e also used salicylic tea to reduce $evers! 4illow
,ar. e5tract then ,ecame .nown $or its e6ectiveness in reducin+ $ever, pain and
in0ammation in the mid/ ei+hteenth century! (y nineteenth century, pharmacists
were e5perimentin+ with and prescri,in+ a variety o$ chemicals related to
salicylic acid, an active component o$ willow e5tract!
#n "789, chemist Charles :r;d;ric 2erhardt treated acetyl chloride with
sodium salicylate to produce acetylsalicylic acid $or the <rst time= in the second
hal$ o$ the nineteenth century, other academic chemists esta,lished the
compound>s chemical structure and devised more e6icient methods o$ synthesis!
#n "7?@, scientists at the dru+ and dye <rm (ayer ,e+an investi+atin+
acetylsalicylic acid as a less/irritatin+ replacement $or standard common
salicylate medicines! Aspirin was <rst isolated ,y :eli5 3o6mann, a chemist in
the 2erman company (ayer! (y "7??, (ayer had du,,ed this dru+ Aspirin and
was sellin+ it around the world! The word Aspirin was (ayer>s ,rand name,
rather than the +eneric name o$ the dru+= however, (ayer>s ri+hts to the
trademar. were lost or sold in many countries! Aspirin>s popularity +rew over
the <rst hal$ o$ the twentieth century, spurred ,y its e6ectiveness #n the wa.e o$
Spanish 0u pandemic o$ "?"7, and aspirin>s pro<ta,ility led to <erce
competition and the proli$eration o$ aspirin ,rands and products! Some o$ the
"?"7 0u deaths were pro,a,ly due to Aspirin poisonin+!
Aspirin>s popularity declined a$ter the development o$ acetaminophenA
paracetamol in "?8B and i,upro$en in "?BC! #n the "?Bs and "?@s, John Vane
and others discovered the ,asic mechanism o$ aspirin>s e6ects, while clinical
trials and other studies $rom the "?Bs to the "?7s esta,lished aspirin>s
e6icacy as an anti/clottin+ a+ent that reduces the ris. o$ clottin+ diseases!
Aspirin sales revived considera,ly in the last decades o$ the twentieth century,
and remain stron+ in the twenty/<rst with widespread use as a preventive
treatment $or heart attac.s and stro.es!
#n the preparation aspirin, salicylic acid is reacted with an e5cess o$
acetic anhydride! A small amount o$ a stron+ acid is used as a catalyst which
speeds up the reaction! #n this e5periment, phosphoric acid will ,e used as the
catalyst! The e5cess acetic acid will ,e Duenched with the addition o$ water! The
aspirin product is not very solu,le in water so the aspirin product will
precipitate when water is added! The synthesis reaction o$ aspirin is shown
,elowE
##! *,-ectives
This la,oratory e5ercise aims toE
"! to synthesiFe acetylsalicylic acid $rom salicylic acid
,y nucleophilic acyl su,stitution=
and
C! to descri,e and e5plain the di6erences in the
properties o$ acetylsalicylic acid and salicylic acid ,y
simple chemical tests!
###! Methodolo+y

A! Schematic 1ia+ram
" +ram salicylic acid in "C8/m' Erlenmeyer 0as.
G 9/m' acetic anhydride

G " drop 78H phosphoric acid
/swirl
/ heat in steam ,ath $or "8 mins
G C/m' d3
C
*
G C/m' ice cold 3
C
*
/cool to IT
/place in an ice ,ath
/per$orm suction <ltration

residue <ltrate
// wash several times
// trans$er crystals to pre/wei+ht watch +lass
air dry
wei+ht dry aspirin
calculate H yield
crude aspirin
set aside small Duantity $or M& determination
trans$er the rest to "C8/m' E0as.
G ?8H ethanol dropwise
swirl until almost all dissolves
G cold d3C* dropwise until almost all crystals appear
cool 0as. in a cool ,ath
suction <ltration
/ calculate H recovery
(continuation)
residue <ltrate
wash crystals with small portions o$ cold 3
C
*
/ trans$er crystals to pre/wei+ht watch +lass
air dry
wei+ht dry aspirin
calculate H recovery
trans$er aspirin to vial
la,el
determine the M& o$ crude and
recrystalliFed aspirin
Compare
CharacteriFation o$ AspirinE
Ieaction with JMn*
4
E
8 drops dilute, sli+htly acidic JMn*
4
in test tu,e
G pinch o$ the sample

/ warm the tu,e in water ,ath $or 8
mins!
/ e5amine mi5ture

Ieaction with :eCl
9
E
pinch o$ the sample in test tu,e
G 9 drops C!8H aDueous :eCl
9
G "/m' d3
C
*
/ e5amine mi5ture
1i6erentiation o$ the synthesiFed acetylsalycylic acid $rom commercially
availa,le aspirinE
pinch o$ the sample test tu,e
G 8 drops 3
C
* and iodine
/ e5amine
(! Set/ups


:i+ure ""!"! Suction <ltration set/up
C! Chemical 1ata Sheet
Ta,le ""!" Chemical data sheet $or the synthesis o$ aspirin
Kame and
structure o$
the rea+ents
:unctions in
the e5ercise
&hysical
properties
3aFards &recautions
salicylic acid Startin+
material
a white
powder/li.e
su,stance with
an M& o$
S.in and eyes
irritants
#n case o$
contact,
immediately
0ush s.in with
"8?LC and a
density o$
"!44+Acm
9
plenty o$ water
acetic
anhydride
Converts
salicylic acidMs
hydro5yl +roup
into an acetyl
+roup
a colorless
liDuid with a
density o$ "!7
+Acm
9
Corrosive and
0amma,le
Jeep away
$rom heat!
4ear +loves,
eye protection
and $ace
protection
phosphoric
acid
Serves as the
catalyst
a colorless
viscous liDuid
with a density
o$ "!77 +Acm
9
and a ,oilin+
point o$ "87LC
E5tremely
corrosive
Avoid direct
contact! 4ear
chemical
protective
clothin+
?8H ethanol %sed $or the
recrystalliFatio
n
a colorless
liDuid with a
meltin+ point
o$ ""4LC and a
density o$
@7?!.+Am
9
S.in and eyes
irritants! 'on+
term use can
result to
serious liver
dama+e
Jeep away
$rom heat!
4ear +loves,
eye protection
and $ace
protection
JMn*
4
1i6erentiatin+
a+ent
a purple liDuid 3i+hly
e5plosive
when reacted
with
concentrated
sul$uric acid
#n case o$
contact,
immediately
0ush s.in with
plenty o$ water
$or at least "8
minutes
:eCl
9
:or the
characteriFatio
n o$ the
synthesiFed
aspirin and
commercial
aspirin
(rown liDuid
with a molar
mass o$
"BC!C+Amol, a
,oilin+ point
o$ 9B LC and
a density o$
C!?+Am'
Corrosive,
to5ic and
acidic
:lush s.in with
water in case
o$ direct
contact
#V! 1ata
Ta,le ""!C! 1escription o$ rea+ents
SAM&'E 1ESCI#&T#*K
salicylic acid white, powder/li.e su,stance
acetic anhydride clear liDuid with stron+ odor
phosphoric acid clear, colorless liDuid with stron+ odor
?8H ethanol clear, colorless liDuid with stron+ odor
JMn*
4
purple liDuid
:eCl
9
,rown liDuid
#odine solution clear liDuid
Ta,le ""!9! &reparation o$ Aspirin
SAM&'E 1ESCI#&T#*K
Salicylic acid G acetic anhydride G
78H phosphoric acid
salicylic acid was dissolved
Mi5ture at room temperature crystals were $ormed
Mi5ture a$ter ice ,ath more crystals were $ormed
Suction :iltrationE
residue
<ltrate
<ne, white crystals
clear liDuid with small amounts o$ crystals
Crude aspirin <ne white crystals
Ta,le ""!4! IecrystalliFation o$ Aspirin
1ESCI#&T#*K
Crude aspirin G ethanol dissolution o$ most crystals occurred
Mi5ture durin+ coolin+ crystals were $ormed
Mi5ture a$ter coolin+ more crystals were $ormed
Suction :iltrationE
residue
<ltrate
<ne, white crystals
clear liDuid
Ta,le ""!8! Iecovery data o$ recrystalliFed aspirin
*(SEIVAT#*KS
4ei+ht o$ watch +lass G <lter paper
(+)
"!988
4ei+ht o$ watch +lass G <lter paper G
product (+)
C!"98
4ei+ht o$ product (+) !@7
Theoretical yield "!9
H yield BH
H recovery 8?H
Ta,le ""! B! Meltin+ point determination
SAM&'E ME'T#K2 &*#KT IAK2E (LC)
Crude aspirin "B/""C
IecrystalliFed aspirin ""4/""7
Ta,le ""!@! 1i6erentiation o$ startin+ material $rom the product
TEST SNKT3ES#OE1 AS&#I#K SA'#CN'#C AC#1
JMn*
4
disappearance o$ violet
color and $ormation o$
,rown precipitate
the solution remained purple
:eCl
9
the solution remained
,rown and not all o$ the
sample dissolved
the solution ,ecame dar.er shade
o$ ,rown and not all o$ the
sample dissolved
Ta,le ""!7! 1i6erentiation o$ synthesiFed acetylsalicylic acid $rom commercially/
availa,le aspirin ,y iodine test
SAM&'E *(SEIVAT#*KS
SynthesiFed
acetylsalicylic acid
all o$ the sample dissolved and the solution is tur,id
Commercially/ availa,le
aspirin
all o$ the sample dissolved and the solution ,ecame
$aint purple
V! Sample Calculations
"!+ SA ( " mol SAA "97!"B +) ( " mol ASAA" mol SA) ( "7!C"+A " mol ASA) P
"!9+
9! m' AA ( "!7+ AAA "m')( " mol AAA "C!""+)(" mol ASAA " mol AA)
("7! C"+A " mol ASA) P 8!@C+
H yield P Actual yieldA Theoretical yield Q "H
P !@7+A "!9+ Q "H P BH
H recovery P Iecovery yield A Actual yield Q "H
P !48@+A !@7+ Q "H P 8?H
V#! Iesults and 1iscussion
#n this e5ercise, the +oal was to produce acetylsalicylic acid
throu+h the or+anic synthesis $rom the reaction o$ salicylic acid to acetic
anhydride, the startin+ materials! #nstead o$ usin+ acetic acid, acetic anhydride
was used as solvent since the anhydride reactin+ with water to $orm acetic acid
tends to drive the reaction to the ri+ht! #t results $rom the elimination o$ a
molecule o$ water $rom two molecules o$ acetic acid (see :i+! ""!C)! :i+ure ""!9
,elow shows the ,alanced chemical reaction o$ the synthesis o$ acetylsalicylic
acid!

:i+ure ""!C! Structure o$ Acetic Anhydride

:i+ure ""!9! The ,alanced chemical reaction o$ the $ormation o$
aspirin!
(ecause the reaction is slow in pure acetic anhydride, the catalyst,
commonly stron+ acids li.e phosphoric acid was used $or the reaction!
Accordin+ to 'e ChatelierMs principle, the presence o$ e5cess acetic anhydride
$orces the eDuili,rium towards the desired product, which in this case is the
aspirin! #n addition to this, the catalysts were also used to ensure that side
reactions, which may cause the percenta+e yield to increase, will ,e avoided!
The reaction ,ehind the synthesis is nucleophilic acyl su,stitution!
Accordin+ to McMurry (C), nucleophilic acyl su,stitution happens when the
initially $ormed intermediate e5pels one o$ the su,stitutes ori+inally ,onded to
the car,onyl car,on leadin+ to the $ormation o$ a new car,onyl compound! #n
this e5periment, the speci<c nucleophilic acyl su,stitution is esteri<cation! #t
occurs when a car,o5ylic acid in salicylic acid and an alcohol com,ine in a
reaction to produce an ester!
:i+ure ""!4! Mechanisms on the $ormation o$ aspirin
&hosphoric acid protonates the car,onyl o5y+en atom (CP*) o$ the
anhydride to ma.e it more prone to nucleophilic attac.s! #t +ives the anhydride
a positive char+e thus, ma.in+ it more suscepti,le to nucleophilic attac.s! The
nucleophilic hydro5yl +roup o$ salicylic acid attac.s the electron de<cient acetic
anhydride resultin+ to a tetrahedral intermediate! The hydro5yl +roup (/*3)
attached to the electrophilic car,on removed the hydro+en as proton thus
donatin+ the electron to $orm a dou,le ,ond (CP*)!The loss o$ the proton
re+enerates the phosphoric acid and thus, producin+ acetylsalicylic acid!
To enhance the synthesis reaction, addition o$ heat and water a$ter
heatin+ were done! The synthesis o$ reaction is $avored ,y heatin+ the mi5ture
,ecause it speeds up the dissolution process o$ salicylic acid and increases its
solu,ility as well! (ecause this speci<c reaction is an endothermic process,
addition o$ heat would $avor a $orward reaction resultin+ to the $ormation o$
products! Aside $rom that, nucleophile was completely $acilitated ,y the
addition o$ water a$ter heatin+! 4ater was used in order to provide medium $or
$urther nucleophilic su,stitution!
The theoretical yield o,tained is "!9 +rams a$ter .nowin+ that salicylic
acid is the limitin+ rea+ent! The actual yield o,tained is !@7 +rams thus, the H
yield is BH ! This results are relatively low ,ecause o$ possi,le sources o$ error
such as loss o$ product in the <lter paper ,ecause o$ prolon+ed air dyin+,
decomposition to acetic acid in solution so there wasn>t a complete conversion
o$ rea+ents and insu6icient heatin+!
%pon o,tainin+ the crude aspirin, recrystalliFation was done! This is
per$ormed to remove the traces o$ impurities! A$ter coolin+ to room
temperature and immersin+ on an ice cold water ,ath, suction <ltration method
was done to separate the <ltrate $rom the residue which contains the
recrystalliFed products! Suction <ltration is the most practical techniDue to use
when $ast <ltration o$ mi5ture is desired! #t employs vacuum which can aid in
the passa+e o$ <ltrate throu+h the <lter paper ((asic *r+anic ChemistryE
'a,oratory Manual, C"C)! #n addition, since aspirin is an ester, it should not ,e
recrystalliFed $rom hot water ,ecause it will allow the crude sample to ,e
hydrolyFed and yield undesira,le products! The H recovery o,tained is 8?H!
A$ter per$ormin+ the synthesis o$ aspirin $rom salicylic acid, the
veri<cation o$ the identity and purity o$ the product throu+h meltin+ point
determination was also per$ormed!
#n di6erentiatin+ salicylic acid $rom the synthesiFed product, :eCl
9
test
and JMn*
4
test were conducted! :or the :eCl
9
test, the positive will +ive a
chan+e $rom yellow/,rown solution to a violet colored comple5! :or this test, the
result is positive ,ecause o$ the presence o$ phenol in it! The o5y+en atoms o$
the acid +roup RC**3, and o$ the /*3 +roup on the salicylic acid to+ether can
$orm a comple5 with :e(3
C
*)
B

G9
! The test result on aspirin is ne+ative ,ecause
iron comple5 cannot ,e $ormed due to the a,sence o$ a hydro5yl +roup attached
to ,enFene!
:or the JMn*
4
test, a positive result was o,tained $rom the synthesiFed
aspirin as seen ,y the disappearance o$ violet color and $ormation o$ the ,rown
precipitate! Theoretically, salicylic acid would +ive a positive result ,ecause o$
the presence o$ hydro5yl +roup (/*3)! Iecallin+ the reactions in alcohols,
JMn*
4
was used to detect the presence o$ primary and secondary alcohols!
Since the phenol +roup is a,sent in the synthesiFed aspirin, a ne+ative result
should ,e o,tained!
Another test was conducted to di6erentiate the synthesiFed aspirin $rom
the commercially/availa,le aspirin! :or the iodine test, the positive result is the
solution turnin+ ,lue or violet ,ecause o$ the presence o$ starch! #n this
particular e5periment, it is the commercially/availa,le aspirin that has a color
chan+e which is the solution e5hi,ited a $aint violet color! Theoretically, this
holds true ,ecause pharmaceutical companies add starch to ta,let medicines to
+ive them its characteristic shapes!
'astly, the meltin+ point determination was conducted! *ne way o$
identi$yin+ a su,stance is throu+h its meltin+ point! The ran+e o$ the meltin+
point can +ive one an idea on the purity o$ the sample! The theoretical meltin+
point ran+e o$ aspirin is "C7/"9@LC! #n this e5periment, the o,tained meltin+
point ran+e o$ o$ the crude aspirin is "B/ ""CLC and $or the recrystalliFed
aspirin, it is ""4/""7LC! The result o$ meltin+ point determination means that
the samples have impurities in it! Karrow di6erence in the meltin+ point ran+e
o$ the sample and the theoretical meltin+ point ran+e means that the su,stance
is pure ,ecause o$ the uni$orm $orces present in the molecules! 4hen the ran+e
is wide, it means that the sample contains impurities! #n this e5ercise, meltin+
point determination is done! And the results show that it has a wide di6erence
$rom the theoretical meltin+ point ran+e o$ aspirin! Thus it can ,e in$erred $rom
the results that the sample is not pure!
V##! Summary and Conclusion
Synthesis o$ or+anic compounds involves +uidelines and steps that should
,e $ollowed! The <rst one is the esta,lishment o$ the startin+ materials which is
in this are the salicylic acid and acetic anhydride to+ether with the phosphoric
acid that served as the catalyst $or the reaction! The synthesis o$ aspirin
involved the acid/catalyFed nucleophilic acyl su,stitution! The speci<c
nucleophilic acyl su,stitution $or this e5periment is esteri<cation! #t happens
when a car,o5ylic acid $rom the salicylic acid and an alcohol com,ine in a
reaction there$ore producin+ an ester!
#n this e5periment, phosphoric acid was used as a catalyst to hasten the
reaction ,etween the salicylic acid and acetic anhydride! 3eat and addition o$
water was also done $or e6icient production o$ the desired product! The percent
yield o,tained $or this e5periment is BH! 'ow Hyield can ,e caused ,y
insu6icient heatin+ and that the product was lost in the <lter paper ,ecause o$
prolon+ed air dryin+!
The ne5t step that was done was the recrystalliFation o$ the crude sample
to o,tain a more puri<ed or+anic compound! IecrystalliFation was done ,y
suction <ltration! The last step $or this e5periment is the veri<cation and
di6erentiation o$ the samples! Throu+h the JMn*
4
test, it was veri<ed that the
synthesiFed product was indeed to ,e acetylsalicylic acid or most commonly
.nown as aspirin! Another test that was conducted is the iodine test wherein the
commercially/availa,le aspirin +ave the positive result due to the presence o$
starch in it! %n$ortunately, :eCl
9,
did not +ive the theoretical results!
V###! Ie$erences
Aspirin timeline! (C"9)! Ietrieved on *cto,er 8, C"9 $rom
httpEAAwww!tele+raph!co!u.AhealthAhealthnewsA7"78"B4AAspirin/timeline!html
3istory o$ Aspirin! (C"9)! Ietrieved on *cto,er 8, C"9 $rom
httpEAAen!wi.ipedia!or+Awi.iA3istorySo$Saspirin
#nstitute o$ Chemistry! (C"C)! (asic *r+anic Chemistry 'a,oratory
Manual! %niversity o$ the &hilippines 'os (a)os Colle+e 'a+una! @C/@8!
Material sa$ety data sheet! (C"9)! Ietrieved on *cto,er B, C"9 $rom
httpEAAwww!inchem!com!phAproductpa+esA$ecl9Smsds!pd$
McMurry, John! (C)! *r+anic Chemistry! @
th
Edition %SA!
MS1S $or potassium perman+anate! (C"9)! Ietrieved on *cto,er B, C"9
$rom httpEAAwww!sciencela,!comAmsds#dP??C@4B
&hosphoric acid! (C"9) retrieved on *cto,er B, C"9 $rom
httpEAAwww!ccohs!caAoshanswersAchemicalsAchemSpro<lesAphosphoric!html
Iodri+ueF, E!(! ("??@)! (asic &rinciples o$ *r+anic Chemistry! %& *pen
%niversityE 1iliman TueFon City ! C?8 R 99B!

#Q! Iemar.s and Iecommendation
The synthesis o$ or+anic compounds is indeed very help$ul in chemistry
and throu+h this process, one can have a +limpse on how chemical processes
wor.s in real li$e!
The researcher recommends the use o$ other tests in order to o,tain more
accurate results in the di6erentiation o$ the synthesiFed aspirin $rom the
commercially/availa,le aspirin!