1. Background and Properties

The important classes of organic compounds known as alcohols, phenols, ethers, amines and halides consist of alkyl and/or aryl groups bonded to hydroxyl, alkoxyl, amino and halo substituents respectively. If these same functional groups are attached to an acyl group (RCO–) their properties are substantially changed, and they are designated as carboxylic acid derivatives. Carboxylic acids have a hydroxyl group bonded to an acyl group, and their functional derivatives are prepared by replacement of the hydroxyl group with substituents, such as halo, alkoxyl, amino and acyloxy. Some examples of these functional derivatives were displayed earlier.
The following table lists some representative derivatives and their boiling points. An aldehyde and ketone of equivalent molecular weight are also listed for comparison. Boiling points are given for 760 torr (atmospheric pressure), and those listed as a range are estimated from values obtained at lower pressures. As noted earlier, the relatively high boiling point of carboxylic acids is due to extensive hydrogen bonded dimerization. Similar hydrogen bonding occurs between molecules of 1º and 2º-amides (amides having at least one N–H bond), and the first three compounds in the table serve as hydrogen bonding examples.

The last nine entries in the above table cannot function as hydrogen bond donors, so hydrogen bonded dimers and aggregates are not possible. The relatively high boiling points of equivalent 3º-amides and nitriles are probably due to the high polarity of these functions. Indeed, if hydrogen bonding is not present, the boiling points of comparable sized compounds correlate reasonably well with their dipole moments.

hree examples of acyl groups having specific names were noted earlier. These are often used in common names of compounds. In the following examples the IUPAC names are color coded, and common names are given in parentheses.

• Esters: The alkyl group is named first, followed by a derived name for the acyl group, the oic or ic suffix in the acid name is replaced by ate.
    e.g. CH₃(CH₂)₂CO₂C₂H₅ is ethyl butanoate (or ethyl butyrate).
    Cyclic esters are called lactones. A Greek letter identifies the location of the alkyl oxygen relative to the carboxyl carbonyl group.
• Acid Halides: The acyl group is named first, followed by the halogen name as a separate word.
    e.g. CH₃CH₂COCl is propanoyl chloride (or propionyl chloride).
• Anhydrides: The name of the related acid(s) is used first, followed by the separate word "anhydride".
    e.g. (CH₃(CH₂)₂CO)₂O is butanoic anhydride   &   CH₃COOCOCH₂CH₃ is ethanoic propanoic anhydride (or acetic propionic anhydride).
• Amides: The name of the related acid is used first and the oic acid or ic acid suffix is replaced by amide (only for 1º-amides).
    e.g. CH₃CONH₂ is ethanamide (or acetamide).
    2º & 3º-amides have alkyl substituents on the nitrogen atom. These are designated by "N-alkyl" term(s) at the beginning of the name.
    e.g. CH₃(CH₂)₂CONHC₂H₅ is N-ethylbutanamide;   &   HCON(CH₃)₂ is N,N-dimethylmethanamide (or N,N-dimethylformamide).
    Cyclic amides are called lactams. A Greek letter identifies the location of the nitrogen on the alkyl chain relative to the carboxyl carbonyl group.
• Nitriles: Simple acyclic nitriles are named by adding nitrile as a suffix to the name of the corresponding alkane (same number of carbon atoms).
    Chain numbering begins with the nitrile carbon . Commonly, the oic acid or ic acid ending of the corresponding carboxylic acid is replaced by onitrile.
    A nitrile substituent, e.g. on a ring, is named carbonitrile.
    e.g. (CH₃)₂CHCH₂C≡N is 3-methylbutanenitrile (or isovaleronitrile).

Reactions of Carboxylic Acid Derivatives

1. Acyl Group Substitution

This is probably the single most important reaction of carboxylic acid derivatives. The overall transformation is defined by the following equation, and may be classified either as nucleophilic substitution at an acyl group or as acylation of a nucleophile. For certain nucleophilic reagents the reaction may assume other names as well. If Nuc-H is water the reaction is often called hydrolysis, if Nuc–H is an alcohol the reaction is called alcoholysis, and for ammonia and amines it is called aminolysis.

Different carboxylic acid derivatives have very different reactivities, acyl chlorides and bromides being the most reactive and amides the least reactive, as noted in the following qualitatively ordered list. The change in reactivity is dramatic. In homogeneous solvent systems, reaction of acyl chlorides with water occurs rapidly, and does not require heating or catalysts. Amides, on the other hand, react with water only in the presence of strong acid or base catalysts and external heating.

Reactivity:   acyl halides > anhydrides >> esters ≈ acids >> amides

Because of these differences, the conversion of one type of acid derivative into another is generally restricted to those outlined in the following diagram. Methods for converting carboxylic acids into these derivatives were shown in a previous section, but the amide and anhydride preparations were not general and required strong heating. A better and more general anhydride synthesis can be achieved from acyl chlorides, and amides are easily made from any of the more reactive derivatives. Specific examples of these conversions will be displayed by clicking on the product formula. The carboxylic acids themselves are not an essential part of this diagram, although all the derivatives shown can be hydrolyzed to the carboxylic acid state (light blue formulas and reaction arrows). Base catalyzed hydrolysis produces carboxylate salts.

Before proceeding further, it is important to review the general mechanism by means of which all these acyl transfer or acylation reactions take place. Indeed, an alert reader may well be puzzled by the facility of these nucleophilic substitution reactions. After all, it was previously noted that halogens bonded to sp² or sp hybridized carbon atoms do not usually undergo substitution reactions with nucleophilic reagents. Furthermore, such substitution reactions of alcohols and ethers are rare, except in the presence of strong mineral acids. Clearly, the mechanism by which acylation reactions occur must be different from the S_N1 and S_N2 procedures described earlier.
In any substitution reaction two things must happen. The bond from the substrate to the leaving group must be broken, and a bond to the replacement group must be formed. The timing of these events may vary with the reacting system. In nucleophilic substitution reactions of alkyl compounds examples of bond-breaking preceding bond-making (the S_N1 mechanism), and of bond-breaking and bond-making occuring simultaneously (the S_N2 mechanism) were observed. On the other hand, for most cases of electrophilic aromatic substitution bond-making preceded bond-breaking.

Acid and base-catalyzed variations of this mechanism will be displayed in turn as the "Mechanism Toggle" button is clicked. Also, a specific example of acyl chloride formation from the reaction of a carboxylic acid with thionyl chloride will be shown. The number of individual steps in these mechanisms vary, but the essential characteristic of the overall transformation is that of addition followed by elimination. Acid catalysts act to increase the electrophilicity of the acyl reactant; whereas, base catalysts act on the nucleophilic reactant to increase its reactivity. In principle all steps are reversible, but in practice many reactions of this kind are irreversible unless changes in the reactants and conditions are made. The acid-catalyzed formation of esters from carboxylic acids and alcohols, described earlier, is a good example of a reversible acylation reaction, the products being determined by the addition or removal of water from the system. The reaction of an acyl chloride with an alcohol also gives an ester, but this conversion cannot be reversed by adding HCl to the reaction mixture.

Thus far we have not explained the marked variation, noted above, in the reactivity of different carboxylic acid derivatives. The distinguishing carbonyl substituents in these compounds are: chloro (acyl chlorides), acyloxy (anhydrides), alkoxy (esters) and amino (amides). All of these substituents have bonds originating from atoms of relatively high electronegativity (Cl, O & N). They are therefore inductively electron withdrawing when bonded to carbon, as shown in the diagram on the right. The consequences of such inductive electron withdrawal on the acidity of carboxylic acids was previously noted.

When these substituents are attached to an sp² carbon that is part of a π-electron system, a similar inductive effect occurs, but p-π conjugation moves electron density in the opposite direction. By clicking the "Toggle Effect" button the electron shift in both effects will be displayed sequentially. This competition between inductive electron withdrawal and conjugative electron donation was discussed earlier in the context of substituent effects on electrophilic aromatic substitution. Here, it was noted that amino groups were strongly electron donating (resonance effect >> inductive effect), alkoxy groups were slightly less activating, acyloxy groups still less activating (resonance effect > inductive effect) and chlorine was deactivating (inductive effect > resonance effect). In the illustration on the right, R and Z represent the remainder of a benzene ring.
This analysis also predicts the influence these substituent groups have on the reactivity of carboxylic acid derivatives toward nucleophiles (Z = O in the illustration). Inductive electron withdrawal by Y increases the electrophilic character of the carbonyl carbon, and increases its reactivity toward nucleophiles. Thus, acyl chlorides (Y = Cl) are the most reactive of the derivatives. Resonance electron donation by Y decreases the electrophilic character of the carbonyl carbon. The strongest resonance effect occurs in amides, which exhibit substantial carbon-nitrogen double bond character and are the least reactive of the derivatives. An interesting exception to the low reactivity of amides is found in beta-lactams such as penicillin G. The angle strain introduced by the four-membered ring reduces the importance of resonance, the non-bonding electron pair remaining localized on the pyramidally shaped nitrogen. Finally, anhydrides and esters have intermediate reactivities, with anhydrides being more reactive than esters.

Reactions #4 & 5 display the acylating capability of anhydrides. Bear in mind that anhydrides may also be used as reagents in Friedel-Crafts acylation reactions. Esters are less reactive acylating reagents than anhydrides, and the ester exchange reaction (#6) requires a strong acid or base catalyst. The last example demonstrates that nitrogen is generally more nucleophilic than oxygen. Indeed, it is often possible to carry out reactions of amines with acyl chlorides and anhydrides in aqueous sodium hydroxide solution! Not only is the amine more nucleophilic than water, but the acylating reagent is generally not soluble in or miscible with water, reducing the rate of its hydrolysis.
No acylation reactions of amides were shown in these problems. The most important such reaction is hydrolysis, and this normally requires heat and strong acid or base catalysts. One example, illustrating both types of catalysis, is shown here. Mechanisms for catalyzed reactions of this kind were presented earlier.

Nitriles

Although they do not have a carbonyl group, nitriles are often treated as derivatives of carboxylic acids. Hydrolysis of nitriles to carboxylic acids was described earlier, and requires reaction conditions (catalysts and heat) similar to those needed to hydrolyze amides. This is not surprising, since addition of water to the carbon-nitrogen triple bond gives an imino intermediate which tautomerizes to an amide.

2. Reduction

Catalytic Hydrogenation

As a rule, the carbonyl group does not add hydrogen as readily as do the carbon-carbon double and triple bonds. Thus, it is fairly easy to reduce an alkene or alkyne function without affecting any carbonyl functions in the same molecule. By using a platinum catalyst and increased temperature and pressure, it is possible to reduce aldehydes and ketones to alcohols, but carboxylic acids, esters and amides are comparatively unreactive. The exceptional reactivity of acyl halides, on the other hand, facilitates their reduction under mild conditions, by using a poisoned palladium catalyst similar to that used for the partial reduction of alkynes to alkenes. This reduction stops at the aldehyde stage, providing us with a useful two-step procedure for converting carboxylic acids to aldehydes, as reaction #1 below demonstrates. Equivalent reductions of anhydrides have not been reported, but we might speculate that they would be reduced more easily than esters. The only other reduction of a carboxylic acid derivative that is widely used is that of nitriles to 1º-amines. Examples of these reductions are provided in the following diagram.

he second and third equations illustrate the extreme difference in hydrogenation reactivity between esters and nitriles. This is futher demonstrated by the last reaction, in which a nitrile is preferentially reduced in the presence of a carbonyl group and two benzene rings. The resulting 1º-amine immediately reacts with the carbonyl function to give a cyclic enamine product (colored light blue).
In most nitrile reductions ammonia is added to inhibit the formation of a 2º-amine by-product. This may occur by way of an intermediate aldehyde imine created by addition of the first equivalent of hydrogen. The following equations show how such an imine species might react with the 1º-amine product to give a substituted imine (2nd equation), which would then add hydrogen to generate a 2º-amine. Excess ammonia shifts the imine equilibrium to the left, as written below.

(2)

RCH=NH  +  RCH2NH2 imine         1º-amine

RCH=NCH2R  +  NH3 substituted imine

H2 & catalyst

RCH2NHCH2R 2º-amine

Complex Metal Hydride Reductions

The use of lithium aluminum hydride (LiAlH₄) and sodium borohydride (NaBH₄) as reagents for the reduction of aldehydes and ketones to 1º and 2º-alcohols respectively has been noted. Of these, lithium aluminum hydride, often abbreviated LAH, is the most useful for reducing carboxylic acid derivatives. Thanks to its high reactivity, LAH easily reduces all classes of carboxylic acid derivatives, generally to the –1 oxidation state. Acids, esters, anhydrides and acyl chlorides are all reduced to 1º-alcohols, and this method is superior to catalytic reduction in most cases. Since acyl chlorides and anhydrides are expensive and time consuming to prepare, acids and esters are the most commonly used reactants for this transformation.
Amides are reduced to amines by treatment with LAH, and this has proven to be one of the most general methods for preparing all classes of amines (1º, 2º & 3º). Because the outcome of LAH reduction is so different for esters and amides, we must examine plausible reaction mechanisms for these reactions to discover a reason for this divergent behavior. As in the reductions of aldehydes and ketones, the first step in each case is believed to be the irreversible addition of hydride to the electrophilic carbonyl carbon atom. This is shown in the following diagrams, with the hydride-donating moiety being written as AlH₄^(–). All four hydrogens are potentially available to the reduction, but when carboxylic acids are reduced, one of the hydrides reacts with the acidic O–H to generate hydrogen gas. Although the lithium is not shown, it will be present in the products as a cationic component of ionic salts.

One explanation of the different course taken by the reductions of esters and amides lies in the nature of the different hetero atom substituents on the carbonyl group (colored green in the diagram). Nitrogen is more basic than oxygen, and amide anions are poorer leaving groups than alkoxide anions. Furthermore, oxygen forms especially strong bonds to aluminum. Addition of hydride produces a tetrahedral intermediate, shown in brackets, which has a polar oxygen-aluminum bond. Neither the hydrogen nor the alkyl group (R) is a possible leaving group, so if this tetrahedral species is to undergo an elimination to reform a carbonyl group, one of the two remaining substituents must be lost. For the ester this is an easy choice (described by the curved arrows). By eliminating an aluminum alkoxide (R'O–Al), an aldehyde is formed, and this is quickly reduced to the salt of a 1º-alcohol by LAH. In the case of the amide, aldehyde formation requires the loss of an aluminum amide (R'₂N–Al), an unlikely process. Alternatively, the more basic nitrogen may act to eject an aluminum oxide species (Al–O^(–)), and the resulting iminium double bond would be reduced rapidly to an amine. This is the course followed in amide reductions.

Lithium aluminum hydride also reduces nitriles to 1º-amines, as shown in the following equation. An initial hydride addition to the electrophilic nitrile carbon atom generates the salt of an imine intermediate. This is followed by a second hydride transfer, and the resulting metal amine salt is hydrolyzed to a 1º-amine. This method provides a useful alternative to the catalytic reduction of nitriles, described above, when alkene or alkyne functions are present.

The facile addition of alkyl lithium reagents and Grignard reagents to aldehydes and ketones has been described. These reagents, which are prepared from alkyl and aryl halides, are powerful nucleophiles and very strong bases. Reaction of an excess of these reagents with acyl chlorides, anhydrides and esters leads to alcohol products, in the same fashion as the hydride reductions. As illustrated by the following equations (shaded box), this occurs by sequential addition-elimination-addition reactions, and finishes with hydrolysis of the resulting alkoxide salt. A common bonding pattern is found in all these carbonyl reactions. The organometallic reagent is a source of a nucleophilic alkyl or aryl group (colored purple), which bonds to the electrophilic carbon of the carbonyl group (colored orange). Substituent Y (colored green) is eliminated from the tetrahedral intermediate as its anion. The aldehyde or ketone product of this elimination then adds a second equivalent of the reagent.

The acidity of carboxylic acids and 1º & 2º-amides acts to convert Grignard and alkyl lithium reagents to hydrocarbons (see equations), so these functional groups should be avoided when these reagents are used.

Since acyl chlorides are more reactive than esters, isolation of the ketone intermediate formed in their reactions with organometallic reagents becomes an attractive possibility. To achieve this selectivity we need to convert the highly reactive Grignard and lithium reagents to less nucleophilic species. Two such modifications that have proven effective are the Gilman reagent (R₂CuLi) and organocadmium reagents (prepared in the manner shown).

Specific examples of ketone synthesis using these reagents are presented in the following diagram. The second equation demonstrates the low reactivity of organocadmium reagents, inasmuch as the ester function is unchanged. Another related approach to this transformation is illustrated by the third equation. Grignard reagents add to nitriles, forming a relatively stable imino derivative which can be hydrolyzed to a ketone. Imines themselves do not react with Grignard reagents.

4. Other Reactions

Reactivity of Carboxylic Acid Derivatives

Carboxylic acid derivatives react tend to react via nucleophilic acyl substitution where the group on the acyl unit, R-C=O undergoes substitution:

 
The observed reactivity order is shown below:

This reactivity order is important. You should be able to understand, rationalise and use it.

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There are 3 resonance structures to consider for carboxylic acid derivatives.

I  and II are similar to those of aldehydes and ketones, but there is also a third possibility III where a lone pair on the heteroatom Z is able to donate electrons to the adjacent positive center. The stronger this electron donation from Z the less positive the carbonyl C and the less electrophilic the carbonyl group.  The ability of Z to donate electrons is linked to its electronegativity...the more electronegative Z is, the less the stabilising effect.

Use the following series of electrostatic potential  maps to look at the electrophilicity of the carbonyl C in a example of each the more common carboxylic acid derivatives. Note how the blue colour gradually reduces in intensity down the series.

It is also useful to appreciate where aldehydes and ketones fit into the reactivity scale towards nucleophiles:

acyl halides > anhydrides > aldehydes > ketones > esters = carboxylic acids > amides

Overview of Nucleophilic Acyl Substitution

Overall nucleophilic acyl substitution is most simply represented as follows:

What does the term "nucleophilic acyl substitution" imply ?

A nucleophile is an electron rich species that will react with an electron poor species (Nu in scheme).
An acyl group is R-C=O (where R can be alkyl or aryl).... note the acyl group in both the starting material and the product.
A substitution note that the leaving group (LG) is replaced by the nucleophile (Nu).

There are two fundamental events in a nucleophilic acyl substitution reaction:

• formation of the new s bond to the nucleophile, Nu.
• breaking of the s bond to the leaving group, LG.

The difference in nucleophilic acyl substitution is that when the nucleophile adds to the electrophilic C, it becomes tetrahedral and an intermediate forms, then the leaving group departs as shown below:

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Reactions for Interconverting Carboxylic Acids Derivatives

Here is a table that summarises the methods for interconverting carboxylicacid derivatives.  The more important reactions in emphasised in bold,and the reactions of the parent carboxylic acids in blue.

 Reactions of Carboxylic Acid Derivatives

Interconversion Reactions of Acyl Chlorides

Reaction type:  Nucleophilic Acyl Substitution

Summary

• Acyl chlorides are the most reactive of the carboxylic acid derivativesand therefore can be readily converted into all other carboxylic acid derivatives(see above).
• They are sufficiently reactive that they react quite readily with coldwater and hydrolyse to the carboxylic acid.
• The HCl by-product is usually removed by adding a base such as pyridine,C₆H₅N, or triethyl amine, Et₃N.

Interconversion Reactions of Acid Anhydrides

Reaction type:  Nucleophilic Acyl Substitution

Summary

• Acid anhydrides are the second most reactive of the carboxylic acid derivatives and can therefore, be fairly readily converted into the other less reactive carboxylic acid derivatives (see above).
• A base in often added to neutralise the carboxylic acid by product that is formed.

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 Interconversion Reactions of Esters

Reaction type:  Nucleophilic Acyl Substitution

Summary

• Esters can be converted into other esters (transesterification), the parent carboxylic acid (hydrolysis) or amides  (see above).
  • Transesterification : heat with alcohol and acid catalyst
  • Hydrolysis:  heat with aq. acid o base (e.g. aq. H₂SO₄ or aq. NaOH) .
  • Amide preparation :  heat with the amine, methyl  or ethyl esters are the most reactive

 Interconversion Reactions of Amides

Reaction type:  Nucleophilic Acyl Substitution

Summary

• Amides are the least reactive of the neutral carboxylic acid derivatives.
• The only interconversion reaction that amides undergo is hydrolysis back to the parent carboxylic acid and the amine.
• Reagents : Strong acid (e.g. H₂SO₄) or strong base (e.g. NaOH) / heat.
• More details on the following page.

 Reactions of Nitriles

Reaction type:  Nucleophilic Addition

Overview

• Nitriles typically undergo nucleophilic addition to give products that often undergo a further reaction.
• The chemistry of the nitrile functional group, C≡N, is very similar to that of the carbonyl, C=O of aldehydes and ketones. Compare the two schemes:

        versus 

• However, it is convenient to describe nitriles as carboxylic acid derivatives because:
  • the oxidation state of the C is the same as that of the carboxylic acid derivatives.
  • hydrolysis produces the carboxylic acid
• Like the carbonyl containing compounds, nitriles react with nucleophiles via two scenarios:

• Strong nucleophiles (anionic) add directly to the C≡N to form an intermediate imine salt that protonates (and often reacts further) on work-up with dilute acid.

            Examples of such nucleophilic systems are :  RMgX, RLi, RC≡CM, LiAlH₄
 

• Weaker nucleophiles (neutral) require that the C≡N be activated prior to attack of the Nu.
       This can be done using a acid catalyst which protonates on the Lewis basic N and makes the system more electrophilic.

 Examples of such nucleophilic systems are :  H₂O, ROH
 

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Friedel-Crafts Acylation of Benzene

 

Reaction type: Electrophilic Aromatic Substitution

Summary

• Overall transformation :  Ar-H to Ar-COR(a ketone)
• Named after Friedel and Crafts who discovered the reaction.
• Reagent : normally the acyl halide (e.g. usually RCOCl) with aluminum trichloride, AlCl₃, a Lewis acid catalyst
• The AlCl₃ enhances the electrophilicity of the acyl halide by complexing with the halide
• Electrophilic species : the acyl cation or acylium ion (i.e. RCO ⁺ ) formed by the "removal" of the halide by the Lewis acid catalyst
• The acylium ion is stabilised by resonance as shown below. This extra stability prevents the problems associated with the rearrangement of simple carbocations:

• The reduction of acylation products can be used to give the equivalent of alkylation but avoids the problems of rearrangement  (more details)
• Friedel-Crafts reactions are limited to arenes as or more reactive than mono-halobenzenes
• Other sources of acylium can also be used such as acid anhydrides with AlCl₃

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Hydrolysis of Esters

Reaction type:  Nucleophilic Acyl Substitution

Summary

• Carboxylic esters hydrolyse to the parent carboxylic acid and an alcohol.
• Reagents : aqueous acid (e.g. H₂SO₄) / heat,or aqueous NaOH / heat (known as "saponification").
• These mechanisms are among some of the most studied in organic chemistry.
• Both are based on the formation of a tetrahedral intermediate which then dissociates.
• In both cases it is the C-O bond between the acyl group and the oxygen that is cleaved.

Reaction under BASIC conditions:

• The mechanism shown below leads to acyl-oxygen cleavage (see step2).
• The mechanism is supported by experiments using ¹⁸O labeled compounds and esters of chiral alcohols.
• This reaction is known as "saponification" because it is the basis of making soap from glycerol triesters in fats.
• The mechanism is an example of the reactive system type.

Reaction under ACIDIC conditions:

• Note that the acid catalysed mechanism is the reverse of the Fischer esterification.
• The mechanism shown below also leads to acyl-oxygen cleavage (see step 5).
• The mechanism is an example of the less reactive system type.

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Preparation of Esters

Reaction type:  Nucleophilic Acyl Substiution

Summary

• This reaction is also known as the Fischer esterification.
• Esters are obtained by refluxing the parent carboxylic acid with the appropraite alcohol with an acid catalyst.
• The equilibrium can be driven to completion by using an excess of either the alcohol or the carboxylic acid, or by removing the water as it forms.
• Alcohol reactivity order :  CH₃OH > 1^o > 2^o > 3^o (steric effects)
• Esters can also be made from other carboxylic acid derivatives, especially acyl halides and anhydrides, by reacting them with the appropriate alcohol in the presence of a weak base .
• If a compound contains both hydroxy- and carboxylic acid groups, then cyclic esters or lactones can form via an intramolecular reaction. Reactions that form 5- or 6-membered rings are particularly favourable.

Reduction of Esters
 

Reactions usually in Et₂O or THF followed by H₃O⁺work-ups

Reaction type:  Nucleophilic Acyl Substitution then NucleophilicAddition

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Summary

• Carboxylic esters are reduced give 2 alcohols, one from the alcohol portion of the ester and a 1^o alcohol from the reduction of the carboxylate portion.
• Esters are less reactive towards Nu than aldehydes or ketones.
• They can only be reduced by LiAlH₄ but NOT by the less reactive NaBH₄
• The reaction requires that 2 hydrides (H^-) be added to the carbonyl group of the ester
• The mechanism is an example of the reactive system type.
• The reaction proceeds via a aldehyde intermediate which then reacts with the second equivalent of the hydride reagent (review)
• Since the aldehyde is more reactive than the ester, the reaction is not normally used as a preparation of aldehydes .

 Reactions of RLi and RMgX with Esters
 

Reaction usually in Et₂O followed by H₃O⁺ work-up

Reaction type:  Nucleophilic Acyl Substitution then NucleophilicAddition

Summary

·         Carboxylic esters, R'CO₂R'', react with 2 equivalents of organolithium or Grignard reagents to give tertiary alcohols.

·         The tertiary alcohol that results contains 2 identical alkyl groups (from R in the scheme)

·         The reaction proceeds via a ketone intermediate which then reacts with the second equivalent of the organometallic reagent .

·         Since the ketone is more reactive than the ester, the reaction cannot be used as a preparation of ketones.

·         The mechanism is an example of the reactive system type.

Hydrolysis of Amides

Reaction type:  Nucleophilic Acyl Substitution

Summary

• Amides hydrolyse to the parent carboxylic acid and the appropriate amine.
• The mechanisms are similar to those of esters.
• Reagents : Strong acid (e.g. H₂SO₄) / heat (preferred) or strong base (e.g. NaOH) / heat.

Reaction under ACIDIC conditions:

• Note that the acid catalysed mechanism is analogous to the acid catalysed hydrolysis of esters.
• The mechanism shown below proceeds via protonation of the carbonyl not the amide N (see step 1).
• The mechanism is an example of the less reactive system type.

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Reduction of Amides
 

Reactions usually in Et₂O or THF followed by H₃O⁺ work-ups

Reaction type:  Nucleophilic Acyl Substitution then Nucleophilic Addition

Summary

• Amides, RCONR'₂, can be reduced to the amine, RCH₂NR'₂ by conversion of the C=O to -CH₂-
• Amides can be reduced by LiAlH₄ but NOT the less reactive NaBH₄
• Typical reagents :  LiAlH₄  / ether solvent followedby aqueous work-up.
• Note that this reaction is different to that of other C=Ocompounds which reduce to alcohols
• The nature of the amine obtained depends on the substituents present onthe original amide.
  ook at the N substituents in the following examples (those bonds don'tchange !)

• R, R' or R" may be either alkyl or aryl substituents.
• In the potential mechanism note that it is an O system that leaves.This is consistent with O systems being better leaving groups thatthe less electronegative N systems.

Hydrolysis of Nitriles

Reaction type:  Nucleophilic Addition then NucleophilicAcyl Substitution

Summary

• Nitriles, RC≡N, can be hydrolysedto carboxylic acids, RCO₂H via the amide, RCONH₂.
• Reagents : Strong acid (e.g. H₂SO₄) or strongbase (e.g. NaOH) / heat.

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Reduction of Nitriles
 

Reactions usually in Et₂O or THF followed by H₃O⁺work-up

Reaction type: Nucleophilic Addition

Summary

• The nitrile, RC≡N, gives the 1^o amine by conversion of the C≡N to -CH₂-NH₂
• Nitriles can be reduced by LiAlH₄ but NOT the less reactive NaBH₄
• Typical reagents :  LiAlH₄  / ether solvent followed by aqueous work-up.
• Catalytic hydrogenation (H₂ / catalyst) can also be used giving the same products.
• R may be either alkyl or aryl substituents

Reactions of RLi or RMgX with Nitriles

Reaction usually in Et₂O or  THF

Reaction type:  Nucleophilic Acyl Substitution then Nucleophilic Addition

Summary:

• Nitriles, RC≡N, react with Grignard reagents or organolithium reagents to give ketones.
• The strongly nucleophilic organometallic reagents add to the C≡N bond in a similar fashion to that seen for aldehydes and ketones.
• The reaction proceeds via an imine salt intermediate that is then hydrolysed to give the ketone product.

• Since the ketone is not formed until after the addition ofwater, the organometallic reagent does not get the opportunity to react with the ketone product.
• Nitriles are less reactive than aldehydes and ketones.
• The mechanism is an example of the reactive system type.

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Spectroscopic Analysis

Spectroscopic Analysis of Acyl Chlorides

• IR  - presence of high frequency C=O, C-Cl too low to be useful

• ¹H NMR - only the protons adjacent to the C=O are particularly characteristic.

• ¹³C NMR
  C=O typically 160-180 ppm (deshielding due to O)
  • minimal intensity, characteristic of C's with no attached H's

•   UV-VIS
  two absorption maxima p→p^* (<200 nm) n→p^* (~235 nm)
  • p electron from p of C=O
  • n electron from O lone pair
  • p^* antibonding C=O

• Mass Spectrometry
  Prominent peak corresponds to formation of acyl cations (acylium ions)

Spectroscopic Analysis of Anhydrides

• IR  - presence of two, high frequency C=O

• ¹H NMR - only the protons adjacent to the C=O are particularly characteristic.

• ¹³C NMR
  C=O typically 160-180 ppm (deshielding due to O)
  • minimal intensity, characteristic of C's with no attached H's

•   UV-VIS
  two absorption maxima p→p^* (<200 nm) n→p^* (~225nm, diagnostic)
  • p electron from p of C=O
  • n electron from O lone pair
  • p^* antibonding C=O

• Mass Spectrometry
  Prominent peak corresponds to formation of acyl cations (acylium ions)
  

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Spectroscopic Analysis of Esters

• IR  - presence of C=O, and two C-O bands (Csp²-O and Csp³-O bonds)

• ¹H NMR - deshielded proton of H-C-O is often recognisable, and H-C-C=O.

• ¹³C NMR
  C=O typically 160-180 ppm (deshielding due to O)
  • minimal intensity, characteristic of C's with no attached H's

•   UV-VIS
  two absorption maxima p→p^* (<200 nm) n→p^* (~207 nm)
  • p electron from p of C=O
  • n electron from O lone pair
  • p^* antibonding C=O

• Mass Spectrometry
  Prominent peak corresponds to formation of acyl cations (acylium ions)

Spectroscopic Analysis of Amides

• IR  - presence of low frequency C=O, N-H stretches for 1^o or 2^o amides.

• ¹H NMR - N-H protons often broad,

• ¹³C NMR
  C=O typically 160-180 ppm (deshielding due to O)
  • minimal intensity, characteristic of C's with no attached H's

•   UV-VIS
  absorption maxima n→p^* (~215 nm)
  • n electron from O lone pair
  • p^* antibonding C=O

• Mass Spectrometry
  Molecular ion M+ often visible.
  A prominent peak corresponds to formation of acyl cations (acylium ions)

Spectroscopic Analysis of Nitriles

• IR  - very characteristic C≡N stretch (only C≡C is similar region)

• ¹H NMR - only protons adjacent to C≡N are likely to be characterisitic.

• ¹³C NMR
  C≡N typically 115 -125 ppm (deshielding due to N)
  • minimal intensity, characteristic of C's with no attached H's

•   UV-VIS
  Simple nitriles usually show no absorption above 200 nm.
   
   
• Mass Spectrometry

Molecular ion M+ is often weak or absent, but a weak M-1 peak due to loss of an a-H is often present.

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                                                                                                                                                                                  Alcohols

                                                                                                                                                                                   Aldehydes & Ketones

                                                                                                                                               Alkyl Halide Reaction

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© M.EL-Fellah ,Chemistry Department, Garyounis University