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Acid derivatives
Carboxylic
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5/18/2011
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Carboxylic Acid Derivatives
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.
Physical Properties of Some Carboxylic Acid Derivatives
Formula
IUPAC Name
Molecular Weight
Boiling Point
Water Solubility
CH3(CH2)2CO2H
butanoic acid
88
164 ºC
very soluble
CH3(CH2)2CONH2
butanamide
87
216-220 ºC
soluble
CH3CH2CONHCH3
N-methylpropanamide
87
205 -210 ºC
soluble
CH3CON(CH3)2
N,N-dimethylethanamide
87
166 ºC
very soluble
HCON(CH3)CH2CH3
N-ethyl, N-methylmethanamide
87
170-180 ºC
very soluble
CH3(CH2)3CN
pentanenitrile
83
141 ºC
slightly soluble
CH3CO2CHO
ethanoic
anhydride
88
105-112 ºC
reacts with water
CH3CH2CO2CH3
methyl propanoate
88
80 ºC
slightly soluble
CH3CO2C2H5
ethyl ethanoate
88
77 ºC
moderately soluble
CH3CH2COCl
propanoyl chloride
92.5
80 ºC
reacts with water
CH3(CH2)3CHO
pentanal
86
103 ºC
slightly soluble
CH3(CH2)2COCH3
2-pentanone
86
102 ºC
slightly soluble
methanoic
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.
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Nomenclature of Carboxylic Acid Derivatives
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
-2-
-3-
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 1ºamides).
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,Ndimethylformamide).
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).
Acyl Chlorides
Functional group suffix = oyl chloride (review)
Anhydrides
Functional group suffix = alkanoic anhydride (review)
Thioesters
Functional group suffix = alkyl -oate
Functional group prefix = alkoxycarbonyl- or carbalkoxy-
Esters
Functional group suffix = alkyl -oate (review)
Functional group prefix = alkoxycarbonyl- or carbalkoxyCyclic esters are called lactones
Carboxylic Acids
Functional group suffix = -oic acid (review)
Functional group prefix = carboxy-
Amides
Functional group suffix = amide (review)
Functional group prefix = carbamoylCyclic amides are called lactams
Nitriles
Functional group suffix = nitrile or -onitrile (review)
Functional group prefix = cyano-
Acyl Halides or Acid Halides
Nomenclature
Formula
Functional class name = acyl or acid halide
Substituent suffix = -oyl halide
-3-

Acyl or acid halides are derivatives of carboxylic acids.

The root name is based on the longest chain including the carbonyl group of the acyl group.
-4
Since the acyl group is at the end of the chain, the C=O carbon must be C1.

The acyl halide suffix is appended after the hydrocarbon suffix minus the "e" : e.g. -ane + -oyl halide = -anoyl halide etc.

The most common halide encountered is the chloride, hence acyl or acid chlorides, e.g. ethanoyl chlorid

Functional group is an acyl halide therefore suffix = -oyl chloride

Hydrocarbon structure is an alkane therefore -an-

The longest continuous chain is C2 therefore root = eth
CH3C(=O)Cl
ethanoyl chloride

Functional group is an acyl halide therefore suffix = -oyl chloride

Hydrocarbon structure is an alkane therefore -an-

The longest continuous chain is C4 therefore root = but
CH3CH2CH2C(=O)Cl
butanoyl chloride

Functional group is an acyl halide therefore suffix = -oyl chloride

Hydrocarbon structure is an alkane therefore -an-

The longest continuous chain is C3 therefore root = prop

The branch is a C1 alkyl group i.e. a methyl group

The functional groups requires numbering from the right as drawn, the substituent locant is 2-
(CH3)2CHC(=O)Cl
2-methylpropanoyl chloride
Acid Anhydrides
Nomenclature
Formula
Functional class name = alkanoic anhydride
Substituent suffix = -oic anhydride

As the name implies, acid anyhydrides are derivatives of carboxylic acids.

In principle, they can be symmetric (where the two R groups are identical) or asymmetric (where the two R groups are different).

Symmetric anhydrides are the most common, they are named as alkanoic anhydrides

Asymmetric anhydrides are name in a similar fashion listing the alkyl groups in alphabetical order.

Cyclic anhydrides derived from dicarboxylic acids are name as -dioic anhydrides.

Functional group is an acid anhydride therefore suffix = -oic anhydride

Hydrocarbon structure is an alkane therefore -an-

The longest continuous chain is C2 therefore root = eth
ethanoic anhydride

Functional group is an acid anhydride therefore suffix = -oic anhydride

Hydrocarbon structure is an alkane therefore -an-

The longest continuous chain is C4 therefore root = but

The other group is C3 = prop
butanoic propanoic anhydride
-4-
CH3C(=O)OC(=O)CH3
-5-

Functional group is a cyclic acid anhydride therefore suffix = -dioic anhydride

Hydrocarbon structure is an alkane therefore -an-

The longest continuous chain is C5 therefore root = pent
pentandioic anhydride
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Esters
Nomenclature
Formula
Functional class name = alkyl alkanoate
Substituent suffix = -oate

Esters are alkyl derivatives of carboxylic acids.

The easiest way to deal with naming esters is to recognise the carboxylic acid and the alcohol that they can be prepared
from.

The general ester, RCO2R' can be derived from the carboxylic acid RCO2H and the alcohol HOR'

The first component of an ester name, the alkyl is derived from the alcohol, R'OH.

The second component of an ester name, the -oate is derived from the carboxylic acid, RCO2H.

Alcohol component


o
the root name is based on the longest chain containing the -OH group.
o
The chain is numbered so as to give the -OH the lowest possible number.
Carboxylic acid component
o
the root name is based on the longest chain including the carbonyl group.
o
Since the carboxylic acid group is at the end of the chain, it must be C1.
o
The ester suffix for the acid component is appended after the hydrocarbon suffix minus the "e" : e.g. -ane + -oate = anoate etc.
The complete ester name is the alkyl alkanoate

Functional group is an ester

The alcohol component here is methanol, so the alkyl = methyl

The acid component here is propanoic acid, so propanoate
CH3CH2C(=O)OCH3
methyl propanoate
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Amides
Nomenclature
Formula
Functional class name = alkyl alkanamide
Substituent suffix = -amide
-5-

Amides are amine derivatives of carboxylic acids.

The root name is based on the longest chain including the carbonyl group of the amide group.

Since the amide group is at the end of the chain, the C=O carbon must be C1.

The amide suffix is appended after the hydrocarbon suffix minus the "e" : e.g. -ane + -amide = -anamide etc.

If the amide nitrogen is substituted, the these substituents are given N- as the locant.
-6
The N- locant is listed first.

Functional group is an amide therefore suffix = -amide

Hydrocarbon structure is an alkane therefore -an-

The longest continuous chain is C4 therefore root = but
butanamide

Functional group is an amide therefore suffix = -amide

Hydrocarbon structure is an alkane therefore -ane

The longest continuous chain is C4 therefore root = but

The nitrogen substituent is C1 i.e. an N-methyl group
CH3CH2CH2C(=O)NH2
CH3CH2CH2C(=O)N(CH3)H
N-methylbutanamide

Functional group is an amide therefore suffix = -amide

Hydrocarbon structure is an alkane therefore -ane

The longest continuous chain is C2 therefore root = eth

The two nitrogen substituents are C1 i.e. an N-methyl group

There are two methyl groups, therefore multiplier = diCH3C(=O)N(CH3)2
N,N-dimethylethanamide
Nitriles
Nomenclature
Formula
Functional class = alkyl cyanide
Functional group suffix = nitrile or -onitrile
Substituent prefix = cyanoNotes :
 The cyano prefix is used in a very similar manner to haloalkanes.

The cyano nomenclature is most common when the alkyl group is simple.

The nitrile suffix is used in a very similar manner to carboxylic acids.
Cyano substituent style:
 The root name is based on the longest chain with the -C≡N as a substituent.

This root give the alkane part of the name.

The chain is numbered so as to give the -C≡N group the lowest possible locant number
Nitrile style:
 The root name is based on the longest chain including the carbon of the nitrile group.

This root give the alkyl part of the name.

Since the nitrile must be at the end of the chain, it must be C1 and no locant needs to be specified.

Nitriles can also be named by replacing the -oic acid suffix of the corresponding carboxylic acid with -onitrile.
Cyano substituent style:
 Functional group is an alkane, therefore suffix = -ane

-6-
The longest continuous chain is C3 therefore root = prop
-7-

The substituent is a -CN therefore prefix = cyano

The first point of difference rule requires numbering from the right as drawn, the substituent locant is 1-
CH3CH2CH2C≡N
1-cyanopropane
Nitrile style:
 Functional group is a -C≡N, therefore suffix = -nitrile

Hydrocarbon structure is an alkane therefore -ane

The longest continuous chain is C4 therefore root = but
butanenitrile
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Structure of Carboxylic Acid Derivatives

The carbonyl group consists of an O atom bonded to a C atom via a double bond in a planar, sp2 hybridisation model similar
to that of a ketone or an alkene.

The heteroatom group is connected to this C=O unit via a s bond.

To see these features, compare the JMOL images to the below.

JMOL images of the other carboxylic acid derivatives can be found on the previous page.

The resonance interaction of the carbonyl C=O with the lone pair of the adjacent heteroatom (structure III) has important implications on the reactivity

It also has implications for structure... Look at the JMOL image of the amide to the right.

Amines and ammonia are usually pyramidal .

The planar sp2 N system allows the N lone pair to align with the C=O  system (see image below, with the other bonds omitted for clarity)

The resonance interaction in the amide results in the C-N bond having some double bond character (shorter, restricted rotation)

Nitriles are slightly different to the other derivatives in that they involved a triple bond.

Nitriles consists of a N atom bonded to a C atom via a triple bond in a linear, sp hybridisation model similar to that of an alkyne. Compare the JMOL images to the right.
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.
-7-
-8-
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 SN2 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 SN1 mechanism), and of bond-breaking
and bond-making occuring simultaneously (the SN2 mechanism) were observed. On the other hand, for most cases of electrophilic
aromatic substitution bond-making preceded bond-breaking.
As illustrated in the following diagram, acylation reactions generally take place by an addition-elimination process in which a nucleophilic reactant bonds to the electrophilic carbonyl carbon atom to create a tetrahedral intermediate. This tetrahedral intermediate then undergoes an elimination to yield the products. In this two-stage mechanism bond formation occurs before bond cleavage,
and the carbonyl carbon atom undergoes a hybridization change from sp 2 to sp3 and back again. The facility with which nucleophilic
reagents add to a carbonyl group was noted earlier for aldehydes and ketones.
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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 dis-8-
-9-
tinguishing 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 fourmembered 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.
The first three examples concern reactions of acyl chlorides, the most reactive acylating reagents discussed here. Although amines
are among the most reactive nucleophiles, only 1º and 2º-amines give stable amide products. Reaction of 3º-amines with strong
acylating reagents may generate acylammonium species reversibly (see below), but these are as reactive as acyl chlorides and will
have only a very short existence. This explains why reactions #2 & 3 do not give amide products.
RCONR'3(+) Cl(–) (an acylammonium salt)
RCOCl + R'3N
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.
R–CO2(–) + CH3NH2
OH(–)
heat
&
R–CO–NH(CH3) + H2O
H(+) & heat
R–CO2H + CH3NH3(+)
Other Acylation Reagents and Techniques
Because acylation is such an important and widely used transformation, the general reactions described above have been supplemented by many novel procedures and reagents that accomplish similar overall change.
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.
acid or base
R–C≡N + H2O
R–C(OH)=NH
R–CO–NH2
2. Reduction
Reductions of carboxylic acid derivatives might be expected to lead either to aldehydes or alcohols, functional groups having a lower oxidation state of the carboxyl carbon. Indeed, it was noted earlier that carboxylic acids themselves are reduced to alcohols by
lithium aluminum hydride. At this point it will be useful to consider three kinds of reductions:
-9-
- 10 -
(i) catalytic hydrogenation
(ii) complex metal hydride reductions
(iii) diborane 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.
H2
catalyst
(1) R–C≡N + H2
RCH=NH
imine
RCH2NH2
1º-amine
H2 & catalyst
(2) RCH=NH + RCH2NH2
imine
1º-amine
RCH=NCH2R + NH3
substituted imine
Complex Metal Hydride Reductions
- 10 -
RCH2NHCH2R
2º-amine
- 11 -
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.
In contrast to the usefulness of lithium aluminum hydride in reducing various carboxylic acid derivatives, sodium borohydride is seldom chosen for this purpose. First, NaBH4 is often used in hydroxylic solvents (water and alcohols), and these would react with acyl
chlorides and anhydrides. Furthermore, it is sparingly soluble in relatively nonpolar solvents, particularly at low temperatures.Second, NaBH4 is much less reactive than LAH, failing to reduce amides and acids (they form carboxylate salts) at all, and
reducing esters very slowly.
Since relatively few methods exist for the reduction of carboxylic acid derivatives to aldehydes, it would be useful to modify the reactivity and solubility of LAH to permit partial reductions of this kind to be achieved. The most fruitful approach to this end has been
to attach alkoxy or alkyl groups on the aluminum. This not only modifies the reactivity of the reagent as a hydride donor, but also
increases its solubility in nonpolar solvents. Two such reagents will be mentioned here; the reactive hydride atom is colored blue.
Lithium tri-tert-butoxyaluminohydride (LtBAH), LiAl[OC(CH3)3]3H : Soluble in THF, diglyme & ether.
Diisobutylaluminum hydride (DIBAH), [(CH3)2CHCH2]2AlH : Soluble in toluene, THF & ether.
- 11 -
- 12 -
Each of these reagents carries one equivalent of hydride. The first (LtBAH) is a complex metal hydride, but the second is simply an
alkyl derivative of aluminum hydride. In practice, both reagents are used in equimolar amounts, and usually at temperatures well
below 0 ºC. The following examples illustrate how aldehydes may be prepared from carboxylic acid derivatives by careful application of these reagents. A temperature of -78 ºC is easily maintained by using dry-ice as a coolant. The reduced intermediates that
lead to aldehydes will be displayed on clicking the "Show Intermediates" button. With excess reagent at temperatures above 0 ºC
most carboxylic acid derivatives are reduced to alcohols or amines.
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Diborane, B2H6
The reducing characteristics of diborane (disassociated to BH3 in ether or THF solution) were first introduced as addition reactions
to alkenes and alkynes. This remains a primary application of this reagent, but it also effects rapid and complete reduction of carboxylic acids, amides and nitriles. Other than LAH, this reagent provides one of the best methods for reducing carboxylic acids to
1º-alcohols.
ether
(1) R–CO2H + BH3 soln.
ether
(2) R–C≡N + BH3 soln.
H2O2
RCH2–OH
[RCH2O–B]
H2O
RCH2–NH–B
RCH2–NH2
Overview of Reducing Agents
The following table summarizes the influence each of the reducing systems discussed above has on the different classes of carboxylic acid derivatives. Note that LAH is the strongest reducing agent listed, and it reduces all the substrates. In a similar sense,
acyl chlorides are the most reactive substrate. They are reduced by all the reagents, but only a few of these provide synthetically
useful transformations.
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Function
Reagent
Aldehydes
& Ketones
Carboxylic Carboxylic Acyl
Acids
Esters
Chlorides
H2
& catalyst
alcohols
( slow, Pt, Pd (v. slow)
)
NaBH4
polar solvent
alcohols
LiAlH4
ether or THF
Amides
Nitriles
(v. slow)
aldehydes
( Pd/BaSO4 (v. slow)
)
amines
( Ni cat. )
N.R.
alcohols
(slow)
complex
mixture
N.R.
N.R.
alcohols
1º-alcohol
alcohols
1º-alcohol
amines
1º-amine
LiAlH(Ot-Bu)3
1 eq. in THF
alcohols
(slow at 0º)
N.R.
v. slow
aldehyde
(-78 º C)
aldehyde aldehyde
(-78 º C) (0 º C)
(iso-Bu)2AlH
alcohols
1º-alcohol
aldehyde
1º-alcohol
aldehyde aldehyde
- 13 -
(-78º C)
1 eq. in toluene
B2H6
THF
alcohols
(slow)
1º-alcohol
(v. slow)
(-78 º C)
complex
mixture
(-78 º C)
1º-amine 1º-amine
Color Code
Reduction occurs readily under normal conditions of temperature and pressure.
Reduction occurs readily, but selectivity requires low temperature.
Slow reduction occurs. Heating and/or high pressures of hydrogen are needed for effective use.
Reduction occurs very slowly or not at all (N.R.).
3. Reactions with Organometallic Reagents
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.
Reactions of this kind are important synthetic transformations, because they permit simple starting compounds to be joined to form
more complex structures. Esters are the most common carbonyl reactants, since they are cheaper and less hazardous to use than
acyl chlorides and anhydrides. Most esters react with organometallic reagents to give 3º-alcohols; but formate esters (R=H) give 2ºalcohols. Some examples of these reactions are provided in the following diagram. As demonstrated by the last equation, lactones
undergo ring opening and yield diol products.
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.
ether soln.
R–CO2(–) MgBr(+) + R'–H
R–CO2H + R'–MgBr
ether soln.
R–CONH2 + R'–Li
R–CONH(–) Li(+) + R'–H
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
- 13 -
- 14 -
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).
ether
2 R–MgBr + CdCl2 zene
&
benR2Cd + MgBr2 + MgCl2
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
Amides are very polar, thanks to the n-π conjugation of the nitrogen non-bonded electron pair with the carbonyl group. This delocalization substantially reduces the basicity of these compounds (pK a ca. –1) compared with amines (pKa ca. 11). When electrophiles bond to an amide, they do so at the oxygen atom in preference to the nitrogen. As shown below, the oxygen-bonded conjugate acid is stabilized by resonance charge delocalization; whereas, the nitrogen-bonded analog is not. One practical application of
this behavior lies in the dehydration of 1º-amides to nitriles by treatment with thionyl chloride. This reaction is also illustrated in the
following diagram. Other dehydrating agents such as P2O5 effect the same transformation.
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:
Study Tip:
Note that unlike aldehydes and ketones, this reactivity of carboxylic acids retains the carbonyl group, C=O. .
The observed reactivity order is shown below:
- 14 -
- 15 -
This reactivity order is important. You should be able to understand, rationalise and use it.
It is useful to view the carboxylic acid derivatives as an acyl group, R-C=O, with a different
substituent attached.
The important features of the carboxylic acid derivatives that influence their reactivity are governed by this substituent in the following ways:


the effect the substituent has on the electrophilicity of the carbonyl C .
o if the substituent is electron donating, then the electrophilicity is reduced, \ less
reactive
o if the substituent is electron withdrawing, the the electrophilicity is increased,
\more reactive
the ability of the substitutent to function as a leaving group.
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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.
The image shows the electrostatic potential for ethanoyl chloride.
The more red an area is, the higher the electron density and the
more blue an area is, the lower the electron density.
The image shows the electrostatic potential for ethanoic anhydride.
The more red an area is, the higher the electron density and the
more blue an area is, the lower the electron density.
- 15 -
- 16 -
The image shows the electrostatic potential for methyl ethanoate.
The more red an area is, the higher the electron density and the
more blue an area is, the lower the electron density.
The image shows the electrostatic potential for ethanamide.
The more red an area is, the higher the electron density and the
more blue an area is, the lower the electron density.
The image shows the electrostatic potential for acetonitrile.
The more red an area is, the higher the electron density and the
more blue an area is, the lower the electron density.
Derivative
Substituent
Acyl chloride
-Cl
Anhydride
-OC=OR
Thioester
Electronic Effect
Leaving Group Ability
Relative Reactivity
withdrawing group (inductive)
very good
1 (most)
weakly donating
good
2
-SR
donating
moderate
3
Ester
-OR
strongly donating
poor
=4
Acid
-OH
strongly donating
poor
=4
Amide
-NH2, -NR2
very strongly donating
very poor
5
Carboxylate
-O-
very, very strongly donating
appalling !
6 (least)
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:
- 16 -
- 17 -
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.
Overall, these events are the same as those in a simple nucleophilic
substitution , note the fundamental similarity in the two general processes.
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.
To make ->
From
-
RCO2-
R'OH
H2O
R2NH
H2O, HO-
-
-
R'OH
H2O
R2NH
H2O, HO-
-
R'OH,
heat
H+ or
B-
H2O,
H3O+
R2NH
H2O, HOheat
Heat, H2O
R'OH,
heat
H+
-
R2NH
heat
HO-
-
H2O, HOheat
-
-
-
SOCl2
or
PCl3
- 17 -
-
-
-
H2O,
H3O+
heat
-
RCOCl
R'-Br
or -I
H3O+
- 18 -
Reactions of Carboxylic Acid Derivatives
Interconversion Reactions of Acyl Chlorides
acid anhydrides
esters
acids
amides
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
esters
acids
amides
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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- 18 -
- 19 -
Interconversion Reactions of Esters
esters
acids
amides
Reaction type: Nucleophilic Acyl Substitution
Summary

Esters can be converted into other esters (transesterification), the parent carboxylic acid (hydrolysis) or amides (see above).
o
Transesterification : heat with alcohol and acid catalyst
o
Hydrolysis: heat with aq. acid o base (e.g. aq. H2SO4 or aq. NaOH) .
o
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

- 19 -
Nitriles typically undergo nucleophilic addition to give products that often undergo a further reaction.
- 20 
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:
o
the oxidation state of the C is the same as that of the carboxylic acid derivatives.
o
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
The protonation of a nitrile gives a structure that can be redrawn in another resonance form that reveals the electrophilic
character of the C since it is a carbocation.
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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.
- 20 -
- 21 
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
MECHANISM FOR THE FRIEDEL-CRAFTS ACYLATION OF BENZENE
Step 1:
The acyl halide reacts with the Lewis acid to form a a more electrophilic C, an acylium ion
Step 2:
The p electrons of the aromatic C=C act as a nucleophile, attacking the electrophilic C+. This step
destroys the aromaticity giving the cyclohexadienyl cation intermediate.
Step 3:
Removal of the proton from the sp3 C bearing the acyl- group reforms the C=C and the aromatic
system, generating HCl and regenerating the active catalyst.
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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.
- 21 -
- 22 
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.
MECHANISM OF THE BASE HYDROLYSIS OF ESTERS
Step 1:
The hydroxide nucleophiles attacks at the electrophilic C ofthe ester C=O, breaking the  bond
and creating the tetrahedral intermediate.
Step 2:
The intermediate collapses, reforming the C=O
results in the loss of the leaving group the alkoxide, RO-, leading to the carboxylic acid.
Step 3:
An acid / base reaction. A very rapid equilibrium where the alkoxide,RO- functions as a base
deprotonating the carboxylic acid, RCO2H, (an acidic work up would allow the carboxylic acid
to be obtained from the reaction).
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.
MECHANISM OF THE ACID CATALYSED HYDROLYSIS OF ESTERS
Step 1:
An acid/base reaction. Since we only have a weak nucleophile and a poor electrophile we
need to activate the ester. Protonation of the ester carbonyl makes it more electrophilic.
Step 2:
The water O functions as the nucleophile attacking the electrophilic C in the C=O, with the
electrons moving towards the oxonium ion, creating the tetrahedral intermediate.
Step 3:
An acid/base reaction. Deprotonate the oxygen that came from the water molecule to neutralise the charge.
Step 4:
An acid/base reaction. Need to make the -OCH3 leave, but need to convert it into a good leaving group first by protonation.
Step 5:
Use the electrons of an adjacent oxygen to help "push out" the leaving group, a neutral methanol molecule.
Step 6:
An acid/base reaction. Deprotonation of the oxonium ion reveals the carbonyl C=O in the carboxylic acid product and regenerates the acid catalyst.
- 22 -
- 23 -
Back to the Top
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 > 1o > 2o > 3o (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.
Study Tip:
The carboxylic acid and alcohol combination used to prepare an ester are reflected by the name of the ester,
e.g. ethyl acetate (or ethyl ethanoate), CH3CO2CH2CH3 can be made from CH3CO2H, acetic acid (or ethanoic
acid) and HOCH2CH3 (ethanol). This general "disconnection" is shown below:
MECHANISM FOR REACTION FOR ACID CATALYSED ESTERIFICATION
Step 1:
An acid/base reaction. Protonation of the carbonyl makes it more electrophilic.
Step 2:
The alcohol O functions as the nucleophile attacking the electrophilic C in the C=O, with the
electrons moving towards the oxonium ion, creating the tetrahedral intermediate.
Step 3:
An acid/base reaction. Deprotonate the alcoholic oxygen.
Step 4:
An acid/base reaction. Need to make an -OH leave, it doesn't matter which one, so convert it
into a good leaving group by protonation.
Step 5:
Use the electrons of an adjacent oxygen to help "push out" the leaving group, a neutral water
molecule.
- 23 -
- 24 -
Step 6:
An acid/base reaction. Deprotonation of the oxonium ion reveals the carbonyl in the ester
product.
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 1o 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 .
MECHANISM OF THE REACTION OF LiAlH4 WITH AN ESTER
Step 1:
The nucleophilic H from the hydride reagent adds to the electrophilic C in the polar carbonyl
group of the ester. Electrons from the C=O move to the electronegative O creating the tetrahedral intermediate a metal alkoxide complex.
Step 2:
The tetrahedral intermediate collapses and displaces the alcohol portion of the ester as a
leaving group, in the form of the alkoxide, RO-. This produces an aldehyde as an intermediate.
Step 3:
Now we are reducing an aldehyde (which we have already seen)
The nucleophilic H from the hydride reagent adds to the electrophilic C in the polar carbonyl
group of the aldehyde. Electrons from the C=O move to the electronegative O creating an intermediate metal alkoxide complex.
Step 4:
This is the work-up step, a simple acid/base reaction. Protonation of the alkoxide oxygen creates the primary alcohol product from the intermediate complex.
- 24 -
- 25 -
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.
MECHANISM OF THE REACTION OF RMgX WITH AN ESTER
Step 1:
The nucleophilic C in the organometallic reagent adds to theelectrophilic C in the polar
carbonyl group of the ester. Electrons from the C=O move to the electronegative O
creating thetetrahderal intermediate, a metal alkoxide complex.
Step 2:
The tetrahedral intermediate collapses and displaces the alcohol portion of the ester as
a leaving group, in the form of the alkoxide, RO-.This produces a ketone as an intermediate.
Step 3:
The nucleophilic C in the organometallic reagent adds to the electrophilic C in the polar
carbonyl group of the ketone. Electrons from the C=O move to the electronegative O
creating an intermediate metal alkoxide complex.
Step 4:
This is the work-up step, a simple acid/base reaction. Protonationof the alkoxide oxygen creates the alcohol product from the intermediate complex.
Hydrolysis of Amides
Reaction type: Nucleophilic Acyl Substitution
- 25 -
- 26 -
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.
MECHANISM OF THE ACID CATALYSED HYDROLYSIS OF AMIDES
Step 1:
An acid/base reaction. Since we only have a weak nucleophile and apoor electrophile we need
to activate the amide. Protonation of the amidecarbonyl makes it more electrophilic.
Step 2:
The water O functions as the nucleophile attacking the electrophilicCin the C=O, with the electrons moving towards the oxonium ion, creatingthe tetrahedral intermediate.
Step 3:
An acid/base reaction. Deprotonate the oxygen that came from the watermolecule to neutralise
the charge.
Step 4:
An acid/base reaction. Need to make the -NH2leave, but need to convert it into a good leaving
group first byprotonation.
Step 5:
Use the electrons of an adjacent oxygen to help "push out" the leavinggroup, a neutral ammonia molecule.
Step 6:
An acid/base reaction. Deprotonation of the oxonium ion reveals thecarbonyl in the carboxylic
acid product and regenerates the acid catalyst.
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Reduction of Amides
- 26 -
- 27 -
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.
MECHANISM OF THE REACTION OF LiAlH4 WITH AN AMIDE
Step 1:
The nucleophilic H from the hydride reagent adds to the electrophilic C in the polar carbonyl group of
the ester. Electrons from the C=O move to the electronegative O creating the tetrahedral intermediate, a metal alkoxide complex.
Step 2:
The tetrahedral intermediate collapses and displaces the O as part of a metal alkoxide leaving group,
this produces a highly reactive iminium ion an intermediate.
Step 3:
Rapid reduction by the nucleophilic H from the hydride reagent as it adds to the electrophilic C in the
iminium system. electrons from the C=N move to the cationic N neutralising the charge creating the
amine product.
- 27 -
- 28 -
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.
MECHANISM OF THE ACID CATALYSED HYDROLYSIS OF NITRILES
Step 1:
An acid/base reaction. Since we only have a weak nucleophile so activate the nitrile, protonation
makes it more electrophilic.
Step 2:
The water O functions as the nucleophile attacking the electrophilic C in the C≡N, with the electrons
moving towards the positive center.
Step 3:
An acid/base reaction. Deprotonate the oxygen that came from the water molecule. The remaining
task is a tautomerization at N and O centers.
Step 4:
An acid/base reaction. Protonate the N gives us the -NH2 we need....
Step 5:
Use the electrons of an adjacent O to neutralise the positive at the N and form the  bond in the
C=O.
Step 6:
An acid/base reaction. Deprotonation of the oxonium ion reveals the carbonyl in the amide intermediate....halfway to the acid.....
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Reduction of Nitriles
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Reactions usually in Et2O or THF followed by H3O+work-up
Reaction type: Nucleophilic Addition
Summary

The nitrile, RC≡N, gives the 1o 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.
MECHANISM FOR THE REACTION OF RMgX WITH A NITRILE
Step 1:
The nucleophilic C in the organometallic reagent adds to theelectrophilic C in the
polar nitrile group. Electrons from the C≡N move to the electronegative N creating
an intermediate imine salt complex.
Step 2:
An acid/base reaction. On addition of aqueous acid, the intermediate salt protonates giving the imine.
Step 3:
An acid/base reaction. Imines undergo nucleophilic addition, but require activation
by protonation (i.e. acid catalysis).
Step 4:
Now the nucleophilic O of a water molecule attacks the electrophilicCwith the
bond breaking to neutralise the change on the N.
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Step 5:
An acid/base reaction. Deprotonate the O from the water molecule to neutralise
the positive charge.
Step 6:
An acid/base reaction. Before the N system leaves, it needs to be made into a
better leaving group by protonation.
Step 7:
Use the electrons on the O in order to push out the N leaving group, a neutral
molecule of ammonia.
Step 8:
An acid/base reaction. Deprotonation reveals the carbonyl group ofthe ketone
product.
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Spectroscopic Analysis
Spectroscopic Analysis of Acyl Chlorides


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IR - presence of high frequency C=O, C-Cl too low to be useful
Absorbance (cm-1)
Interpretation
1800
C=O stretch
1
H NMR - only the protons adjacent to the C=O are particularly characteristic.
Resonance (ppm)
Interpretation
~2 - 2.5
H-C-C=O
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
13
C NMR
C=O typically 160-180 ppm (deshielding due to O)
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)
o
p electron from p of C=O
o
n electron from O lone pair
o
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

Interpretation
1820
C=O stretch
1750
C=O stretch
1
H NMR - only the protons adjacent to the C=O are particularly characteristic.
Resonance (ppm)
Interpretation
~2 - 2.5
H-CC=O
13
C NMR
C=O typically 160-180 ppm (deshielding due to O)
o

Absorbance (cm-1)
minimal intensity, characteristic of C's with no attached H's
UV-VIS
two absorption maxima p→p* (<200 nm) n→p* (~225nm, diagnostic)
o
p electron from p of C=O
o
n electron from O lone pair
o
p* antibonding C=O
Mass Spectrometry
Prominent peak corresponds to formation of acyl cations (acylium ions)
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Spectroscopic Analysis of Esters

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IR - presence of C=O, and two C-O bands (Csp2-O and Csp3-O bonds)
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


Interpretation
1735
C=O stretch
1300-1000
two bands for C-O stretch
1
H NMR - deshielded proton of H-C-O is often recognisable, and H-C-C=O.
Resonance (ppm)
Interpretation
3.5-4.5
H-COC
2-2.5
H-C-C=O
13
C NMR
C=O typically 160-180 ppm (deshielding due to O)
o

Absorbance (cm-1)
minimal intensity, characteristic of C's with no attached H's
UV-VIS
two absorption maxima p→p* (<200 nm) n→p* (~207 nm)
o
p electron from p of C=O
o
n electron from O lone pair
o
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 1o or 2o amides.
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Interpretation
1660
C=O stretch
3500 and 3100
N-H stretch (two for NH2, one for NH)
1
H NMR - N-H protons often broad,
Resonance (ppm)
Interpretation
5-8 (broad, exchangeable)
NH
~ 2 - 2.4
H-C-C=O
13
C NMR
C=O typically 160-180 ppm (deshielding due to O)
o

Absorbance (cm-1)
minimal intensity, characteristic of C's with no attached H's
UV-VIS
absorption maxima n→p* (~215 nm)
o
n electron from O lone pair
o
p* antibonding C=O
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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)
Absorbance (cm-1)
Interpretation
2250
C≡N stretch
H NMR - only protons adjacent to C≡N are likely to be characterisitic.
1
Resonance (ppm)
Interpretation
>
H-C-C≡N
2-3

13
C NMR
C≡N typically 115 -125 ppm (deshielding due to N)
o
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
6
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Department, Garyounis University