Carboxylic Acid Derivatives Compounds that can be hydrolyzed to a carboxylic acid in acidic water are called carboxylic acid derivative compounds

H+, H2O

O O O O O O H2C C O H3C C N H3C OH H3C Cl H3C O CH3 H3C OCH3 H3C NH2

Acid Acid Anhydride Ester Amide Ketene Nitrile chloride

O !+ !+ H2C C O H3C C N H3C !+ LG 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

In all cases, however, the carbonyl carbon or the carbon attached to nitrogen are electrophilic 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 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

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

O NUC O O LG H3C LG H C LG H3C NUC 3 NUC

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

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

Identical product pKa of conjugate for leaving group O NUC O Cl -7 H3C Cl H3C NUC

O O O O NUC ~4-5 H3C O CH3 H3C NUC H3C O

O O NUC CH3O 16 H3C OCH3 H3C NUC

O O NUC NH2 35 H3C NH2 H3C NUC

The stability of the leaving group affects the reactivity pattern for the acid derivatives 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 Resonance effect O O O

R !+ Y !- R Y R Y More electronegative Y pulls electron density Lone pair of electrons on Y atom can resonate from carbon, thus making the carbonyl to create a C=Y double bond and a C-O single carbon more electrophilic (δ+) bond, making carbonyl more stable Generally the greater difference in electronegativity between C and Y 3p causes inductive effect to become dominant 2p Y group also affects the stability amongst the resonance forms !+ !- !+ O Cl O O O O OR O OR O NH2 O NH2

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

Resonance stability 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

O O O O O

H3C Cl H3C O CH3 H3C OCH3 H3C NH2 Acid chlorides Anhydrides Esters Amides Strong induction, weak Presence of second Placing positive charge Placing positive charge resonance stabilization carbonyl affects partial on electronegative on less electronegative due to electronegative charges, also causes oxygen destabilizes nitrogen atom makes Cl and poor overlap two carbonyl stretching resonance form this the most stable peaks in IR resonance form ν ~ 1810 cm-1 ν ~ 1760 + 1830 cm-1 ν ~ 1750 cm-1 ν ~ 1650-1680 cm-1

O O O O

H3C O CH3 H3C O CH3 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 O

OH 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 O O

Cl H Cl Cl Cl

Acetyl chloride Formyl chloride Phosgene (ethanoyl chloride) (methanoyl chloride) Acid Chlorides

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

O SOCl2 O

H3C OH H3C Cl

The acid chloride can also be converted back to the carboxylic acid by reaction with water (in either acidic or basic conditions) Characteristic for all O H O O 2 carboxylic acid H3C Cl H3C OH derivatives

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

O O OH O Cl H3C Cl H C Cl H3C OH 3 OH Acid Chlorides

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

O O O O H3C OH

H3C Cl H3C O CH3

O O CH3OH

H3C Cl H3C OCH3

O NH3 O

H3C Cl H3C NH2

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

O O O RMgBr Cl H3C Cl H C Cl H3C R 3 R

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

Since this ketone is formed in the presence of the Grignard reagent, a second addition occurs

O O OH RMgBr H+ H C R H C R H C R 3 3 R 3 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

CuI 2 LiI Li 2CuLi

Organocuprates react with acid chlorides but they are not reactive enough to add to ketones

O 2CuLi O

H3C Cl H3C 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

O LAH OH

H C H H3C Cl 3 H

There have been two solutions developed to stop reduction at aldehyde stage First is to use a less reactive, bulky aluminum hydride reagent

CH3 Li H Al O CH O 3 O Bulky hydride CH3 3 agent does not H3C Cl (lithium aluminum H3C H reduce aldehyde tri-t-butoxy hydride)

Second is called the “Rosenmund” reduction

O H2, BaSO4, Pd O Poisoned catalyst stops at aldehyde quinoline, ! H3C Cl H3C H stage Anhydrides

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

O O O

H3C OH H3C O CH3 Acetic acid Acetic anhydride (ethanoic acid) (ethanoic anhydride)

Unsymmetrical anhydrides have both constituent acids named, listed alphabetically and then followed with -anhydride

O O O O

H3C 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

O O O CH3O O O O CH3 H3C O CH3 H C O CH3 H C O O CH3 3 O 3 H3C

O O O CH3NH2 O O O O CH CH3 H3C O CH3 H3C 3 H3C N HO CH3 NH2 H H3C

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

O O H+ O O O

HO OH -H2O

When cyclic anhydrides react with either an alcohol or amine, difunctional unsymmetrical carbonyl compounds are obtained

O O O O O CH3NH2

HO NHCH3

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 O

OH OCH3

2-methylpentanoic acid Methyl 2-methylpentanoate

Cyclic esters are called “lactones”

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

Esters can react under either acidic or basic conditions to be hydrolyzed to the acid

H H O H+ O H2O O H C OR H C OR H C OH2 3 3 3 OR

-H+

H H O -ROH O H+ O H C OH H C OH H C OH 3 3 OR 3 OR H

This mechanism is the exact reverse of a Fischer esterification

Fischer esterification O H+, ROH O

H3C OH H+, H2O H3C OR 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”

O O O EtONa H+, EtOH

H3C O H3C OCH3 H3C O

As with ester hydrolysis, reaction can occur under either acidic or basic conditions

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

O CH3CH2MgBr O CH3CH2MgBr OH Two of the R groups on 3˚ alcohol must H3C OCH3 H3C CH2CH3 H3C be identical

Same mechanism occurs with LAH as two hydrides are delivered to generate 1˚ alcohol

O LAH OH H3C OCH3

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

C(CH3)2 H Al Need to run reaction O O C(CH3)2 at low temperature to

H3C OCH3 (DIBAL-H) H3C H prevent second addition -70˚C Amides

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

O O Substituents on amide CH CH nitrogen are labeled as N- H C OH H C N 2 3 3 3 alkyl in alphabetical order CH3 Acetic acid N-ethyl-N-methyl acetamide (ethanoic acid) (N-ethyl-N-methylethanamide)

Cyclic amides are called “lactams”, similar to cyclic esters called “lactones”

Nitrogen analogs of anhydrides O are called “imides” 2-azacyclohexanone ! NH δ-lactam H " $ 5-aminopentanoic acid lactam O N O # 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

O O O NaOH H+, H2O CH2CH3 H3C OH H3C N H3C OH ! ! CH3

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

O Reactivity H3C Cl

O O Amongst the derivatives, O H3C O CH3 however, only the more reactive can be converted to the less H C OH 3 reactive directly O (cannot synthesize a more reactive derivative directly from a less H3C OCH3 reactive)

O

H3C NH2

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 Amides

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

O O O CH CH LAH 2 3 CH2CH3 CH2CH3 N H3C N H3C N H H3C H CH3 CH3 CH3 The amide (negative charged nitrogen) AlH is too unstable to allow H C CH CH O 2 3 N 2 3 reaction to occur CH2CH3 H3C N H3C H H CH3 Instead alkoxide coordinates to aluminum to make a leaving group LAH and formation of imminium ion

H3C CH2CH3 N The imminium ion will be reduced with H C H LAH to form an amine, 3 H overall amide was thus reduced to amine Amides

Another convenient reaction is that nitriles are the “dehydrated” forms of amides

O -H2O H3C N H3C NH2

Can cause this interconversion with strong dehydrating agents

(e.g. POCl3 or P2O5 are common)

O N POCl3 NH2

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 SN2 reaction of cyanide with alkyl halides) Amides

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)

H R N H S O N O CO2H Penicillin

Unlike normal amides or lactams, β-lactams are more reactive due to the strain of the 4-membered ring Amides

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

O

H H HN R R N H R N H S S NUC S O O N O N O HN O NUC CO2H CO2H NUC

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

O enzyme O H2N OH HN Polymer chain of cell wall Penicillin interferes with enzyme

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 Nitriles

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

O N CH2CH2CH3 HO CH2CH2CH3

Butanoic acid Butanenitrile (include nitrile carbon in root)

If nitrile is not the highest priority group, then name group as a cyano prefix

O CN

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 P2O5 or POCl3) or SN2 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

H H N N H+ H2O -H+ R C N R C N H R OH2 R OH

H+

H H OH NH NH N H+, H2O 2 -H+ 2 R O R O R OH R OH

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

H N N O CH3MgBr H+ H+, H2O R C N R CH3 R CH3 R CH3

Cannot react a second Imines hydrolyze to ketones equivalent due to negative with acidic water 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

O CH3CH2MgBr O CH3CH2MgBr OH

H3C OCH3 H3C CH2CH3 H3C Nitriles

When nitriles are reduced with LAH, both π bonds are reduced to obtain an amine

1) LAH 2) H2O R C N R CH2NH2

Nitriles can also be reduced to amines with catalytic hydrogenation

CN CH2NH2 H2 Pd 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

1) LAH NaCN 2) H2O Br CN NH2

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

1) LAH NaN3 2) H2O Br N3 NH2

(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) Amines 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

NH3 Br NH2 N N N H

10.9% 17.9% 19.1% <1%

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 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

Another way to avoid this problem is instead of reacting ammonia, use the phthalimide anion O O O KOH Br NaOH CO2H NH N N NH2 CO2H O O O Called the “Gabriel” Due to carbonyls, only In base, phthalimide synthesis one addition occurs hydrolyzes to amine and acid 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

H H3C C C O C C O H H3CH2C

Ethenone 2-methyl-1-buten-1-one (ketene) (ethylmethylketene)

Ketenes are synthesized by elimination reactions of acid chlorides using tertiary amines

O H3C Et3N Cl C C O H H3CH2C Ketenes

The carbonyl carbon of ketenes is very electrophilic and will react with weak nucleophiles

H O OH O NUC H+ C C O H H2C NUC H2C NUC H3C 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

H O H2O C C O H H3C OH

H O CH3OH C C O H H3C OCH3

H O CH3NH2 C C O H H3C NHCH3 Reduction of Carbonyl Compounds O O O O O N Reducing C H C CH H C OH H C Cl H C OCH H C NH2 H3C reagent 3 3 3 3 3 3 3 OH LAH H3C CH3 H3C OH H3C OH H3C OH H3C NH2 H3C NH2

OH

NaBH4 NR NR slow NR NR H3C CH3 (NR at RT)

O O O O LiAlH(OtBu) slow at 3 NR (bulky) RT H3C H H3C H H3C H H3C H (-78˚C) (-78˚C) (-78˚C) (0˚C) OH O O O DIBAL H3C CH3 H3C OH H3C OH H3C H H3C H H3C H (-78˚C) (-78˚C) (-78˚C) R OH O R OH R OH O RMgBr Poor H3C CH3 H3C R H3C R H3C R reaction H3C R 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

Alkenes oxidized, if H present obtain aldehyde Alkenes oxidized, if H present obtain acid O O OH O O OH HO HO H H OH HO

1) O3, 2) H2O2 1) O3, 2) Zn

O OH OH O O MnO2 Cr(VI), acidic H HO HO Only allylic Consider this diol 1˚ alcohols alcohols oxidized starting material Cr(VI), basic oxidized to acid Swern (PDC or PCC) -78˚C O O O O

H H 1˚ alcohols oxidized to 1˚ alcohols oxidized aldehyde, no metal to aldehyde Baeyer-Villiger 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) A Baeyer-Villiger reaction allows conversion of ketone to ester

O O RCO3H R R R R O

Mechanism of oxygen insertion?

H O O O O O O R R H O R R R O R

H O O HO R R R O O R O R Weak oxygen-oxygen R O single bond O Mechanism is not an insertion, but rather a reaction at carbonyl followed by a migration Baeyer-Villiger

Migration with unsymmetrical carbonyls

If the two alkyl components of the ketone are different, which one migrates?

O O O RCO3H R2 or R1 R1 R2 R1 O R2 O

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 O More substituted substituent RCO3H O migrates preferentially

O O O Cyclic ester RCO H 3 (lactone)

O O Another way to oxidize RCO3H H HO aldehyde to carboxylic acid

O O Migration occurs with RCO3H H H retention of configuration O for migrating group H H Beckmann Rearrangement

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

1) NH2OH, H+ O O 2) H2SO4

H3C CH3 H3C NHCH3

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

OH OH2 H3C O NH2OH N H2SO4 N N H+ H3C CH3 H3C CH3 H3C CH3 CH3 Oxime formation H2O

H C H C H C 3 NH 3 N 3 N -H+

O CH3 HO CH3 H2O CH3 Hofmann Rearrangement

Converts primary amides to amines with loss of the carbonyl carbon

The main advantage of this method is to generate amines on 3˚ carbons,

realize that with SN2 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 (Br2 or Cl2) an amine is obtained

O Br2, NaOH NH2 NH2 -CO2

The reaction is driven by loss of carbon dioxide Hofmann Rearrangement

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

O O Br2, NaOH NaOH O O Br Br Br NH2 N N N H

H O NH N O C 2 -CO2 NaOH N O

Carbamic acid isocyanate 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 Carboxylic Acid Derivatives

Example of carboxylic acid derivative chemistry in biology

Why do humans take aspirin?

O

O aspirin OH

O

Found naturally in willow bark and myrtle leaves

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 Carboxylic Acid Derivatives

Biological targets

Arachidonic acid is converted into PGH2 by an enzymatic pathway called prostaglandin synthase

Prostaglandin CO2H synthase CO2H

OH

Arachidonic acid PGH2 Carboxylic Acid Derivatives

PGH2 is converted into prostaglandins and thromboxanes biologically HO

CO2H Prostaglandins HO OH Amongst other things, O stimulate inflammation and induce fever CO2H

CO2H HO OH OH CO H O 2 PGH2 O Thromboxanes OH OH Stimulate platelet aggregration CO2H HO O OH 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 (CH2OH) attached to a serine amino acid, thus called a serine hydroxy group

O CH 3 O O OH HOH2C H3C OH2C

CO2 CO2

Active enzyme Inactive enzyme

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 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 PGH2 (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