mcmurry 7e ch19-23 notes 5-29-07

Organic II McMurry 7th Edition

CHAPTER 19

ALDEHYDES AND KETONES:

NUCLEOPHILIC ADDITION REACTIONS

Suggested Problems: ,30,32,34,45,48

Properties:

Review the structure of the carbonyl group. The carbon is sp2 hybridized and is trigonal planar with a

bond angle of 120°. The bond is planar. The carbonyl group is polarized and therefore is weakly

associated causing aldehydes and ketones to have higher boiling points than alkanes but not as high as

alcohols. Carbonyl groups do not have hydrogen bonding and therefore their boiling points are lower than

the alcohols.

19.1 Nomenclature:

Aldehydes

Replace the terminal "e" with the suffix "al". The longest carbon chain must include the CHO group and the

CHO group is assigned the number one. If the CHO group is attached to a ring, then "carbaldehyde" is used

to designate the aldehyde group.

Ketone

The terminal "e" is replaced by the suffix "one". The longest carbon chain must include the carbonyl group

and the number must be done so that the carbonyl group has the lowest number.

Examples:

Watch out for the common names!

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19.2 Preparation of Aldehydes and Ketones

Aldehydes

I. Oxidation of 1° Alcohols Using a Mild Oxidizing Agent, PCC: Pyridinium Chlorochromate

II. Oxidative Cleavage of Alkenes Using Ozone

The work-up could be either Zn/H2O or H2O2.

III. Reduction Reactions of More Highly Oxidized Compounds

A. Acid Chlorides Using Rosenmund Catalyst and Hydrogen Gas

B. Hydride Reductions of Esters and Acid Chlorides Using DIBAH.

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Ketones

I. Oxidation of 2° Alcohols by Any Oxidizing Agent

There are 4 common oxidizing agents employed:

(1) CrO3/H2SO4

(2) Na2Cr2O7/H2SO4

(3) KMnO4/H+

(4) PCC, pyridinium chlorochromate, in a polar aprotic solvent.

II. Oxidative Cleavage

A. Ozonolysis of Di, Tri or Tetrasubstituted Alkenes

The work-up could be either Zn/H2O or H2O2.

B. Basic Permanganate

Note: If the alkene has a hydrogen on the sp2 carbon, then the aldehyde initially formed is

further oxidized to the carboxylate ion. Terminal alkenes produce carbon dioxide as one of the products.

III. Reactions with Aromatic Rings via Friedel-Crafts Acylation

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IV. Reactions with Organocopper Reagents

Reactivity Considerations:

In comparison, aldehydes are generally more reactive than ketones. One factor contributing to this

observation is steric hindrance. The least sterically hindered the carbonyl carbon, the more reactive it is.

This can be seen in that, methanal (formaldehyde) is most reactive followed by other aldehydes and then

ketones. The relative reactivities of the carbonyl compounds covered so far are given below.

acyl halides > anhydrides > aldehydes > ketones > carboxylic acids ~ esters > amidesmost reactive least reactive

19.4-11 Nucleophilic Addition Reactions of Aldehydes and Ketones:

The main types of reactions involving aldehydes and ketones are Nucleophilic Addition Reactions.

If the attacking nucleophilic atom has a pair of nonbonding electrons in the addition product, then it also

undergoes elimination.

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Reactions:

I. Oxidation

A. Aldehydes Go to Carboxylic Acids

There are a variety of oxidizing agents that can be used. Synthetically you must keep in mind the other

functional groups present and their sensitivity to the oxidizing agent. Some common oxidizing agents

include: hot nitric acid, KMnO4, CrO3/H2SO4, Ag2O/NH3 (Tollen's) and others.

B. Ketones are usually inert to oxidizing agents but will undergo cleavage with hot KMnO4

to form the diacid.

II. Nucleophilic Additions

Nucleophiles can fall into two broad categories

1. Negatively Charged Nucleophiles: OH-, H-, R3C-, RO-, and CN-

2. Neutral Nucleophiles: H2O, ROH, NH3, and RNH2

The general reaction scheme showing both types of nucleophiles is shown below.

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The relative reactivity of aldehydes and ketones depend upon the accessibility of the carbonyl carbon and the

groups attached to the adjacent carbon atoms. Aldehydes only have one electron-releasing group attached to

the carbonyl and therefore are less stable (more reactive) than ketones, which have two electron-releasing

groups attached. If electron-withdrawing groups are attached, then this increases the electrophilicity of the

carbonyl carbon.

A. Hydration of Carbonyls to Form Hydrates (Gemdiols)

The gemdiol formation is reversible and can be catalyzed by either acid or base.

Acid-Catalyzed

Base-Catalyzed

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Examples:

B. Cyanohydrin Formation (Addition of HCN)

The first step is the protonation of the carbonyl oxygen followed by the attack of the cyanide ion. This is a

very useful intermediate in the synthesis of amino acids.

C. Addition of Grignard Reagents to form Alcohols

Unlike hydration and cyanohydrin formation Grignard addition is generally irreversible. Grignard reagents

are nucleophilic because the Mg-C bond is very polarized with the negative charge on the carbon. The

carbon group acts as if it were a carbanion. Initially the magnesium complexes with the carbonyl oxygen

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making the carbonyl a better electrophile. The nucleophilic addition takes place via a tetrahedral

intermediate. Subsequent reaction of this intermediate with aqueous acid yields the alcohol.

Examples:

D. Addition of Hydride Ion-Reduction to Alcohols

The two most common reducing agents used are lithium aluminum hydride and sodium borohydride. The

reducing agent acts as a hydride donor, thus adding the nucleophile. The subsequent addition of water or

aqueous acid yields the alcohol.

Examples:

E. Addition of Amines to Form Imines and Enamines

Primary amines (RNH2) react with carbonyls to form imines and secondary amines (R2NH) react with

carbonyls to form enamines.

Formation of Imines:

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CR H

O: :

CR H

O H

R'

CR R'

O: :

1. R'MgX

2. H3O+

a 20 alcohol

1. R"MgX

2. H3O+

CR OH

R"

R'

a 30 alcohol


In general:

Mechanism:

Reaction is usually done in benzene because it forms an azeotrope with water and the therefore the water can

be removed by using a Dean-Stark Trap.

Examples:

Preparation of Enamines:

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C O + H2N-RH+

C N-R + H2O


In general:

Examples:

F. Wolff-Kishner Reaction-Addition of Hydrazine and Clemmensen Reduction

This is a variation on the imine theme. The treatment of aldehydes or ketones with the primary amine,

hydrazine in the presence of base transforms the carbonyl compound into an alkane. The overall reaction

appears to be a complete reduction of the carbonyl group to an alkane. Usually the reaction is carried out at

240° C in boiling diethylene glycol. Recent advances have used DMSO as the solvent and carried the

reaction out at room temperature. The Wolff-Kishner reaction is used when the molecule contains portions

that are sensitive to acid. If the molecule contains segments that are sensitive to basic conditions of Wolff-

Kishner, then the reduction can be done with amalgamated zinc in concentrated acid. This is known as the

Clemmensen reduction. The Clemmensen reduction mechanism is not fully understood, but the Wolff-

Kishner is. Examples are shown below.

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G. Acetal/Ketal Formation

Aldehydes and ketones react reversibly with alcohols to form acetals (and in the older literature ketals). If

only one molecule of alcohol reacts with the carbonyl, the prefix hemi is used. Like water alcohols react

very slowly with carbonyls to form the nucleophilic product. In the presence of acid, the carbonyl is

protonated and the nucleophilicity is greatly increased. Acetals are most often used as protecting groups for

carbonyls because of the relative ease of formation and deprotection. The mechanism and examples are

shown below.

H. Formation of Thioacetals

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The mechanism is the same as that of acetal formation. In this case, the thiol ethanedithiol is used to form

the cyclic thioacetal. Thioacetals are however, stronger than their oxygen counterparts and deprotection is

accomplished using Raney nickel in a protic solvent like ethanol.

Example:

I. Wittig Reaction the Formation of Alkenes

The reaction is very useful in producing alkenes that are mono, di or tri substituted. Tetrasubstituted are not

formed due to the high degree of steric hindrance. The overall reaction is that a carbon group is attached to

the carbonyl carbon with a double bond. There is no mixture of stereochemical isomers other than E and Z.

The Wittig reagent is a phosphorus ylide. The ylide is formed from the SN2 reaction of triphenylphosphine

with an appropriate primary or secondary alkyl halide. The phosphonium salts are reacted with a strong base

such as NaH or n-BuLi. The proton on the carbon next to the positively charged phosphorus is slightly

acidic. This forms a neutral zwitterion, a betaine. The mechanism involves the formation of a cyclic

intermediate known as an oxaphosphatane. Because of this cyclic intermediate, there is considerable

stereochemical control.

General Scheme:

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Mechanism:

Example:

J. Cannizzaro Reaction

The Cannizzaro Reaction is a special kind of reaction known as a disproportionation reaction. The

reaction occurs by the nucleophilic addition of OH- to an aldehyde that does not contain any alpha hydrogens

to form a tetrahedral intermediate. This tetrahedral intermediate expels a hydride ion as the leaving group

thus forming a carboxylic acid from the original aldehyde. The hydride ion nucleophilically attacks another

aldehyde carbonyl carbon and after acid water work up affords an alcohol. The net result of this reaction is

that two aldehydes without alpha hydrogens are reacted in aqueous hydroxide solution to form an oxidized

product, the carboxylic acid and a reduced product, the alcohol. This reaction works well only on

formaldehyde and benzaldehyde. It also has physiological applications and is the basis behind NADH

catalyzed reactions. The reaction using benzaldehyde is shown below.

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19.13 Conjugate Nucleophilic Additions to -Unsaturated Aldehydes and Ketones

Up to this point, the nucleophilic addition reactions have been directly to the carbonyl carbon of the

aldehyde or ketone. The nucleophilic addition reactions can be expanded to include additions to carbonyl

compounds that have a double bond adjacent to the carbonyl carbon. These compounds are generally

referred to as -unsaturated carbonyl compounds. The conjugated carbon-carbon double bond sets up

alternating sites of positive and negative charges. When we studied conjugated dienes, we looked at the two

sites of nucleophilic attack, 1,2 or 1,4. Whenever the carbonyl compound does not have an unsaturated

conjugated bond, the attack is 1,2. However, under certain conditions the attack on the conjugated system

can be 1,4. The beta carbon of the conjugated carbon-carbon double bond is said to be activated by the

carbonyl group, since carbonyl groups are electron withdrawing. The nucleophiles that attack the beta

carbon site can be neutral as in the case of primary and secondary amines or they can be negatively charged

as in the case of carbanions. The following reactions illustrate these types of reactions.

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I. Conjugate Addition of Neutral Amines

II. Conjugate Addition of Carbanions

If the carbanion is from a Grignard reagent, it is a strong carbanion and will most likely attack the

carbonyl carbon in the 1,2 addition. However, if the carbanion comes from a weaker reagent such as a

lithium cuprate, then the attack is primarily at the beta carbon of the conjugated double bond (1,4). Below

are some examples showing this.

The organocuprates are generated by the reaction of one equivalent of copper(I) iodide and two

equivalents of organolithium reagent. Primary, secondary and even tertiary groups as well as aryl and vinyl

(alkenyl) groups undergo the addition reaction.

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CHAPTERS 20 & 21

Chapter 20: 21,22,25,26,30,31,32,33,34,35,36,38,39,52

Chapter 21: 32,33,36,37,46,60

Nomenclature:

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Carboxylic Acids

IUPAC rules allow for two systems of nomenclature depending on the complexity of the molecule.

Carboxylic acids derived from open chains are systematically named by replacing the "e" at the end of the

parent chain with "oic acid". The carboxyl group is always C1 in the numbering scheme.

Examples:

If the carboxylic acid has a more complex unit, then name the complex unit and add the words “carboxylic

acid”.

Acyl Halides

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The acyl group is derived from the carboxylic acid name by replacing the ic acid with yl or the

carboxylic acid with carbonyl and then the halide name follows.

Acid Anhydrides

Symmetrical anhydrides of straight-chain monocarboxylic acids and cyclic anhydrides of

dicarboxylic acids are named by replacing the word acid with anhydride.

Asymmetric (mixed) anhydrides are named by naming each acid and then adding the word “anhydride”.

Esters

The systematic names for esters are derived from the alkyl group attached to oxygen through a single

bond (which comes from the alcohol) and then the name of the carboxylic acid with the ending ate on it.

This is the actual name of the conjugate base ion of the carboxylic acid.

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Amides

Amides formed from unsubstituted NH2 groups are named by replacing the oic acid or ic acid ending

with amide or by replacing the carboxylic acid with carboxamide. If the nitrogen has substituents on it, they

are designated by using N and the alkyl name.

Nitriles

Simple acyclic nitriles are named by adding the ending nitrile as a suffix to the alkane name with the

nitrile carbon counting as position number 1. More complex nitriles are named as derivatives as the

carboxylic acids by replacing ic acid or carboxylic acid with onitrile or carbonitrile.

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Structure and Physical Properties of Carboxylic Acids:

Carboxylic acids resemble both aldehydes/ketones and alcohols. Like aldehydes and ketones the

carbonyl carbon is sp2 hybridized with bond angles of 120°. Like alcohols, carboxylic acids are strongly

associated with each other through hydrogen bonds. Because of the strong hydrogen bonding capabilities,

carboxylic acids normally exist as dimers. These strong hydrogen bonds have a noticeable effect on the

physical property of boiling point. The boiling points are much higher than those of alcohols.

Dissociation of Carboxylic Acids

Compare the dissociations of a carboxylic acid, water and an alcohol.

Carboxylic acids are more acidic than alcohols (1011), but less than mineral acids. Since they are acids, they

react with bases (both strong and weak) to yield salts. Most undissociated carboxylic acids are insoluble in

water (>C6) but their salts are very soluble in water. In practice, this is exploited to extract and purify

carboxylic acids. What is commonly done in the laboratory is to react the insoluble carboxylic acid with

base so that it is soluble in water and remove all of the water insoluble impurities. Then re-acidify the salt

with strong mineral acid to make it more soluble in the organic solvent.

Why are carboxylic acids stronger acids than alcohols? The answer lies in the structure of the conjugate

bases. The carboxylic acid forms a carboxylate ion that has both resonance stabilization and delocalization

of the negative charge. The alkoxide ion formed from alcohols cannot be resonance stabilized nor

delocalized. Evidence for the resonance stabilized structures came from x-ray crystallographic studies of

sodium formate. The x-ray data showed that the bond lengths were equal and somewhere in-between a pure

single and pure double bond length. The resonance stabilized structures of the carboxylate ion are shown

below.

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Substituent Effects on Acidity:

Any substituent that will stabilize the negative carboxylate ion charge, will increase the acidity. A

brief comparison is given below:

Carboxylic Acid pKa

CH3CH2CO2H 4.87

ClCH2CH2CO2H 3.98

ClCH2CO2H 2.85

Cl2CHICO2H 1.26

Cl3CCO2H 0.64

F3CCO2H 0.23

Electron-withdrawing groups will stabilize the anion and therefore increase acidity. There is also an

increased effect based on the number of electron-withdrawing groups, their electronegativity values, and

their relative position to the carboxyl group.

Substituent Effects on Substituted Benzoic Acids:

Recall the discussion concerning the effect of certain groups (activating/deactivating) on the

reactivity of substituted benzenes and electrophilic aromatic substitution reactions. These same groups will

also have an effect on the relative acidity of benzoic acid derivatives because of their inductive or resonance

effects. If the group is electron-withdrawing (inductively), it will lower the pKa of the substituted benzoic

acid relative to benzoic acid. If the group is electron-donating, then it will increase the pKa of the substituted

benzoic acid relative to benzoic acid.

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Deactivating groups such as NO2, CN, CHO, Cl, and Br will increase the acidity relative to benzoic

acid. Activating groups such as CH3, OCH3, and OH will decrease the acidity relative to benzoic acid.

Hammett proposed a numerical treatment of the effect of substituents on the reactivity of certain compounds.

The compounds used were benzoic esters, namely substituted ethyl benzoates. Hammett proposed a Linear

Free Energy Relationship to relate the rate constants for the hydrolysis of the benzoic esters (both substituted

and unsubstituted) to the ratio of the equilibrium constants of benzoic acids (both substituted and

unsubstituted). He used benzoic acids and esters that the substituents located in the meta and para positions.

This precluded the interference of steric factors caused by substituents in the ortho positions. The logarithm

of the ratio of the rates of ester hydrolysis (substituted/unsubstituted) was plotted against the logarithm of the

ratio of the dissociation constants for the substituted and unsubstituted benzoic acids. The two differed by a

constant, . Rho was assigned a value of 1.00 for the ionization of XC6H4COOH in water at 25o C and the

values (log K/Ko) were calculated for each type of substituent group. Once a set of values could be

obtained, then values could be obtained from the rates of just two other substituted compounds. This then

was a way of predicting the rate of reactions that had not yet been run. The most familiar form of the

Hammett equation is shown below.

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Preparation of Carboxylic Acids

A. Oxidation of Alkylbenzenes Using KMnO4

B. Oxidative Cleavage of Alkenes Using KMnO4 or Na2Cr2O7

C. Jones Oxidation of Primary Alcohols

D. Oxidation of Aldehydes via Jones' Reagent or Tollen's Reagent

E. Hydrolysis of Nitriles Formed From Alkyl Halides Using Strong Acid or Base

Acid:

Base:

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F. Haloform Reaction of Methyl Ketones (to be covered in more detail later)

G. Carboxylation of Grignard Reagents

Practically in the laboratory, the reaction is carried out by either pouring the Grignard reagent over dry ice or

by bubbling CO2 through the Grignard reagent. The reaction is limited to alkyl halides that can form good

Grignard reagents to begin with.

Mechanism:

Examples:

Reactions of Carboxylic Acids and Carboxylic Acid Derivatives

There are 4 general reactions of carboxylic acids. They are:

1. Reduction

2. Deprotonation

3. Alpha Substitution

4. Nucleophilic Acyl Substitution

1. Reduction reactions of carboxylic acids and derivatives

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A. Using Hydrogen Gas

Note: Carboxylic acids, ester and amides are not reduced using hydrogen gas. However,

nitriles and acid chlorides are reduced using hydrogen gas.

1. Nitrile Reduction

2. Acid Chloride Reduction

B. Hydride Reductions

Note: LiAlH4 and NaBH4 both reactions are worked up in H3O+. NaBH4 is a weaker

reducing agent compared to LAH. NaBH4 cannot reduce esters, carboxylic acids and amides. It can reduce

aldehydes and ketones to alcohols. Hydrides do not reduce carbon-carbon multiple bonds.

1. Carboxylic Acids/Esters

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2. Amides to Amines

3. Using Bulky Aluminum Hydrides Produces Aldehydes

2. Deprotonation

3. Alpha Substitution: The Hell-Volhard-Zelinskii Reaction

This reaction is also known as an -halogenation of carboxylic acids. The halogenating reagent can

be a phosphorus trihalide, such as PCl3 or PBr3 and the halogen or it can be the N-halosuccinimide, like NBS

or NCS, with the corresponding hydrohalic acid.

General Scheme:

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Examples

4. Nucleophilic Acyl Substitution

Reactivity Considerations in a General Nucleophilic Acyl Substitution:

1. Tetrahedral Intermediate

2. Weaker Base is Eliminated

3. Three Possible Scenarios

a. Incoming nucleophile is weaker than leaving group: No Reaction

b. Incoming nucleophile is stronger than leaving group: Reaction

c. Incoming nucleophile and leaving group are similar: Equilibrium

Introduction:

Relative Reactivities of Acyl Derivatives:

Nucleophilic acyl substitution reactions take place in two steps: addition of a nucleophile to the acyl

carbon and elimination of the leaving group. The step that is generally the rate-limiting step is the attack of

the nucleophile on the acyl carbon. Thus, any factor that makes the acyl carbon easily attacked by the

nucleophile will enhance the reactivity.

Steric and electronic factors play the major roles in determining the reactivity rates. Sterically the acyl

carbon must be easily accessible to the incoming attack of the nucleophile. For this reason the less

substituted the alpha carbon is the faster the reaction. In light of this then, a CH3 group is more reactive than

a CR3 group. Electronically, strongly polarized derivatives are more reactive than less polar derivatives.

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Thus, acid chlorides are the most reactive because of the electronegativity of the chlorine atom polarizing the

acyl group more strongly. Amides and esters are not as reactive because they polarize the acyl group much

less. The order of reactivity is: acid chloride> acid anhydride> ester> amide. The way the various groups

enhance the polarization of the acyl group is very similar to the way they effect the reactivity of the benzene

ring toward aromatic substitution.

General Mechanism of Acyl Nucleophilic Substitution:

If the nucleophile is neutral, like water, then an additional step is added. It is a proton transfer step.

Conversions of Carboxylic Acids into Various Derivatives:

Conversion Into Acid Chlorides:

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This conversion can be achieved by reacting the carboxylic acid with thionyl chloride (SOCl2),

phosphorus trichloride (PCl3) or oxalyl chloride (ClCOCOCl). Thionyl chloride is both inexpensive and

convenient to use but is very acidic and therefore can only be used on acid stable compounds. Oxalyl

chloride is very expensive but gives much higher yields and reacts under milder conditions. The

mechanisms of these reactions involve initially the conversion of the carboxylic acid into an activated

derivative. This activated derivative is then attacked by the nucleophilic chloride ion thus yielding the acyl

chloride. The mechanisms involving thionyl chloride and oxalyl chloride are shown below.

Conversion Into Acid Anhydrides:

Acid anhydrides are formed from two molecules of carboxylic acids with the removal of one

molecule of water. Acyclic anhydrides other than acetic anhydride are difficult to prepare, but cyclic

anhydrides that form rings of 5 and 6-members are readily obtained from the high temperature dehydration

reaction. The mechanism for the formation of a cyclic anhydride is shown below.

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Conversion Into Amides:

Carboxylic acids are not converted into amides by directly reacting them with amines. This is

because since amines are bases the overwhelming reaction is the acid base reaction. The amino-carboxylate

salt produced is a very poor electrophile and is essentially unreactive with nucleophiles.

Conversion Into Esters:

There are many methods used to prepare one of the most important conversion reactions. One

method is the SN2 reaction between the carboxylate ion and an alkyl halide, such as an alkyl iodide.

The most common and productive method is the Fischer esterification reaction. This is the reaction between

a carboxylic acid and an alcohol in the presence of mineral acid catalyst. The reaction is governed by the

equilibrium between reactants, carboxylic acid and alcohol and products, ester and water. The yields are

good but must be pushed by using an excess of alcohol. Because of this, the reaction is normally limited to

the formation of methyl, ethyl, and propyl esters. The mechanism of the Fischer esterification reaction is the

reverse reaction of one we have seen before, the Acid Catalyzed Ester Hydrolysis. The mechanistic pathway

was established from isotopic labeling experiments using 18O alcohol. This showed that the carboxylic

oxygen came from the alcohol and not water, because the 18O label was incorporated into the ester and not

the water.

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A final method that is considered for forming methyl esters is the diazomethane reaction of carboxylic acids.

The reaction and its mechanism are shown below.

Reactions of Acid Halides:

One of the most reactive acid derivative and most of the reactions are conversions.

1. Hydrolysis to Carboxylic Acids

2. Reactions with Aromatic Rings via Friedel-Crafts Acylation

3. Alcoholysis to Esters

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4. Aminolysis to Amides

5. Reduction to Alcohols and Aldehydes

6. Hydrogenation via Rosenmund Reduction

7. Reactions with Grignard Reagents and Organocopper Reagents

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Reactions of Acid Anhydrides:

The chemistry of acid anhydrides is very similar to that of acid halides. The difference being that

acid anhydrides react more slowly.

1. Hydrolysis to Carboxylic Acids

2. Reaction with Aromatics via Friedel-Crafts Acylation

3. Alcoholysis to Form Esters

4. Aminolysis to Form Amides

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Reactions of Esters:

Esters show the same kinds of reactions that were seen for the other derivatives except that they are

less reactive toward nucleophilic attack. All of the following reactions are applicable to acyclic and cyclic

(lactones) esters.

1. Hydrolysis to Carboxylic Acids and Alcohols

Base Catalyzed (Saponification):

Acid Catalyzed (Reverse Fischer Esterification):

2. Aminolysis to Amides


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4. Reaction with Grignard Reagents

5. Decarboxylation, the Hunsdieker Reaction

The reaction involves the loss of carbon dioxide and the formation of an alkyl halide with one less carbon

than the starting acid.

Reactions of Amides:

Amides are much less reactive than acid chlorides, anhydrides and esters. This is a good thing since

protein primary structure is made of these amide linkages and it is beneficial to have them somewhat inert.

1. Hydrolysis to Carboxylic Acids and Ammonia or Amines

Acid Catalyzed:

Base Catalyzed:

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2. Reduction to Amines

Reactions of Nitriles:

The reactions of nitriles are very similar to the chemistry of carbonyl compounds. This is because the

nitrile group is strongly polarized like the carbonyl group. When nitrile carbons are attacked by nucleophiles

they form an sp2 imine anion intermediate analogous to the sp3 alkoxide ion intermediate from carbonyls.

1. Hydrolysis to Carboxylic Acids and Amines via Amides

Base Catalyzed:

Acid Catalyzed:

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2. Reduction to Amines

3. Reaction with Grignard Reagents

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CHAPTER 22

CARBONYL SUBSTITUTION REACTIONS

Suggested problems at the end of the chapter: 20,21,22,23,24,25,28,29,30,35,44

22.1 Keto-Enol Tautomerism:

Carbonyl compounds that have hydrogen atoms on the carbon adjacent to the carbonyl (the alpha

position) are in rapid equilibrium with their enol form. This rapid interconversion produces two chemically

distinct species, known as tautomers.

Most carbonyl compounds exist almost exclusively in the keto form at equilibrium. Keto-enol

tautomerism is catalyzed by both acids and bases. The acid catalyzed formation produces the enol.

Whereas the base catalyzed produces the enolate ion. This enolate ion can be readily protonated by water

to form the enol or it can react with other reagents, as we shall see later.

Acid Catalyzed Enol Formation:

Base Catalyzed Enolate-Enol Formation:

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Acidity of Alpha-Hydrogen Atoms: Enolate Formation

The topic of this chapter is reactions involving the alpha hydrogen of carbonyl compounds. Let's

look at how these are formed and their relative reactivity. The acidity of the -hydrogen is due to the

alignment of the C-H orbital with the carbonyl p orbitals. The negative charge formed can overlap with the

bond and delocalize (stabilize). If 2 carbonyl groups are present, then the acidity is greatly enhanced.

The -hydrogen are only weakly acidic and therefore require strong bases to cause the abstraction.

The strong bases required are usually either metal hydrides or metal amides. Examples of these types of

bases include NaH, NaNH2 and LDA (lithium diisopropylamide). Refer to Table 18.1 to compare some

acidity values of organic compounds.

Enolates

Enolates are more reactive than enols because of the full negative charge. The two resonance forms are

shown below.

Reactions can take place either at the oxygen site or the -carbon site. Most of the time the reactions happen

at the carbon site. This is because oxygen is quickly protonated. This makes the position of the enol or

enolate the nucleophile.

22.2 Reactivity of Enols: The Mechanism of -Substitution Reactions

The general mechanism for this reaction type is given below:

22.3 Alpha Halogenation of Aldehydes and Ketones:

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The reaction usually takes place with an acid catalyst and is limited to aldehydes and ketones. Bromine is

most often used, but the reaction will take place with iodine and chlorine also. There is a great deal of

evidence supporting the following mechanism.

Mechanistic Evidence

1. The rate of halogenation is independent of the halogen. This indicates that the same rate-

determining step is involved for all halogenation reactions.

2. Acid-catalyzed ketone halogenations exhibit second-order kinetics in which the rate depends on

the concentrations of H+ and ketone. Since the rate is independent of the concentration of halogen, the

halogen therefore must not be involved in the rate-determining step.

3. Placing the ketone in D3O+ instead of H3O+ places a deuterium on the -carbon. The rate of

deuteration is identical to the rate of halogenation for a given ketone. This suggests that the same

intermediate exists in both mechanisms. This common intermediate is the enol.

-Bromoketones are useful in organic synthesis because they can be dehydrobrominated using base to form

-unsaturated ketones.

Halogenation of Enolate Ions: Haloform Reaction

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If excess halogen and base are used, then the halogenated ketone (of which the -hydrogens are more acidic)

can further halogenate. If the ketone is a methyl ketone, then the triply halogenated enolate forms which is

cleaved by base to form haloform. In the laboratory, this is known as the Iodoform Test for methyl ketones.

An example is below:

Formation of -Unsaturated Carbonyls

A. Halogenation Followed by Elimination

This is limited by the competing substitution reaction and aldol condensation (in base).

B. Phenylselenenylation Followed by Oxidation

In order to accomplish the selenenylation the carbonyl compound must react with a strong base to form the

enolate. The enolate solution is then treated with one equivalent of benzeneselenenyl bromide. The

selenenylated carbonyl is then reduced using peroxide.

General Scheme:

Examples

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This reaction works well for ketones, esters and nitriles. Aldehydes give a poor yield due to aldol

condensations.

LDA is a strong base used to create enolates. Another strong base often used is nBuLi or other alkyl

lithiums.

22.4 Alpha Bromination of Carboxylic Acids: Hell-Volhard-Zelinskii Reaction

This reaction is also known as an -halogenation of carboxylic acids. The halogenating reagent can be a

phosphorus trihalide, such as PCl3 or PBr3 and the halogen or it can be the N-halosuccinimide, like NBS or

NCS, with the corresponding hydrohalic acid.

General Scheme:

Examples

22.7 Alkylation at the Carbon Site of Enolates

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The alkylation reaction is under the normal constraints of any SN2 reaction. The leaving group can be

Cl, Br, I, or tosylate and the alkyl group must be 1° or CH3 but preferably, allylic or benzylic. Vinylic and

aryl halides are unreactive because of steric hindrance. The order of reactivity is as follows:

-Y: Tosylate > I > Br > Cl

R-Y R: Allylic = benzylic > CH3 > 1°

General Mechanistic Scheme:

Ketones, esters and nitriles can be alkylated this way. Aldehydes give poor yields. Alkylation of

unsymmetrical ketones gives 2 products. The product formed is based on the energetics of the reaction. We

describe these reactions as either being under kinetic control or thermodynamic control.

Kinetic Control

The conditions that are used to produce kinetic control are strong base and low temperatures. These

are considered to be mild conditions and the result is that the enolate ion formation is irreversible.

Kinetically controlled reactions will form enolate ions at the least hindered site, alpha to the carbonyl.

Thermodynamic Control

The conditions used to produce thermodynamic control are weak base and higher temperatures.

These are considered to be harsh conditions and the result is that the enolate ion formation is reversible.

Thermodynamically controlled reactions will form the enolate ion that is the most thermodynamically stable.

Some examples are shown below.

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There are two alternative approaches to forming the kinetic product without having to use the strong

base and low temperatures. They are (1) forming a hydrazone intermediate and (2) forming an enamine.

Both of these form activated derivatives which produce the least hindered enolate ion.

1. Using a hydrazone intermediate:

2. Using an enamine derivative:

Enamines can react with alkyl halides and acid chlorides and unsaturated carbonyls.

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Specific Types of Alkylations

A. Malonic Ester Synthesis

This reaction prepares substituted acetic acids from alkyl halides. There are 4 steps involved:

1. Enolate of malonic ester

2. Nucleophilic attack onto alkyl halide

3. Hydrolysis of esters

4. Decarboxylation

Malonic Ester Decomposition

Overall Reaction

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Mechanism (Decarboxylation requires a -Keto acid)

Examples

Intramolecular

B. Acetoacetic Ester Synthesis

This is the preparation of -substituted acetone derivatives from alkyl halides. There are 3 steps involved:

115


1. Enolate formation'

2. Alkylation

3. Hydrolysis-Decarboxylation

Overall Reaction

This reaction follows the same mechanistic pathway as the malonic ester synthesis except one of the ethyl

esters is replaced with a methyl ketone.

Examples

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CHAPTER 23

CARBONYL CONDENSATION REACTIONS

Suggested problems at the end of the chapter: 25,27,33,35,39,42,45,53,56

General Mechanism of Carbonyl Condensations

There are three types of carbonyl additions/condensations we will discuss. They are the aldol

addition, the Claisen condensation and the Dieckmann condensation. The requirements of these reactions

and their variations are that at least one of the carbonyl compounds must have an acidic -hydrogen and a

strong base is employed.

General Mechanism:

Carbonyl condensation reactions take place between two carbonyl components and involve a combination of

nucleophilic and alpha substitution steps. All types of carbonyl compounds (aldehydes, ketones, esters,

amides, anhydrides, thiol esters, and nitriles) can undergo these condensation reactions.

23.1 Aldol Addition/Condensation (For All Aldehydes and Ketones with -Hydrogens):

General Scheme:

Mechanism:

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Examples

23.3 Dehydration of Aldol Products (-Hydroxyaldehydes and Ketones):

The -hydroxy aldehydes and -hydroxy ketones formed can be dehydrated to yield conjugated

enones (unsaturated aldehydes and ketones). The condensation of the water out of the reaction is what

gives the aldol condensation reaction its name. The general reaction is shown below.

-Hydroxy groups to carbonyls are more reactive than normal alcohols. Therefore, milder conditions are

needed for dehydration. Often the dehydration reaction only requires a lightly elevated temperature over the

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original aldol conditions. Because of this, the -hydroxy intermediate is not isolated. Conjugated enones are

more stable than nonconjugated ones for the same reasons that conjugated dienes are more stable than isolate

dienes. Interaction between the pi electrons of the carbon-carbon double bond and the pi electrons of the

carbonyl group leads to a molecular orbital description of conjugated enones that shows a partial

delocalization of the pi electrons over all four atomic centers.

The real driving force of the aldol condensation reaction is the dehydration step. The initial condensation to

form the -hydroxy intermediate is an equilibrium, step that is in favor of the single compounds. However,

when the condensation takes place the conjugated enone is more favored over the -hydroxy intermediate.

23.5 Mixed Aldol Reactions:

Normally mixed aldol reactions between similar carbonyl compounds leads to four possible products.

Two of the products are from the symmetrical condensation and the other two from the mixed condensation.

Mixed aldol reactions can lead to a single product if one of two conditions is met.

1. If one of the carbonyl components does not contain any -hydrogens and therefore cannot form

an enolate ion. This carbonyl compound will act as the electrophilic site for attack by the other enolate ion.

Carbonyl compounds that fit this requirement and that are usually used in mixed aldol reactions are

benzaldehyde and formaldehyde. Of course any carbonyl compound without -hydrogens will work, for

example trichloroacetophenone.

2. If one of the carbonyl compounds is exceptionally acidic as in the case with ethyl acetoacetate.

Then it will be easily transformed into the enolate and will serve as the nucleophile. The other carbonyl

compound will only form its corresponding enolate in small amounts with the equilibrium favoring the

carbonyl form. An example is illustrated below.

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23.6 Intramolecular Aldol Condensations:

These reactions lead to cyclic enones. The most common ring sizes formed are 5 and 6-membered

rings. This is due to the increased stability of these two ring sizes. The mechanism of the intramolecular

aldol is similar to the mechanism for the intermolecular. The only difference is that the intramolecular

reaction requires that the reactant contain the nucleophilic carbonyl anion donor and the electrophilic

carbonyl acceptor. 1,4-Diketones react intramolecularly to form cyclopentenones and 1,5-diketones yield

cyclohexenone products.

23.7 Claisen Condensation Reactions:

The reaction involves the condensation of an ester with an -hydrogen with the carbonyl of a second

ester to yield the -keto ester. The activated ester is often ethyl acetate. The mechanism is very similar to

the aldol reaction. This reaction like aldol is reversible.

General Scheme:

Example

23.8 Mixed Claisen Reactions:

This is very similar to mixed aldol reactions. In this case, two different esters are used. The reaction

is only successful when one of the two esters does not have -hydrogens. In addition, the condensation can

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take place between the ester and an aldehyde without any -hydrogens. Usually the -hydroxy ester formed

undergoes elimination to form the -unsaturated ester.

Examples

23.9 Dieckmann Cyclization (Intramolecular Claisen):

These intramolecular Claisen reactions involving diesters are analogous to the intramolecular aldol

reactions noted before. The cyclization works best with 1,6-diesters and 1,7-diesters. The 1,6-diesters

produce the 5-membered -keto cyclic ester and the 1,7-diesters produce the 6-membered -keto cyclic

ester. The mechanism is similar to the Claisen mechanism. The Dieckmann cyclic ester products can be

further alkylated and decarboxylated by reactions analogous to the acetoacetic ester reactions.

General Scheme:

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Examples

23.10-12 Special reactions of Carbonyls and Unsaturated Carbonyls:

Michael Addition:

The Michael addition reactions are conjugate addition reactions in which a nucleophile adds to the

carbon-carbon double bond of an -unsaturated ketone. The only requirement of the Michael acceptors is

that they must have a conjugated double bond with an electron-withdrawing group attached. These electron-

withdrawing groups could be aldehydes, esters, nitriles, ketones, nitro groups and amide groups. In the same

sense, the Michael donor must have an acidic hydrogen which means it must have an electron-withdrawing

group attached to it. These could be compounds such as -diketones, -keto esters, malonic esters, -keto

nitriles, and nitro compounds.

General Reaction:

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Examples

Stork Enamine Addition to Unsaturated Carbonyl Groups

This is an adaptation to the Michael Addition reaction. The enamine can also react with acid

chlorides. Some examples are shown below.

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Robinson Annulation

The Robinson annulation reaction is used to prepare polycyclic compounds. The reaction takes place in two

steps:

1. Michael addition reaction between a Michael-type donor such as a -keto ester or a -diketone

and an -unsaturated ketone, a Michael acceptor

2. The ring closure takes place via an intramolecular aldol condensation followed by the elimination

reaction to form the substituted cyclic -unsaturated ketone.

The Michael donor, the enolate, can be prepared from both acid and base.

General Scheme:

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mcmurry 7e ch19-23 notes 5-29-07

Documents

resonance stabilized structures

longest carbon chain

conjugated double bond

aqueous acid yields

fischer esterification reaction

carbon double bond

malonic ester synthesis

mixed aldol reactions