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Carboxylic Acid Derivatives Compounds that can be hydrolyzed to a carboxylic acid in acidic water are called carboxylic acid derivative compounds Likewise carboxylic acid can be converted into any of the derivative compounds either in a single step, or through a couple of steps, thus making all derivatives interconvertible

H 3 C O OCH 3 H 3 C O O O CH 3 H 3 C O ClH 3 C O OHH 3 C O NH 2 H 2 CCOH 3 CC N Acid

Acid chloride Anhydride Ester Amide Ketene Nitrile While most of these compounds have an acyl structure with a leaving group attached to the carbonyl, some have two double bonds from one carbon (ketenes) and some are nitriles

H 3 C O LG In all cases, however, the carbonyl carbon or the carbon attached to nitrogen are electrophilic H+, H 2 O H 3 C O LG !+ H 2 CCO !+ H 3 CC N !+

Carboxylic Acid Derivatives Carboxylic acid derivatives will react similar to ketones and aldehydes in that the first step is reaction of the nucleophile with the electrophilic carbonyl carbon

H 3 C O H H 3 C O LG

NUCNUC

H 3 C O NUC H H 3 C O NUC LG H 3 C OH NUC H H 3 C O NUC H+

A ketone or aldehyde does not have a suitable leaving group with the initial alkoxide intermediate, thus it can only be protonated on work-up to the alcohol The leaving group present with carboxylic acid derivatives, however, allows the compound to reform a carbonyl and expel the leaving group

LG Thus carboxylic acid derivatives typically react through an addition/elimination mechanism

Carboxylic Acid Derivatives All of the carboxylic acid derivatives with an acyl structure can react with a nucleophile to generate the same carbonyl product - the difference is the leaving group pKa of conjugate for leaving group -7 ~4-5 16 35 The stability of the leaving group affects the reactivity pattern for the acid derivatives

H 3 C O Cl NUC H 3 C O NUC Cl H 3 C O O O CH 3 NUC H 3 C O NUCH 3 C O OH 3 C O OCH 3 NUC H 3 C O NUC CH 3 O H 3 C O NH 2 NUC H 3 C O NUC NH 2

Identical product

Carboxylic Acid Derivatives Reactivity of the carbonyl carbon in derivatives is also affected by the C=O bond strength As seen in IR, substituents on the carbonyl carbon can affect the C=O bond in two ways: Inductive effect

O RY

More electronegative Y pulls electron density from carbon, thus making the carbonyl carbon more electrophilic (δ+) Resonance effect

O RY

Lone pair of electrons on Y atom can resonate to create a C=Y double bond and a C-O single bond, making carbonyl more stable

O RY Generally the greater difference in electronegativity between C and Y causes inductive effect to become dominant !+ !- OCl OOR OOR O NH 2 O NH 2 OOO

Positive charge on electronegative oxygen Positive charge on less electronegative nitrogen More inductive effect than ester Poor orbital overlap in acid chloride

!+!+ !-

Resonance stability

Y group also affects the stability amongst the resonance forms 2p 3p

Carboxylic Acid Derivatives These differences in relative effects of induction and resonance with carbonyl compounds, and the relative stability of the various resonance forms for the acyl derivatives are indicated directly in the differences in carbonyl stretching frequency in the IR

H 3 C O ClH 3 C O O O CH 3 H 3 C O OCH 3 H 3 C O NH 2 H 3 C O O O CH 3 H 3 C O O O CH 3

Acid chlorides

Strong induction, weak resonance stabilization due to electronegative Cl and poor overlap Anhydrides Presence of second carbonyl affects partial charges, also causes two carbonyl stretching peaks in IR Esters Placing positive charge on electronegative oxygen destabilizes resonance form Amides Placing positive charge on less electronegative nitrogen atom makes this the most stable resonance form ν ~ 1810 cm-1 ν ~ 1760 + 1830 cm-1 ν ~ 1750 cm-1 ν ~ 1650-1680 cm-1 Symmetrical stretch Unsymmetrical stretch Always obtain 2 stretching peaks for coupled vibrations (need vibrating bonds to be connected by a common atom for coupling to occur) characteristic of anhydrides

Acid Chlorides Acid chlorides are named by replacing the final -ic acid in the name for the corresponding carboxylic acid and replacing it with -yl halide

O OH O Cl

Butanoic acid Butanoyl chloride By far the most common acid halides that are used are the acid chlorides (instead of acid bromides or iodides) and thus most discussion will be with acid chlorides Some common names for small acid chlorides:

O Cl H O ClCl O Cl

Acetyl chloride

(ethanoyl chloride) Formyl chloride (methanoyl chloride) Phosgene

Acid Chlorides Remember carboxylic acids can be converted into acid chlorides by reaction with thionyl chloride

H 3 C O OH SOCl 2 H 3 C O Cl The acid chloride can also be converted back to the carboxylic acid by reaction with water (in either acidic or basic conditions) H 3 C O Cl H 3 C O OH H 2 O

This reaction follows the general scheme for acyl derivatives by reacting through an addition/elimination route

H 3 C O Cl OH H 3 C O OH Cl H 3 C O OH Cl Characteristic for all carboxylic acid derivatives

Acid Chlorides The acid chlorides can also be converted directly into any of the other acyl derivatives through the same addition/elimination mechanism

H 3 C O ClH 3 C O ClH 3 C O ClH 3 C O OH CH 3 OH NH 3 H 3 C O O O CH 3 H 3 C O OCH 3 H 3 C O NH 2 Since the acid chloride is more reactive than the anhydride, ester or amide, the acid chloride can be converted directly to any of these acyl derivatives

Acid Chlorides As seen in discussion of carbonyl reactions, addition of one equivalent of Grignard reagent to an acid chloride (or ester) will generate a tetrahedral intermediate

H 3 C O Cl RMgBr H 3 C O R Cl Unlike when reacting a Grignard with a ketone or aldehyde, however,

this tetrahedral intermediate has a good leaving group attached (the chlorine) The alkoxide will reform a carbonyl (strong bond) with the good leaving group present

H 3 C O R Cl Since this ketone is formed in the presence of the Grignard reagent, a second addition occurs H 3 C O R RMgBr H 3 C O R R H+ H 3 C OH R R Thus when either an acid chloride or ester react with a Grignard, two equivalents of Grignard are required and a 3˚ alcohol is obtained

Acid Chlorides In order to stop at the ketone stage, a weaker nucleophile than a Grignard reagent is required A solution is to use organocuprates Organocuprates react with acid chlorides but they are not reactive enough to add to ketones

CuI CuLi 2 Li 2 LiI H 3 C O Cl CuLi 2 H 3 C O

Acid Chlorides Likewise, acid chlorides will react twice with LAH to obtain tertiary alcohols the initial aldehyde after first addition will react a second time

H 3 C O Cl LAH H 3 C OH H H There have been two solutions developed to stop reduction at aldehyde stage First is to use a less reactive, bulky aluminum hydride reagent O CH 3 CH 3 CH 3 Al 3 H Li H 3 C O ClH 3 C O H (lithium aluminum tri-t-butoxy hydride) Second is called the "Rosenmund" reduction H 3 C O ClH 3 C O H H 2 , BaSO 4 , Pd quinoline, ! Bulky hydride agent does not reduce aldehyde Poisoned catalyst stops at aldehyde stage

Anhydrides Symmetrical anhydrides are named from the corresponding carboxylic acid name and then replace -acid in name with -anhydride

H 3 C O OHH 3 C O O O CH 3

Acetic acid

(ethanoic acid) Acetic anhydride (ethanoic anhydride) Unsymmetrical anhydrides have both constituent acids named, listed alphabetically and then followed with -anhydride

H 3 C O O OO O O Butanoic ethanoic anhydride Benzoic propanoic anhydride

Anhydrides Amongst the acyl derivatives, anhydrides can be converted directly into any of the less reactive carbonyl types

H 3 C O O O CH 3 CH 3 O H 3 C O O O O CH 3 H 3 C H 3 C O O CH 3 O O CH 3 H 3 C O O O CH 3 CH 3 NH 2 H 3 C O NH 2 O O CH 3 H 3 C H 3 C O N H CH 3 HO O CH 3 The anhydride is less reactive than an acid chloride

Lose one carbonyl as a leaving group (therefore with acetic anhydride shown lose acetic acid as leaving group)

Anhydrides Cyclic anhydrides can be formed from dicarboxylic acids HO OO OH H+ -H 2 O OOO When cyclic anhydrides react with either an alcohol or amine, difunctional unsymmetrical carbonyl compounds are obtained OOOCH 3 NH 2 HO OO NHCH 3

Both carbonyls are part of the product,

an atom efficient way to create unsymmetrical compounds

Esters Esters are named according to the parent carboxylic acid and the -ic acid is replaced with an -ate suffix, the alkyl ester substituent is named as a separate alkyl group with the name in front of the alkanoate name

O OH O OCH 3

2-methylpentanoic acid

Methyl 2-methylpentanoate Cyclic esters are called "lactones" O O

Possible naming:

2-oxocyclopentanone (place oxo indicating where oxygen substituted in cycloalkanone) γ-Lactone (indicate position of oxygen with Greek letter) 4-hydroxybutanoic acid lactone (name parent hydroxy acid if ester is cleaved, place lactone at end)

O O ! "# Esters Esters can react under either acidic or basic conditions to be hydrolyzed to the acid H 3 C O OR H+ H 3 C O OR H H 2 O H 3 C O OR OH 2 H -H+ H 3 C O OR OH H H+ H 3 C O OR OH H H -ROH H 3 C O OH This mechanism is the exact reverse of a Fischer esterification H 3 C O OHH 3 C O OR

H+, ROH

H+, H 2 O

Fischer esterification Ester hydrolysis

Esters Instead of hydrolyzing the ester with water, the same mechanism can be used to convert one ester into another ester Called "Transesterification" As with ester hydrolysis, reaction can occur under either acidic or basic conditions

H 3 C O OCH 3

H+, EtOH

H 3 C O O EtONa H 3 C O O Important consideration when running reactions with esters,

always use the alkoxide of the ester (ethoxide with ethyl ester for example) otherwise in addition to whatever other reaction is occurring (will see base catalyzed reactions with esters in later chapters) a transesterification of the product will also occur

Esters Similar to acid chlorides, when esters react with Grignard reagents two additions occur to generate 3˚ alcohols

H 3 C O OCH 3 CH 3 CH 2 MgBr H 3 C O CH 2 CH 3 CH 3 CH 2 MgBr H 3 C OH

Two of the R groups on 3˚ alcohol must be identical Same mechanism occurs with LAH as two hydrides are delivered to generate 1˚ alcohol

H 3 C O OCH 3 LAH OH

To stop at one addition, diisobutyl aluminum hydride (DIBAL-H) has been developed to reduce an ester to an aldehyde

H 3 C O OCH 3 HAl (DIBAL-H) C(CH 3 ) 2 C(CH 3 ) 2 -70˚C H 3 C O H Need to run reaction at low temperature to prevent second addition

Amides Amides are named by dropping the -oic acid from the parent carboxylic acid and writing -amide as the suffix

H 3 C O OH H 3 C O N CH 2 CH 3 CH 3

Acetic acid

(ethanoic acid) N-ethyl-N-methyl acetamide (N-ethyl-N-methylethanamide) Substituents on amide nitrogen are labeled as N-alkyl in alphabetical order Cyclic amides are called "lactams", similar to cyclic esters called "lactones"

NH O ! " # $

2-azacyclohexanone

δ-lactam 5-aminopentanoic acid lactam H N OO Nitrogen analogs of anhydrides are called "imides" Succinimide (imide version from succinic acid)

Amides Like all carboxylic acid derivatives, amides can be hydrolyzed to the carboxylic acid form under either acidic or basic conditions

H 3 C O N CH 2 CH 3 CH 3 H+, H 2 O ! ! NaOH H 3 C O OHH 3 C O OH

Due to the lower reactivity of amides compared to the other carboxylic acid derivative compounds, higher temperature is required to allow this transformation to occur Also due to the nature of the leaving group, for amide hydrolysis the acidic conditions are much easier than the basic The amides cannot be converted directly to any of the other acyl carboxylic acid derivatives due to the lower reactivity To change the amide to an ester, for example, first need to hydrolyze the amide to the acid and then convert the acid to the desired ester compound

Carboxylic Acid Derivatives

H 3 C O OHH 3 C O ClH 3 C O O O CH 3 H 3 C O OCH 3 H 3 C O NH 2 All carboxylic acid derivatives can be converted to the acid

under either acidic or basic hydrolysis Also the carboxylic acid can be converted directly to each of the derivatives Amongst the derivatives, however, only the more reactive can be converted to the less reactive directly (cannot synthesize a more reactive derivative directly from a less reactive) Reactivity

Amides While amides cannot be changed directly to the acyl carboxylic acid derivatives, it can react with hydride delivery agents

H 3 C O N CH 2 CH 3 CH 3 LAH H 3 C O N CH 2 CH 3 CH 3 H H 3 C O H N CH 2 CH 3 CH 3 H 3 C O N CH 2 CH 3 CH 3 H AlH 2 H 3 C H N H 3 CCH 2 CH 3 LAH H 3 C N H 3 CCH 2 CH 3 H H

The amide

(negative charged nitrogen) is too unstable to allow reaction to occur Instead alkoxide coordinates to aluminum to make a leaving group and formation of imminium ion The imminium ion will be reduced with LAH to form an amine, overall amide was thus reduced to amine

Amides Another convenient reaction is that nitriles are the "dehydrated" forms of amides H 3 C O NH 2 -H 2 OH 3 C N Can cause this interconversion with strong dehydrating agents (e.g. POCl 3 or P 2 O 5 are common) O NH 2 POCl 3 N Obviously would need a primary amide to allow reaction to occur

(need two hydrogens on amide nitrogen for dehydration) One of two common ways to synthesize nitriles (other is S

N

2 reaction of cyanide with alkyl halides)

A type of amide that is used biologically are β-lactams β refers to nitrogen of amide attached to the second carbon from carbonyl (hence β-carbon) Unlike normal amides or lactams, β-lactams are more reactive due to the strain of the 4-membered ring Amides Penicillin

N S O H CO 2 H H N O R

Amides Therefore nucleophiles will react with the amide carbonyl of the ring to open the ring and release the ring strain

N S O H H N O R NUC

The other amide is unreactive because it does not have ring strain, reacts like other amides discussed earlier

N S H CO 2 H H N O R O NUC NUC O HN S HN O R CO 2 H

Amides β-Lactams as antibacterial agents Bacterial cells survive many conditions that mammalian cells do not due to a rigid cell wall composed of carbohydrates linked together by peptide bonds With the β-lactam penicillin present, the cell walls of the bacterial are disrupted because the enzyme that forms the cell walls is turned off by undergoing a nucleophilic reaction with penicillin and thus the bacterial cells eventually die Penicillin does not disrupt mammalian cells since they are surrounded by a lipid bilayer and not a peptide linked cell wall

O OH H 2 N

Polymer chain of cell wall

enzyme

Penicillin interferes with enzyme

O HN

Nitriles Nitriles are named as alkanenitriles Find longest carbon chain containing nitrile to determine the root name

HO O CH 2 CH 2 CH 3 N CH 2 CH 2 CH 3

Butanoic acid Butanenitrile (include nitrile carbon in root) If nitrile is not the highest priority group, then name group as a cyano prefix

OCN

4-cyano-2-pentanone

Have already seen that the most common methods to synthesize a nitrile are either dehydration of a primary amide (usually with P

2 O 5 or POCl 3 ) or S N

2 reaction with cyanide

Nitriles Obviously nitriles are not acyl derivatives as the other carboxylic acids observed, but they are still considered a type of carboxylic acid derivatives because the nitrile can be hydrolyzed to a carboxylic acid and the acid can be converted to a nitrile through an amide

R C NH+ R C NH H 2 O R N OH 2 H-H+ R N OH H H+ R N OH HH R NH 2 OH -H+ R NH 2 O H+, H 2 O R OH O

Hydrolysis can occur under either acidic or basic mechanism, although reaction under basic conditions can lead to other types of reactions so acidic hydrolysis is preferred

Nitriles The electrophilic carbon of nitriles can also react with strong nucleophiles When reacting nitriles with Grignard reagents, a ketone is obtained after hydrolysis

R C N CH 3 MgBr R N CH 3 H+ R N CH 3 H H+, H 2 O R O CH 3

Imines hydrolyze to ketones with acidic water Cannot react a second equivalent due to negative charge on nitrogen (would generate a -2 charge if reacted again) Allows synthesize of ketones with Grignard reagents, when either acid chlorides or esters reacted with Grignard a tertiary alcohol was obtained

H 3 C O OCH 3 CH 3 CH 2 MgBr H 3 C O CH 2 CH 3 CH 3 CH 2 MgBr H 3 C OH Nitriles When nitriles are reduced with LAH, both π bonds are reduced to obtain an amine R C N

1) LAH

2) H 2 O R CH 2 NH 2 Nitriles can also be reduced to amines with catalytic hydrogenation CN H 2 Pd CH 2 NH 2

Nitriles The LAH reduction of nitriles to primary amines is a convenient way to synthesize primary amines as the nitriles can also be easily synthesized from alkyl halides

Br

NaCNCN

1) LAH

2) H 2 O NH 2

Another functional group that can be reduced to primary amines is an azide, likewise an azide can also be easily synthesized from alkyl halides

Br NaN 3 N 3

1) LAH

2) H 2 O NH 2

(realize that when a nitrile is reduced one extra carbon is included due to the carbon from the nitrile, therefore these two routes synthesize primary amines with a different number of carbons)

Remember also that it is difficult to synthesize primary amines by reacting ammonia directly with the alkyl halide as polyalkylation often occurs to generate the quaternary product

Br NH 3 NH 2 N H N N

When the alkyl halide and ammonia are reacted in a 1:1 ratio, a low yield of the primary amine is obtained because the primary amine is also nucleophilic and can react again 10.9% 17.9% 19.1% <1% If the ammonia is used in excess, majority of product is 1˚ amine while if alkyl halide is used in excess, the majority of product is quaternary amine

NH O O

Amines

Another way to avoid this problem is instead of reacting ammonia, use the phthalimide anion KOH N O O Br N O O NaOH NH 2 CO 2 H CO 2 H

Due to carbonyls, only one addition occurs In base, phthalimide hydrolyzes to amine and acid Called the "Gabriel" synthesis

Ketenes Ketenes are compounds that contain a ketone functionality and the carbonyl carbon also has a double bond attached to another carbon The IUPAC naming for these compounds involve naming as alkene-substituted ketones, the common naming however names the functional group as ketene and then list the alkyl substituents to the ketene alphabetically

CCO H H CCO H 3 C H 3 CH 2 C

Ethenone (ketene) 2-methyl-1-buten-1-one (ethylmethylketene) Ketenes are synthesized by elimination reactions of acid chlorides using tertiary amines

O Cl H Et 3 N CCO H 3 C H 3 CH 2 C Ketenes The carbonyl carbon of ketenes is very electrophilic and will react with weak nucleophiles CCO H H NUC O H 2 CNUC H+ OH H 2 CNUCH 3 C O NUC

Upon initial reaction of nucleophile, an enolate is formed which upon protonation equilibrates to a carbonyl structure Ketenes can thus react to form carboxylic acids or derivatives like esters or amides

CCO H H CCO H H CCO H H H 2 OCH 3 OHCH 3 NH 2 H 3 C O OHH 3 C O OCH 3 H 3 C O NHCH 3 H 3 C O NH 2 H 3 C O OCH 3 H 3 C O ClH 3 C O OHH 3 C O CH 3

Reduction of Carbonyl Compounds

H 3 C C N LAH H 3 C OH CH 3 H 3 COHH 3 COHH 3 COHH 3 C NH 2 H 3 C NH 2 NaBH 4 H 3 C OH CH 3 NR NR slow (NR at RT) NR NR LiAlH(OtBu) 3 (bulky) H 3 C O H (-78˚C) H 3 C O H H 3 C O H H 3 C O H (-78˚C) (-78˚C) (0˚C) DIBAL H 3 C OH CH 3 H 3 COHH 3 COH H 3 C O H H 3 C O H H 3 C O H (-78˚C) (-78˚C) (-78˚C) NR slow at RT RMgBr Reducing reagent H 3 CCH 3 R OH H 3 C O R H 3 C R R OH H 3 C R R OH H 3 C O R

Poor reaction

Oxidation to Synthesize Carbonyl Compounds Similar to there being a variety of reducing agents to selective reduce carbonyl compounds, there are also a variety of oxidizing conditions to synthesize carbonyl compounds

HO OH

Consider this diol starting material

Cr(VI), acidic

HO OO H OO H OO H OHO HO O H O H OH HO O OH O HO OH

1˚ alcohols oxidized to acid 1˚ alcohols oxidized to aldehyde 1˚ alcohols oxidized to aldehyde, no metal Only allylic alcohols oxidized Alkenes oxidized, if H present obtain aldehyde Alkenes oxidized, if H present obtain acid

Cr(VI), basic

(PDC or PCC)Swern -78˚C MnO 2 1) O 3 , 2) Zn1) O 3 , 2) H 2 O 2 Baeyer-Villiger A Baeyer-Villiger reaction allows conversion of ketone to ester R O R RCO 3 H R O O R

Mechanism of oxygen insertion?

R O R H O O O R R O R O O O R H R HO O R O O R R O O R O O R H Mechanism is not an insertion, but rather a reaction at carbonyl followed by a migration

Weak oxygen-oxygen single bond There are some reactions that allow conversion of a ketone to a carboxylic acid derivative (have already seen that organolithiums can convert a carboxylic acid to a ketone)

Baeyer-Villiger Migration with unsymmetrical carbonyls If the two alkyl components of the ketone are different, which one migrates?

RCO 3 H R 1 O R 2 R 1 O O R 2 R 2 O O R 1 or There is a distinct preference for one group to migrate selectively

H > 3˚ alkyl > 2˚ alkyl ~ phenyl > 1˚ alkyl > methyl In general, a hydrogen migrates first, but then a more substituted alkyl group migrates preferentially

Baeyer-Villiger Examples

O RCO 3 H O O RCO 3 H O O O RCO 3 H H O HO O

More substituted substituent

migrates preferentially Cyclic ester (lactone) Another way to oxidize aldehyde to carboxylic acid

H H ORCO 3 HO H H O

Migration occurs with

retention of configuration for migrating group

Beckmann Rearrangement While the Baeyer-Villiger oxidation converts a ketone to an ester, the Beckmann rearrangement converts a ketone to an amide

H 3 C O CH 3 1) NH 2

OH, H+

2) H 2 SO 4 H 3 C O NHCH 3

The Beckmann rearrangement also involves a migration of one of the alkyl substituents of the ketone, but has a water leaving group rather than breaking a O-O single bond

H 3 C O CH 3 NH 2 OH H+ H 3 C N CH 3 OH H 2 SO 4 H 3 C N CH 3 OH 2 N H 3 C CH 3 H 2 O N CH 3 H 2 O H 3 C -H+ N CH 3 HO H 3 C O NH CH 3 H 3 C

Oxime formation

Hofmann Rearrangement The main advantage of this method is to generate amines on 3˚ carbons, realize that with S

N

2 methods cannot place amine on 3˚ carbon

Hofmann rearrangement starts with primary amide that can be generated from the acid chloride Upon introduction of basic halide solution (Br

2 or Cl 2 ) an amine is obtained

The reaction is driven by loss of carbon dioxide Converts primary amides to amines with loss of the carbonyl carbon

O NH 2 Br 2 , NaOH -CO 2 NH 2

Hofmann Rearrangement The mechanism of the Hofmann rearrangement involves a migration of the alkyl group to form an isocyanate

O NH 2 Br 2 , NaOH O N H Br NaOHO N Br O N Br N C ONaOH H N O O -CO 2 NH 2 isocyanate Carbamic acid

Nomenclature The compounds with one carbonyl are named according to the rules presented earlier Compounds with multiple functional groups, however, need a priority for naming Remember that carboxylic acid derivatives outrank all other substituents Amongst carbonyl compounds the following priorities apply: Acid > ester > amide > nitrile > aldehyde > ketone

Example of carboxylic acid derivative chemistry in biology Why do humans take aspirin? O O O OH aspirin

In the fifth century BC, Hippocrates wrote about the curative powers of willow bark In the nineteenth century, the compound was synthesized for the first time from salicylic acid and acetic anhydride Found naturally in willow bark and myrtle leaves Carboxylic Acid Derivatives

Carboxylic Acid Derivatives Biological targets Arachidonic acid is converted into PGH 2 by an enzymatic pathway called prostaglandin synthase CO 2 H CO 2 H OH

Prostaglandin

synthase Arachidonic acid PGH 2

Carboxylic Acid Derivatives

CO 2 H OH PGH 2 is converted into prostaglandins and thromboxanes biologically CO 2 H OH HO HO CO 2 H OH O HO CO 2 H OH O O CO 2 H OH O OH HO PGH 2

Prostaglandins

Amongst other things, stimulate inflammation and induce fever Thromboxanes Stimulate platelet aggregration

Carboxylic Acid Derivatives Aspirin interacts directly with the enzyme cyclooxygenase (which is the initial part of the prostaglandin synthase enzyme) Part of the cyclooxygenase enzyme has a primary hydroxy group (CH

2 OH)

attached to a serine amino acid, thus called a serine hydroxy group Aspirin will transesterify this serine hydroxy group (through a carboxylic acid derivative chemistry) and thus inactivating the enzyme Thus both prostaglandins and thromboxanes will not be produced

O OCH 3 CO 2 HOH 2 C OH CO 2 OH 2 CH 3 C O

Active enzyme

Inactive enzyme

Carboxylic Acid Derivatives How aspirin therefore affects health Aspirin turns off the cyclooxygenase enzyme This enzyme is part of the prostaglandin synthase enzyme which converts arachidonic acid into PGH

2

(which in turn is converted into prostaglandins and thromboxanes) Aspirin will therefore prevent inflammation and reduce fever (effects of prostaglandins) and also will lower platelet aggregation (effect of thromboxanes) Presumably the prevention of thromboxanes is why aspirin has been reported to reduce the incidence of strokes and heart attacks Also reason why aspirin should not be taken in the days before surgery, do not want anticoagulants in the body during surgery