Aldehydes and
Ketones
Background
for Aldehydes and Ketones
An aldehyde contains at
least one hydrogen attached to the C of a C=O (carbonyl
group). A ketone contains two alkyl groups
attached to the C of the carbonyl group. The carbon in
the carbonyl is sp2
hybridized, has a bond angle of 120o, and is
trigonal planar. Aldehydes and ketones have
dipole-dipole attractions between molecules, and no
hydrogen bonding between molecules. These
compounds can hydrogen bond with compounds have O-H or
N-H bonds. The melting points and boiling points
of aldehydes and ketones are between alkanes and
alcohols. Small aldehydes and ketones are soluble
in water. Some compounds are very flammable.
Uses of
Aldehydes and Ketones
Formaldehyde can be
used to preserve dead animals. Acetone is a common
fingernail polish remover and is a solvent.
Acetone is very flammable. 2-Butanone (MEK, methyl ethyl
ketone) is used as a solvent and paint stripper.
2-Butanone is very flammable. Benzaldehyde is an
almond extract. (-)-Carvone is used as spearmint
flavoring. (+)-Carvone is used as caraway seed
flavoring. Vanillin is the vanilla flavoring.
1.
Nomenclature of Aldehydes and Ketones
Aldehydes and
ketones are organic compounds which incorporate a
carbonyl functional group, C=O. The carbon atom of
this group has two remaining bonds that may be occupied
by hydrogen or alkyl or aryl substituents. If at least
one of these substituents is hydrogen, the compound is
an aldehyde. If neither is hydrogen, the compound
is a ketone.
The IUPAC system
of nomenclature assigns a characteristic suffix to these
classes, al to aldehydes and one to
ketones. For example, H2C=O is methanal,
more commonly called formaldehyde. Since an aldehyde
carbonyl group must always lie at the end of a carbon
chain, it is by default position #1, and therefore
defines the numbering direction. A ketone carbonyl
function may be located anywhere within a chain or ring,
and its position is given by a locator number. Chain
numbering normally starts from the end nearest the
carbonyl group. In cyclic ketones the carbonyl group is
assigned position #1, and this number is not cited in
the name, unless more than one carbonyl group is
present. If you are uncertain about the IUPAC rules for
nomenclature you should
review them now.
Examples of IUPAC names are provided (in blue) in the
following diagram. Common names are in red, and derived
names in black. In common names carbon atoms near the
carbonyl group are often designated by Greek letters.
The atom adjacent to the function is
alpha, the next removed is
beta and so on. Since ketones
have two sets of neighboring atoms, one set is labled
α, β etc., and
the other α',
β'
etc.
Very simple
ketones, such as propanone and phenylethanone (first two
examples in the left column), do not require a locator
number, since there is only one possible site for a
ketone carbonyl function. Likewise, locator numbers are
omitted for the simple dialdehyde at the bottom left,
since aldehyde functions must occupy the ends of carbon
chains. The hydroxy butanal and propenal examples (2nd &
3rd from the top, left column) and the oxopropanal
example (bottom right) illustrate the
nomenclature priority of IUPAC suffixes. In all
cases the aldehyde function has a higher status than
either an alcohol, alkene or ketone and provides the
nomenclature suffix. The other functional groups are
treated as substituents. Because ketones are just below
aldehydes in nomenclature suffix priority, the "oxo"
substituent terminology is seldom needed.
Simple
substituents incorporating a carbonyl group are often
encountered. The generic name for such groups is acyl.
Three examples of acyl groups having specific names are
shown below.
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2.
Occurrence of Aldehydes and Ketones
Natural Products
Aldehydes and
ketones are widespread in nature, often combined with
other functional groups. Example are shown in the
following diagram. The compounds in the top row are
found chiefly in plants or microorganisms; those in the
bottom row have animal origins. With the exception of
the first three compounds (top row) these molecular
structures are all chiral. When chiral compounds are
found in nature they are usually enantiomerically pure,
although different sources may yield different
enantiomers. For example, carvone is found as its
levorotatory (R)-enantiomer in spearmint oil,
whereas, caraway seeds contain the dextrorotatory (S)-enantiomer.
Note that the aldehyde function is often written as
–CHO in condensed or complex formulas.
3. Synthetic
Preparation of Aldehydes and Ketones
Aldehydes and
ketones are obtained as products from many reactions .
The following diagram summarizes the most important of
these.
With the exception
of Friedel-Crafts acylation, these methods do not
increase the size or complexity of molecules. In the
following sections we shall find that one of the
most useful characteristics of aldehydes and ketones is
their reactivity toward carbon nucleophiles, and the
resulting elaboration of molecular structure that
results. In short, aldehydes and ketones are important
intermediates for the assembly or synthesis of complex
organic molecules.
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4.
Properties of Aldehydes and Ketones
A comparison of
the properties and reactivity of aldehydes and ketones
with those of the alkenes is warranted, since both have
a double bond functional group. Because of the greater
electronegativity of oxygen, the carbonyl group is
polar, and aldehydes and ketones have larger molecular
dipole moments (D) than do alkenes. The resonance
structures on below illustrate this polarity, and the
relative dipole moments of formaldehyde, other aldehydes
and ketones confirm the stabilizing influence that alkyl
substituents have on carbocations (the larger the dipole
moment the greater the polar character of the carbonyl
group). We expect, therefore, that aldehydes and ketones
will have higher boiling points than similar sized
alkenes.
Furthermore, the
presence of oxygen with its non-bonding electron pairs
makes aldehydes and ketones hydrogen-bond acceptors, and
should increase their water solubility relative to
hydrocarbons. Specific examples of these relationships
are provided in the following table.
|
Compound |
Mol. Wt. |
Boiling Point |
Water
Solubility |
|
(CH3)2C=CH2 |
56 |
-7.0 ºC |
0.04 g/100 |
|
(CH3)2C=O |
58 |
56.5 ºC |
infinite
|
|
CH3CH2CH2CH=CH2 |
70 |
30.0 ºC |
0.03 g/100 |
|
CH3CH2CH2CH=O |
72 |
76.0 ºC |
7
g/100 |
|
 |
96 |
103.0 ºC |
insoluble |
|
 |
98 |
155.6 ºC |
5
g/100 |
|
The polarity of
the carbonyl group also has a profound effect on its
chemical reactivity, compared with the non-polar double
bonds of alkenes. Thus, reversible addition of water to
the carbonyl function is fast, whereas water addition to
alkenes is immeasurably slow in the absence of a strong
acid catalyst. Curiously, relative bond energies
influence the thermodynamics of such addition reactions
in the opposite sense.
The C=C of alkenes has an
average bond energy of 146 kcal/mole. Since a C–C σ-bond
has a bond energy of 83 kcal/mole, the π-bond energy may
be estimated at 63 kcal/mole (i.e. less than the energy
of the sigma bond). The C=O bond energy of a carbonyl
group, on the other hand, varies with its location, as
follows:
|
H2C=O 170
kcal/mole
RCH=O 175 kcal/mole
R2C=O 180
kcal/mole |
The C–O
σ-bond is found to have an
average bond energy of 86 kcal/mole. Consequently, with
the exception of formaldehyde, the carbonyl function of
aldehydes and ketones has a π-bond energy greater than
that of the sigma-bond, in contrast to the pi-sigma
relationship in C=C. This suggests that addition
reactions to carbonyl groups should be thermodynamically
disfavored, as is the case for the addition of water.
All of this is summarized in the following diagram (ΔHº
values are for the addition reaction).
Although the
addition of water to an alkene is exothermic and gives a
stable product (an alcohol), the uncatalyzed reaction is
extremely slow due to a high activation energy . The
reverse reaction (dehydration of an alcohol) is even
slower, and because of the kinetic barrier, both
reactions are practical only in the presence of a strong
acid. The microscopically reversible mechanism for both
reactions was described earlier.
In contrast, both the endothermic addition of water
to a carbonyl function, and the exothermic elimination
of water from the resulting geminal-diol are fast. The
inherent polarity of the carbonyl group, together with
its increased basicity (compared with alkenes), lowers
the transition state energy for both reactions, with a
resulting increase in rate. Acids and bases catalyze
both the addition and elimination of water. Proof that
rapid and reversible addition of water to carbonyl
compounds occurs is provided by experiments using
isotopically labeled water. If a carbonyl reactant
composed of 16O (colored blue above) is
treated with water incorporating the 18O
isotope (colored red above), a rapid exchange of the
oxygen isotope occurs. This can only be explained by the
addition-elimination mechanism shown here.
Reactions of
Aldehydes and Ketones
1.
Reversible Addition Reactions
A. Hydration and Hemiacetal
Formation
It has been
demonstrated (above) that water adds rapidly to the
carbonyl function of aldehydes and ketones. In most
cases the resulting hydrate (a geminal-diol) is
unstable relative to the reactants and cannot be
isolated. Exceptions to this rule exist, one being
formaldehyde (a gas in its pure monomeric state). Here
the weaker pi-component of the carbonyl double bond,
relative to other aldehydes or ketones, and the small
size of the hydrogen substituents favor addition. Thus,
a solution of formaldehyde in water (formalin) is almost
exclusively the hydrate, or polymers of the hydrate.
Similar reversible additions of alcohols to aldehydes
and ketones take place. The equally unstable addition
products are called hemiacetals.
R2C=O
+
R'OH
R'O–(R2)C–O–H
(a hemiacetal)
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B. Acetal Formation
Acetals are
geminal-diether derivatives of aldehydes or ketones,
formed by reaction with two equivalents of an alcohol
and elimination of water. Ketone derivatives of this
kind were once called ketals, but modern usage has
dropped that term. The following equation shows the
overall stoichiometric change in acetal formation, but a
dashed arrow is used because this conversion does not
occur on simple mixing of the reactants.
R2C=O
+ 2 R'OH
R2C(OR')2
+ H2O
(an acetal)
In order to
achieve effective acetal formation two additional
features must be implemented. First, an acid catalyst
must be used; and second, the water produced with the
acetal must be removed from the reaction. The latter is
important, since acetal formation is reversible. Indeed,
once pure acetals are obtained they may be hydrolyzed
back to their starting components by treatment with
aqueous acid. The mechanism shown here applies to both
acetal formation and acetal hydrolysis by the principle
of microscopic reversiblity .
Some examples of
acetal formation are presented in the following diagram.
As noted, p-toluenesulfonic acid (pKa
= -2) is often the catalyst for such reactions. Two
equivalents of the alcohol reactant are needed, but
these may be provided by one equivalent of a diol
(example #2). Intramolecular involvement of a gamma or
delta hydroxyl group (as in examples #3 and 4) may
occur, and is often more facile than the intermolecular
reaction. Thiols (sulfur analogs of alcohols) give
thioacetals (example #5). In this case the carbonyl
functions are relatively hindered, but by using excess
ethanedithiol as the solvent and the Lewis acid BF3
as catalyst a good yield of the bis-thioacetal is
obtained. Thioacetals are generally more difficult to
hydrolyze than are acetals.
The importance of
acetals as carbonyl derivatives lies chiefly in their
stability and lack of reactivity in neutral to strongly
basic environments. As long as they are not treated by
acids, especially aqueous acid, acetals exhibit all the
lack of reactivity associated with
ethers in general.
Among the most useful and
characteristic reactions of aldehydes and ketones is
their reactivity toward strongly nucleophilic (and
basic) metallo-hydride, alkyl and aryl reagents (to be
discussed shortly). If the carbonyl functional group is
converted to an acetal these powerful reagents have no
effect; thus, acetals are excellent protective groups,
when these irreversible addition reactions must be
prevented.
C. Formation of Imines and Related
Compounds
The reaction of
aldehydes and ketones with ammonia or 1º-amines forms
imine derivatives, also known as Schiff bases,
(compounds having a C=N function). This reaction plays
an important role in the synthesis of
2º-amines. Water is eliminated in the reaction,
which is acid-catalyzed and reversible in the same sense
as acetal formation.
R2C=O
+
R'NH2
R'NH–(R2)C–O–H
R2C=NR'
+ H2O
Imines are
sometimes difficult to isolate and purify due to their
sensitivity to hydrolysis. Consequently, other reagents
of the type Y–NH2 have been studied, and
found to give stable products (R2C=N–Y)
useful in characterizing the aldehydes and ketones from
which they are prepared. Some of these reagents are
listed in the following table, together with the
structures and names of their carbonyl reaction
products. An interesting aspect of these carbonyl
derivatives is that stereoisomers are possible when the
R-groups of the carbonyl reactant are different. Thus,
benzaldehyde forms two stereoisomeric oximes, a
low-melting isomer, having the hydroxyl group cis to the
aldehyde hydrogen (called syn), and a higher
melting isomer in which the hydroxyl group and hydrogen
are trans (the anti isomer). At room temperature
or below the configuration of the double-bonded nitrogen
atom is apparently fixed in one trigonal shape, unlike
the rapidly interconverting pyramidal configurations of
the sp3
hybridized amines.
With the exception
of unsubstituted hydrazones, these derivatives are
easily prepared and are often crystalline solids - even
when the parent aldehyde or ketone is a liquid. Since
melting points can be determined more quickly and
precisely than boiling points, derivatives such as these
are useful for comparison and identification of carbonyl
compounds. If the aromatic ring of phenylhydrazine is
substituted with nitro groups at the 2- & 4-positions,
the resulting reagent and the hydrazone derivatives it
gives are strongly colored, making them easy to
identify. It should be noted that although semicarbazide
has two amino groups (–NH2) only one of them
is a reactive amine. The other is amide-like and is
deactivated by the adjacent carbonyl group.
The rate
at which these imine-like compounds are formed is
generally greatest near a pH of 5, and drops at higher
and lower pH's. This agrees with a general acid
catalysis in which the conjugate acid of the carbonyl
reactant combines with a free amino group, as shown in
the above animation. At high pH there will be a
vanishingly low concentration of the carbonyl conjugate
acid, and at low pH most of the amine reactant will be
tied up as its ammonium conjugate acid. With the
exception of imine formation itself, most of these
derivatization reactions do not require active removal
of water (not shown as a product in the previous
equations). The reactions are reversible, but
equilibrium is not established instantaneously and the
products often precipitate from solution as they are
formed.
|
Other
Derivatives of Aldehydes and Ketones
Examples of other carbonyl derivatives, and a
striking case of kinetic control vs.
thermodynamic (equilibrium) control of products
in these reactions may be examined by
Clicking Here.
|
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D. Enamine Formation
The previous
reactions have all involved reagents of the type:
Y–NH2, i.e. reactions with a 1º-amino
group. Most aldehydes and ketones also react with
2º-amines to give products known as enamines. Two
examples of these reactions are presented in the
following diagram. It should be noted that, like acetal
formation, these are acid-catalyzed reversible reactions
in which water is lost. Consequently, enamines are
easily converted back to their carbonyl precursors by
acid-catalyzed hydrolysis.
E. Cyanohydrin
Formation
The last example of reversible
addition is that of hydrogen cyanide (HC≡N), which adds
to aldehydes and many ketone to give products called
cyanohydrins.
RCH=O
+
H–C≡N
RCH(OH)CN
(a cyanohydrin)
Since hydrogen
cyanide itself is an acid (pKa = 9.25), the
addition is not acid-catalyzed. In fact, for best
results cyanide anion, C≡N(-) must be
present, which means that catalytic base must be added.
Cyanhydrin formation is weakly exothermic, and is
favored for aldehydes, and unhindered cyclic and methyl
ketones. Two examples of such reactions are shown below.
The cyanohydrin
from benzaldehyde is named mandelonitrile. The
reversibility of cyanohydrin formation is put to use by
the millipede Apheloria corrugata in a remarkable
defense mechanism. This arthropod releases
mandelonitrile from an inner storage gland into an outer
chamber, where it is enzymatically broken down into
benzaldehyde and hydrogen cyanide before being sprayed
at an enemy.
2.
Irreversible Addition Reactions
The distinction
between reversible and irreversible carbonyl addition
reactions may be clarified by considering the stability
of alcohols having the structure shown below in the
shaded box.
If substituent
Y
is not a hydrogen, an alkyl group or an aryl
group, there is a good chance the compound will be
unstable (not isolable), and will decompose in the
manner shown. Most hydrates and hemiacetals (Y =
OH & OR), for example, are known to decompose
spontaneously to the corresponding carbonyl compounds.
Aminols (Y
= NHR) are intermediates in imine formation, and also
revert to their carbonyl precursors if dehydration
conditions are not employed. Likewise,
α-haloalcohols (Y =
Cl, Br & I) cannot be isolated, since they immediately
decompose with the loss of HY. In all these cases
addition of H–Y to carbonyl groups is clearly
reversible.
If substituent
Y is a hydrogen, an alkyl group or an aryl group,
the resulting alcohol is a stable compound and does not
decompose with loss of hydrogen or hydrocarbons, even on
heating. It follows then, that if nucleophilic reagents
corresponding to H:(–), R:(–) or
Ar:(–)
add to aldehydes and ketones, the alcohol products of
such additions will form irreversibly. Free anions of
this kind would be extremely strong bases and
nucleophiles, but their extraordinary reactivity would
make them difficult to prepare and use. Fortunately,
metal derivatives of these alkyl, aryl and hydride
moieties are available, and permit their addition to
carbonyl compounds.
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A. Reduction by Complex Metal
Hydrides
Addition of a
hydride anion to an aldehyde or ketone would produce an
alkoxide anion, which on protonation should yield the
corresponding alcohol. Aldehydes would give 1º-alcohols
(as shown) and ketones would give 2º-alcohols.
RCH=O
+ H:(–)
RCH2O(–) +
H3O(–)
RCH2OH
Two practical
sources of hydride-like reactivity are the complex metal
hydrides lithium aluminum hydride (LiAlH4)
and sodium borohydride (NaBH4). These are
both white (or near white) solids, which are prepared
from lithium or sodium hydrides by reaction with
aluminum or boron halides and esters. Lithium aluminum
hydride is by far the most reactive of the two
compounds, reacting violently with water, alcohols and
other acidic groups with the evolution of hydrogen gas.
The following table summarizes some important
characteristics of these useful reagents.
|
Reagent |
Preferred
Solvents |
Functions
Reduced |
Reaction
Work-up |
|
Sodium
Borohydride
NaBH4 |
ethanol;
aqueous ethanol
15% NaOH; diglyme
avoid strong acids |
aldehydes
to 1º-alcohols
ketones to 2º-alcohols
inert to most other functions |
1)
simple neutralization
2) extraction of product |
|
Lithium
Aluminum Hydride
LiAlH4 |
ether; THF
avoid
alcohols and amines
avoid
halogenated compounds
avoid strong acids |
aldehydes
to 1º-alcohols
ketones to 2º-alcohols
carboxylic acids to 1º-alcohols
esters to
alcohols
epoxides to alcohols
nitriles &
amides to amines
halides & tosylates to
alkanes
most functions react |
1)
careful addition of water
2) remove aluminum salts
3)
extraction of product |
Some examples of
aldehyde and ketone reductions, using the reagents
described above, are presented in the following diagram.
The first three reactions illustrate that all four
hydrogens of the complex metal hydrides may function as
hydride anion equivalents which bond to the carbonyl
carbon atom. In the LiAlH4 reduction, the
resulting alkoxide salts are insoluble and need to be
hydrolyzed (with care) before the alcohol product can be
isolated. In the borohydride reduction the hydroxylic
solvent system achieves this hydrolysis automatically.
The lithium, sodium, boron and aluminum end up as
soluble inorganic salts. The last reaction shows how an
acetal derivative may be used to prevent reduction of a
carbonyl function (in this case a ketone). Remember,
with the exception of epoxides, ethers are generally
unreactive with strong bases or nucleophiles. The acid
catalyzed hydrolysis of the aluminum salts also effects
the removal of the acetal. This equation is typical in
not being balanced (i.e. it does not specify the
stoichiometry of the reagent).
Reduction of
α,β-unsaturated ketones by
metal hydride reagents sometimes leads to a saturated
alcohol, especially with sodium borohydride. This
product is formed by an initial conjugate addition of
hydride to the β-carbon atom, followed by ketonization
of the enol product and reduction of the resulting
saturated ketone (equation 1 below). If the saturated
alcohol is the desired product, catalytic hydrogenation
prior to (or following) the hydride reduction may be
necessary. To avoid reduction of the double bond,
cerium(III) chloride is added to the reaction and it is
normally carried out below 0 ºC, as shown in equation 2.
|
1)
RCH=CHCOR' |
+ |
NaBH4
(aq. alcohol) |
——> |
RCH=CHCH(OH)R' |
+
|
RCH2-CH2CH(OH)R' |
|
|
1,2-addition product |
|
1,4-addition product |
|
2)
RCH=CHCOR' |
+ |
NaBH4
& CeCl3
-15º |
——> |
RCH=CHCH(OH)R' |
|
|
1,2-addition product |
Before leaving
this topic it should be noted that diborane, B2H6,
a gas that was used in ether solution to prepare alkyl
boranes from alkenes, also reduces many carbonyl groups.
Consequently, selective reactions with substrates having
both functional groups may not be possible. In contrast
to the metal hydride reagents, diborane is a relatively
electrophilic reagent, as witnessed by its ability to
reduce alkenes. This difference also influences the rate
of reduction observed for the two aldehydes shown below.
The first, 2,2-dimethylpropanal, is less electrophilic
than the second, which is activated by the electron
withdrawing chlorine substituents.
|
Dissolving Metal Reduction
Carbonyl
groups and conjugated π-electron systems are
reduced by metals such as Li, Na and K, usually
in liquid ammonia solution.
|
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B. Addition of Organometallic
Reagents
The two most
commonly used compounds of this kind are alkyl
lithium reagents and Grignard reagents. They
are prepared from alkyl and aryl halides, as
discussed earlier.
These reagents are powerful nucleophiles and very strong
bases (pKa's of saturated hydrocarbons range
from 42 to 50), so they bond readily to carbonyl carbon
atoms, giving alkoxide salts of lithium or magnesium.
Because of their ring strain, epoxides undergo many
carbonyl-like reactions. Reactions of this kind are
among the most important synthetic methods available to
chemists, because they permit simple starting compounds
to be joined to form more complex structures. Examples
are shown in the following diagram.
A common pattern,
shown in the shaded box at the top, is observed in all
these reactions. The organometallic reagent is a source
of a nucleophilic alkyl or aryl group (colored blue),
which bonds to the electrophilic carbon of the carbonyl
group (colored magenta). The product of this addition is
a metal alkoxide salt, and the alcohol product is
generated by weak acid hydrolysis of the salt. The first
two examples show that water soluble magnesium or
lithium salts are also formed in the hydrolysis, but
these are seldom listed among the products, as in the
last four reactions. Ketones react with organometallic
reagents to give 3º-alcohols; most aldehydes react to
produce 2º-alcohols; and formaldehyde and ethylene oxide
react to form 1º-alcohols (examples #5 & 6). When a
chiral center is formed from achiral reactants (examples
#1, 3 & 4) the product is always a racemic mixture of
enantiomers.
Two additional examples of the addition
of organometallic reagents to carbonyl compounds are
informative. The first demonstrates that active metal
derivatives of terminal alkynes function in the same
fashion as alkyl lithium and Grignard reagents. The
second example again illustrates the use of acetal
protective groups in reactions with powerful
nucleophiles. Following acid-catalyzed hydrolysis of the
acetal, the resulting 4-hydroxyaldehyde is in
equilibrium with its cyclic hemiacetal.
|
Reactions with Phosphorus and Sulfur Ylides
The ylides are another class of nucleophilic
organic reagents that add rapidly to the
carbonyl function of aldehydes and ketones. |
3. Other
Carbonyl Group Reactions
A. Reduction
The metal hydride
reductions and organometallic additions to aldehydes and
ketones, described above, both decrease the carbonyl
carbon's oxidation state, and may be classified as
reductions. As noted, they proceed by attack of a strong
nucleophilic species at the electrophilic carbon. Other
useful reductions of carbonyl compounds, either to
alcohols or to hydrocarbons, may take place by different
mechanisms. For example, hydrogenation (Pt, Pd, Ni or Ru
catalysts), reaction with diborane, and reduction by
lithium, sodium or potassium in hydroxylic or amine
solvents have all been reported to convert carbonyl
compounds into alcohols. However, the complex metal
hydrides are generally preferred for such
transformations because they give cleaner products in
high yield.
|
Aldehydes
and ketones may also be reduced by hydride
transfer from alkoxide salts.
|
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Meerwein-Pondorf-Verley Reduction
Reduction of
aldehydes and ketones to alcohols is most commonly
carried out by metal hydride reagents, dissolving metal
reagents, and sometimes by catalytic hydrogenation.
Prior to the development of these new and powerful
reduction methods, the conversion of carbonyl compounds
to alcohols was often effected by hydrogen transfer from
an alkoxide salt. This procedure, known as the
Meerwein-Pondorf-Verley reaction, is illustrated by
the following equation and mechanism ( the hydride-like
hydrogen is colored red). Aluminum isopropoxide has been
the most common hydrogen source in most cases, but
lanthanide salts, such as ROSmI2 have been
used with good results. This reduction is specific for
aldehyde and ketone carbonyl functions, so other easily
reduced functions such as nitro groups and halogen are
unaffected.
Not only are two
hydrogens delivered independently from the least
hindered (convex) side of the cis-decalin substrate in
example 1, but the easily reduced double bond of
the enedione remains unchanged. The initially formed
cis-diol undergoes lactonization with the neighboring
methyl ester. It should be noted that a similar
reductive hydride transfer takes place when large alkyl
Grignard reagents react with hindered ketones, as shown
in equation 2.
The MVP reduction
is also an oxidation, as evidenced by the conversion of
isopropoxide to acetone. Consequently, the reaction can
be converted into an oxidation of alcohols to ketones or
aldehydes. This procedure is called the Oppenauer
oxidation. The reaction displayed below is an example of
the Oppenauer oxidation in which benzophenone is the
oxidant. Two significant features may be noted. First,
the oxidation is specific for alcohols, and does not
oxidize other sensitive functions such as amines and
sulphides. Second, although aluminum or other
coordinating metals are often used as cationic partners,
alkali metals alone will suffice.
The
Cannizzaro Reaction
When a
non-enolizable aldehyde is heated in strong aqueous
base, a redox transformation known as the Cannizzaro
reaction takes place. Two examples are shown in the
following diagram. In the first, formaldehyde
disproportionates into methanol and formic acid (sodium
salt). In the second, a benzaldehyde derivative is
similarly converted into an equimolar mixture of the
corresponding benzyl alcohol and benzoic acid
derivatives. A hydride transfer mechanism analogous to
that of the MVP reaction is drawn in the shaded box. If
the Cannizzaro reaction is run in D2O with
NaOD as a base, no C-D incorporation is observed. Thus
the new carbon-bonded hydrogen in the alcohol cannot
have come from the solvent.
It is important to
remember that the the Cannizzaro reaction is restricted
to non-enolizable aldehydes. The strong base used for
this reaction would initiate aldol and other reactions
that take place via enolate anions. A useful crossed
Cannizzaro reaction employs an excess of formaldehyde to
reduce aryl aldehyde substrates to 1 º-alcohols. The
success of this procedure may be attributed to the high
concentration of the hydrate, H2C(OH)2,
in aqueous solutions of formaldehyde, making it the only
significant hydride donor in the system.
An intramolecular
Cannizzaro reaction, sometimes termed a Cannizzaro
rearrangement will be displayed above . A variant of the
Cannizzaro reaction, known as the Tischenko reaction is
also shown. In this reaction the alcohol and acid
products combine to form an ester.
The reductive
conversion of a carbonyl group to a methylene group
requires complete removal of the oxygen, and is called
deoxygenation. In the shorthand equation shown here
the
[H] symbol refers to
unspecified reduction conditions which effect the
desired change. Three very different methods of
accomplishing this transformation will be described
here.
R2C=O
+
[H]
R2CH2 + H2O
1. Wolff-Kishner Reduction
Reaction of an
aldehyde or ketone with excess hydrazine generates a
hydrazone derivative, which on heating with base gives
the corresponding hydrocarbon. A high-boiling hydroxylic
solvent, such as diethylene glycol, is commonly used to
achieve the temperatures needed. The following diagram
shows how this reduction may be used to convert
cyclopentanone to cyclopentane. A second example, in
which an aldehyde is similarly reduced to a methyl
group, also illustrates again the use of an acetal
protective group. The mechanism of this useful
transformation involves tautomerization of the initially
formed hydrazone to an azo isomer, and will be displayed
on pressing the "Show Mechanism" button. The strongly
basic conditions used in this reaction preclude its
application to base sensitive compounds.
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2. Clemmensen Reduction
This alternative
reduction involves heating a carbonyl compound with
finely divided, amalgamated zinc. in a hydroxylic
solvent (often an aqueous mixture) containing a mineral
acid such as HCl. The mercury alloyed with the zinc does
not participate in the reaction, it serves only to
provide a clean active metal surface. The first example
below shows a common application of this reduction, the
conversion of a Friedel-Crafts acylation product to an
alkyl side-chain. The second example illustrates the
lability of functional substituents alpha to the
carbonyl group. Substituents such as hydroxyl, alkoxyl &
halogens are reduced first, the resulting unsubstituted
aldehyde or ketone is then reduced to the parent
hydrocarbon.
3. Hydrogenolysis of Thioacetals
In contrast to the
previous two procedures, this method of carbonyl
deoxygenation requires two separate steps. It does,
however, avoid treatment with strong base or acid. The
first step is to convert the aldehyde or ketone into a
thioacetal, as described earlier. These derivatives may
be isolated and purified before continuing the
reduction. The second step involves refluxing an acetone
solution of the thioacetal over a reactive nickel
catalyst, called Raney Nickel. All carbon-sulfur bonds
undergo hydrogenolysis (the C–S bonds are broken by
addition of hydrogen). In the following example,
1,2-ethanedithiol is used for preparing the thioacetal
intermediate, because of the high yield this reactant
usually affords. The bicyclic compound shown here has
two carbonyl groups, one of which is sterically hindered
(circled in orange). Consequently, a mono-thioacetal is
easily prepared from the less-hindered ketone, and this
is reduced without changing the remaining carbonyl
function.
B. Oxidation
The carbon atom of
a carbonyl group has a relatively high oxidation state.
This is reflected in the fact that most of the reactions
described thus far either cause no change in the
oxidation state (e.g. acetal and imine formation) or
effect a reduction (e.g. organometallic additions
and deoxygenations). The most common and characteristic
oxidation reaction is the conversion of aldehydes to
carboxylic acids. In the shorthand equation shown here
the [O] symbol refers to
unspecified oxidation conditions which effect the
desired change. Several different methods of
accomplishing this transformation will be described
here.
RCH=O
+
[O]
RC(OH)=O
In discussing the
oxidations of 1º and 2º-alcohols, we noted that Jones'
reagent (aqueous chromic acid) converts aldehydes to
carboxylic acids, presumably via the hydrate. Other
reagents, among them aqueous potassium permanganate and
dilute bromine, effect the same transformation. Even the
oxygen in air will slowly oxidize aldehydes to acids or
peracids, most likely by a radical mechanism. Useful
tests for aldehydes, Tollens' test,
Benedict's test & Fehling's test, take
advantage of this ease of oxidation by using Ag(+)
and Cu(2+)
as oxidizing agents (oxidants).
RCH=O
+ 2 [Ag(+)
OH(–)]
RC(OH)=O + 2
Ag (metallic mirror) + H2O
When silver cation
is the oxidant, as in the above equation, it is reduced
to metallic silver in the course of the reaction, and
this deposits as a beautiful mirror on the inner surface
of the reaction vessel. The Fehling and Benedict tests
use cupric cation as the oxidant. This deep blue reagent
is reduced to cuprous oxide, which precipitates as a red
to yellow solid. All these cation oxidations must be
conducted under alkaline conditions. To avoid
precipitation of the insoluble metal hydroxides, the
cations must be stabilized as complexed ions. Silver is
used as its ammonia complex, Ag(NH3)2(+),
and cupric ions are used as citrate or tartrate
complexes.
Saturated ketones
are generally inert to oxidation conditions that convert
aldehydes to carboxylic acids. Nevertheless, under
vigorous acid-catalyzed oxidations with nitric or
chromic acids ketones may undergo carbon-carbon bond
cleavage at the carbonyl group. The reason for the
vulnerability of the alpha-carbon bond will become
apparent in the following section.
Stable Carbonyl
Hydrates & Hemiacetals
Although most
aldehydes and ketones do not form stable hydrates or
hemiacetals, a number of interesting exceptions are
known. Some examples are shown here.
The factors that
act to favor hydrate or hemiacetal formation include
inductive charge repusion (chloral) dipole repusion
(ninhydrin) and angle strain (cyclopropanaone). It is
important to note that cases in which 5 or 6-membered
cyclic hemiacetals can form usually favor such
constitutions. The simple sugars offer many examples of
this kind. Because these additions are readily
reversible, all compounds of this type exhibit
carbonyl-like chemical reactivity.
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Aldehyde and Ketone Derivatives
1. Kinetic
vs. Equilibrium Control in Semicarbazone Formation
A striking
demonstration of kinetic control vs. thermodynamic
(equilibrium) control of products is provided by an
experiment in which equimolar amounts of cyclohexanone,
furfuraldehyde and semicarbazide are mixed in a buffered
solvent at pH=5.
The semicarbazide
reacts with cyclohexanone 60 times faster than it does
with the aldehyde, and within 45 seconds a nearly
quantitative amount of the semicarbazone derivative of
cyclohexanone has precipitated and may be isolated by
filtration. However, if the initial reaction mixture
containing the cyclohexanone product is refluxed for a
few hours an equally good yield of the more stable
furfuraldehyde semicarbazone is obtained. Note that in
both cases the semicarbazone derivative is favored over
the initial reactants, but the equilibrium constant for
the aldehyde is about 300 times greater than that of the
ketone. The aldehyde semicarbazone is therefore the
thermodynamically favored product, assuming there is
equilibrium at all steps.
2.
Dinitrophenylhydrazones
Another commonly
used carbonyl derivative is prepared from
2,4-dinitrophenylhydrazine, as shown below. The reagent
and its hydrazone derivatives are distinctively colored
solids, which can be isolated easily. Saturated ketones
and aldehydes are usually yellow to light orange in
color. Conjugation of the carbonyl group with a double
bond or benzene ring shifts the color to shades of red.
3. Aldehyde
Derivatives
Among aldehydes,
formaldehyde, H2C=O, has many unique
properties. For example, with ammonia it reacts in a 3:2
ratio to give a tricyclic product, shown on the right,
and known as hexamethylenetetramine. This interesting
compound may function as an ammonia derivative for the
synthesis of
1º-amines, or as a convenient high-melting source of
formaldehyde by way of acid-catalyzed hydrolysis.
An interesting
reagent that distinguishes aldehydes from ketones is the
hydrazine derivative,
4-amino-3-hydrazino-5-mercapto-1,2,4-triazole, best
known as Purpald
(formula shown below). Although this reagent reacts with
both aldehydes and ketones, only the aldehyde product is
further oxidized to a purple, 10 π-electron aromatic
heterocycle on exposure to air. Note that the pair of
electrons on the nitrogen atom common to both rings is
part of the π-electron system.
Reactions at the
α-Carbon
Many aldehydes and ketones undergo substitution
reactions at an alpha carbon, as shown in the following
diagram (alpha-carbon atoms are colored blue). These
reactions are acid or base catalyzed, but in the case of
halogenation the reaction generates an acid as one of
the products, and is therefore autocatalytic. If the
alpha-carbon is a chiral center, as in the second
example, the products of halogenation and isotopic
exchange are racemic. Indeed, treatment of this ketone
reactant with acid or base alone serves to racemize it.
Not all carbonyl compounds exhibit these
characteristics, the third ketone being an example.
Two important conclusions may be drawn from these
examples.
First, these substitutions are limited to carbon
atoms alpha to the carbonyl group.
Cyclohexanone (the first ketone) has two alpha-carbons
and four potential substitutions (the alpha-hydrogens).
Depending on the reaction conditions, one or all four of
these hydrogens may be substituted, but none of the
remaining six hydrogens on the ring react. The second
ketone confirms this fact, only the alpha-carbon
undergoing substitution, despite the presence of many
other sites.
Second,the substitutions are limited to hydrogen
atoms. This is demonstrated convincingly by the third
ketone, which is structurally similar to the second but
has no alpha-hydrogen.
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1. Mechanism of
Electrophilic α-Substitution
Kinetic studies of these reactions provide
additional information. The rates of halogenation and
isotope exchange are essentially the same (assuming
similar catalsts and concentrations), and are
identical to the rate of racemization for those
reactants having chiral alpha-carbon units. At low to
moderate halogen concentrations, the rate of halogen
substitution is proportional (i.e.
first order) to aldehyde or ketone concentration,
but independent of halogen concentration. This suggests
the existence of a common reaction intermediate, formed
in a slow (rate-determining step) prior to the final
substitution. Acid and base catalysts act to increase
the rate at which the common intermediate is formed, and
their concentration also influences the overall rate of
substitution.
From previous knowledge and experience,
we surmise that the common intermediate is an
enol tautomer of the carbonyl reactant. Several
facts support this proposal:
(i)
Compounds that do not have any α-hydrogen atoms cannot
enolize and do not undergo any of the reactions
described above.
(ii) The
carbon-carbon double bond of an enol is planar, so any
chirality that existed at the α carbon is lost on
enolization. If chiral products are
obtained from enol intermediates they will necessarily
be racemic.
(iii) In simple
aldehydes and ketones enol tautomers are present in very
low concentration. Reactions that involve enol reactants
will therefore be limited in rate by the enol
concentration. Increasing the amounts of other reactants
will have little effect on the reaction rate.
(iv)
Enolization is catalyzed by acids and bases. These
catalysts will therefore catalyze reactions proceeding
via enol intermediates.
The reactions shown above, and others to be described, may be
characterized as an electrophilic attack on the electron
rich double bond of an
enol tautomer. This resembles closely the first step in the
addition of acids and other electrophiles to alkenes.
Therefore, if electrophilic substitution reactions of
this kind are to take place it is necessary that
nucleophilic character be established at the
alpha-carbon. A full description of the acid and
base-catalyzed keto-enol tautomerization process (shown
below) discloses that only two intermediate species
satisfy this requirement. These are the enol tautomer
itself and its conjugate base (common with that of the
keto tautomer), usually referred to as an enolate
anion.
Clearly, the proportion of enol tautomer present at
equilibrium is a critical factor in alpha substitution
reactions. In the case of simple aldehydes
and ketones this is very small, as noted above. A
complementary property, the acidity of carbonyl
compounds is also important, since this influences the
concentration of the more nucleophilic enolate anion in
a reaction system. Ketones such as cyclohexanone are
much more acidic than their parent hydrocarbons (by at
least 25 powers of ten); nevertheless they are still
very weak acids (pKa
= 17 to 21) compared with water. Together with some
related acidities, this is listed in the following
table. Even though enol tautomers are about a million
times more acidic than their keto isomers, their low
concentration makes this feature relatively unimportant
for many simple aldehydes and ketones.
Acidity of α-Hydrogens in Some Activated
Compounds |
|
Compound |
RCH2–NO2 |
RCH2–COR |
RCH2–C≡N |
RCH2–SO2R |
|
pKa |
9 |
20 |
25 |
25 |
In cases where more than one activating function
influences a given set of alpha-hydrogens, the enol
concentration and acidity is increased.
In view of these facts it may seem surprising that
alpha-substitution reactions occur at all. However, we
often fail to appreciate the way in which a rapid
equilibrium involving a minor reactive component may
spread the consequences of its behavior throughout a
much larger population. Consider, for example, a large
group of hungry, active hampsters running about in a big
cage. Opening onto the cage there is a small annex that
can hold a maximum of three hampsters. Out of two
hundred hampsters in the cage, there are an average of
two hampsters in the annex at any given time. The
hampsters are free to enter and exit the annex, but any
hampster that does so is marked by a bright red dye.
Although the hampster concentration in the annex is
small relative to the whole population, it will not be
long before all the hampsters are dyed red. If we
substitute molecules for hampsters, their numbers will
be extraordinarily large (recall the size of Avogadro's
number), but the equilibrium between keto tautomers
(hampsters in the cage) and enol tautomers (hampsters in
the annex) is so rapid that complete turnover of all the
molecules in a sample may occur in fractions of a second
rather than minutes or hours. The principle is the same
in both cases.
Racemization and isotope exchange are
due to the rapid equilibrium between chiral keto
tautomers and achiral enol tautomers, as well as
statistical competition between hydrogen and its
deuterium isotope. For halogenation there is also a
thermodynamic driving force, resulting from increased
bond energy in the products. For example,the
alpha-chlorination of cyclohexane, shown above, is
exothermic by over 10 kcal/mole.
|
The Haloform Reaction
Methyl ketones undergo a unique oxidative
cleavage on treatment with halogens in
aqueous base. |
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2. The Aldol
Reaction
A useful carbon-carbon bond-forming reaction known as
the
Aldol Reaction
or the Aldol Condensation is yet another example of
electrophilic substitution at the alpha carbon in enols
or enolate anions. Three examples of the base-catalyzed
aldol reaction are shown in the following diagram, and
equivalent acid-catalyzed reactions also occur. The
fundamental transformation in this reaction is a
dimerization of an aldehyde (or ketone) to a
beta-hydroxy aldehyde (or ketone) by alpha C–H addition
of one reactant molecule to the carbonyl group of a
second reactant molecule. By clicking the "Structural
Analysis" button below the diagram, a display showing
the nucleophilic enolic donor
molecule and the electrophilic acceptor molecule
together with the newly formed carbon-carbon bond will
be displayed. Stepwise mechanisms for the base-catalyzed
and acid-catalyzed reactions may be seen by clicking the
appropriate buttons.
In the presence of acid or base catalysts the aldol
reaction is reversible, and the beta-hydroxy carbonyl
products may revert to the initial aldehyde or ketone
reactants. In the absence of such catalysts these aldol
products are perfectly stable and isolable compounds.
Because of this reversibility, the yield of aldol
products is related to their relative thermodynamic
stability. In the case of aldehyde reactants (as in
reactions #1 & 2 above), the aldol reaction is modestly
exothermic and the yields are good. However, aldol
reactions of ketones are less favorable (e.g. #3 above),
and the equilibrium product concentration is small. A
clever way of overcoming this disadvantage has been
found. A comparatively insoluble base, Ba(OH)2,
is used to catalyze the aldol reaction of acetone, and
the product is removed from contact with this base by
filtration and recirculation of the acetone.
A.
Dehydration of Aldol Products
The products of aldol reactions often undergo a
subsequent elimination of water, made up of an
alpha-hydrogen and the beta-hydroxyl group. The product
of this beta-elimination reaction is an α,β-unsaturated
aldehyde or ketone, as shown in the following diagram.
Acid-catalyzed conditions are more commonly used to
effect this elimination (examples #1, 2 & 5), but
base-catalyzed elimination also occurs, especially on
heating (examples #3, 4 & 5). The additional stability
provided by the conjugated carbonyl system of the
product makes some ketone aldol reactions
thermodynamically favorable (#4 & 5), and mixtures of
stereoisomers (E & Z) are obtained from reaction #4.
Reaction #5 is an interesting example of an
intramolecular aldol reaction; such reactions create a
new ring.
Reactions in which a larger molecule is
formed from smaller components, with the elimination of
a very small by-product such as water are termed
Condensations. Hence the following examples are
properly referred to as aldol condensations. The
dehydration step of an aldol condensation is also
reversible in the presence of acid and base catalysts.
Consequently, on heating with aqueous solutions of
strong acids or bases, many α, β-unsaturated carbonyl
compounds fragment into smaller aldehyde or ketones, a
process known as the retro-aldol reaction.
The acid-catalyzed elimination of water is not
exceptional, since this was noted as a
common reaction of alcohols. Nevertheless,
the conditions required for the beta-elimination are
found to be milder than those used for simple alcohols.
The most surprising aspect of beta-elimination, however,
is that it can be base-catalyzed. In earlier discussions
we have noted that
hydroxyl anion is a very poor leaving group. Why
then should the base-catalyzed elimination of water
occur in aldol products? To understand this puzzle we
need to examine plausible mechanisms for
beta-elimination, and these will be displayed by
clicking the "Beta-Elimination Mechanism" button under
the diagram.
As shown by the equations, these
eliminations might proceed from either the keto or enol
tautomers of the beta-hydroxy aldol product. Although
the keto tautomer route is not unreasonable (recall the
enhanced acidity of the alpha-hydrogens in carbonyl
compounds), the enol tautomer provides a more favorable
pathway for both acid and base-catalyzed elimination of
the beta oxygen. Indeed, the base-catalyzed loss of
hydroxide anion from the enol is a conjugated analog of
the base-catalyzed decomposition of a hemiacetal.
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B.
Mixed Aldol Condensations
The previous examples of aldol reactions and
condensations used a common reactant as both the enolic
donor and the electrophilic acceptor.
The product in such cases is always a dimer of the
reactant carbonyl compound. Aldol condensations between
different carbonyl reactants are called crossed
or mixed reactions, nd under certain conditions such
crossed aldol condensations can be effective. Some
examples are shown below, and in most cases
beta-elimination of water occurs under the conditions
used. The exception, reaction #3, is conducted under
mild conditions with an excess of the reactive aldehyde
formaldehyde serving in the role of electrophilic
acceptor. The first reaction demonstrates that ketones
having two sets of alpha-hydrogens may react at both
sites if sufficient acceptor co-reactant is supplied.
The interesting difference in regioselectivity shown in
the second reaction (the reactants are in the central
shaded region) illustrates some subtle differences
between acid and base-catalyzed aldol reactions. The
base-catalyzed reaction proceeds via an enolate anion
donor species, and the kinetically favored proton
removal is from the less substituted alpha-carbon. The
acid-catalyzed aldol proceeds via the enol tautomer, and
the more stable of the two enol tautomers is that with
the
more substituted double bond. Finally, reaction
#4 has two reactive alpha-carbons and a reversible aldol
reaction may occur at both. Only one of the two aldol
products can undergo a beta-elimination of water, so the
eventual isolated product comes from that reaction
sequence. The aldol condensation of ketones with aryl
aldehydes to form α,β-unsaturated derivatives is called
the
Claisen-Schmidt reaction.
The success of these mixed aldol reactions is due to two
factors. First, aldehydes are more reactive acceptor
electrophiles than ketones, and
formaldehyde is more reactive than other aldehydes.
Second, aldehydes lacking alpha-hydrogens can only
function as acceptor reactants, and this reduces the
number of possible products by half. Mixed aldols in
which both reactants can serve as donors and acceptors
generally give complex mixtures of both dimeric (homo)
aldols and crossed aldols. The following abbreviated
formulas illustrate the possible products in such a
case, red letters representing the acceptor component
and blue the donor. If all the reactions occurred at the
same rate, equal quantities of the four products would
be obtained. Separation and purification of the
components of such a mixture would be difficult.ACH2CHO
+ BCH2CHO
+ NaOH
A–A
+ B–B
+ A–B +
B–A
|
Directed Stereoselective
Aldol Reactions
The effectiveness of the aldol reaction as a synthetic tool has
been enhanced by controlling the enolization
of donor compounds, and subsequent reactions
with acceptor carbonyls. |
3. Irreversible
Substitution Reactions
In its simplest form the aldol reaction is reversible,
and normally forms the thermodynamically favored
product. To fully appreciate the complex interplay of
factors that underlie this important synthesis tool, we
must evaluate the significance of several possible
competing reaction paths.
A. The Ambident Character of Enolate Anions
Since the negative charge of an enolate anion is
delocalized over the alpha-carbon and the oxygen, as
shown earlier, electrophiles may bond to either
atom. Reactants having two or more reactive sites are
called ambident, so this term is properly applied
to enolate anions. Modestly electrophilic reactants such
as
alkyl halides are not sufficiently reactive
to combine with neutral enol tautomers, but the
increased nucleophilicity of the enolate anion conjugate
base permits such reactions to take place. Because
alkylations are usually irreversible, their products
should reflect the inherent (kinetic) reactivity of the
different nucleophilic sites.
If an alkyl halide undergoes an SN2
reaction at the carbon atom of an enolate anion the
product is an alkylated aldehyde or ketone. On the other
hand, if the SN2
reaction occurs at oxygen the product is an ether
derivative of the enol tautomer; such compounds are
stable in the absence of acid and may be isolated and
characterized. These alkylations (shown above) are
irreversible under the conditions normally used for SN2 reactions, so the product composition should provide a measure of
the relative rates of substitution at carbon versus
oxygen. It has been found that this competition is
sensitive to a number of factors, including negative
charge density, solvation, cation coordination and
product stability.
For alkylation reactions of
enolate anions to be useful, these intermediates must be
generated in high concentration in the absence of other
strong nucleophiles and bases. The aqueous base
conditions used for the aldol condensation are not
suitable because the enolate anions of simple carbonyl
compounds are formed in
very low concentration, and hydroxide or alkoxide
bases induce competing SN2
and E2 reactions of alkyl halides. It is necessary,
therefore, to achieve complete conversion of aldehyde
or ketone reactants to their enolate conjugate bases
by treatment with a very strong base (pKa
> 25) in a non-hydroxylic solvent before any alkyl
halides are added to the reaction system. Some bases
having pKa's
greater than 30 were
described earlier, and some others that have been
used for enolate anion formation are: NaH (sodium
hydride, pKa
> 45), NaNH2
(sodium amide, pKa = 34), and (C6H5)3CNa
(trityl sodium, pKa = 32). Ether solvents like tetrahydrofuran (THF) are commonly used
for enolate anion formation. With the exception of
sodium hydride and sodium amide, most of these bases are
soluble in THF. Certain other strong bases, such as
alkyl lithium and Grignard reagents, cannot be used to
make enolate anions because they rapidly and
irreversibly
add to carbonyl groups. Nevertheless, these very
strong bases are useful in making soluble amide bases.
In the preparation of lithium diisopropylamide (LDA),
for example, the only other product is the gaseous
alkane butane.
|
C4H9–Li
+
butyl lithium |
[(CH3)2CH]2N–H
diisopropylamine |
[(CH3)2CH]2N(–) Li(+) + C4H10
LDA
|
|
O=C-C-H
|
+
LDA
 |
(–)O–C=C +
[(CH3)2CH]2N–H |
Because of its solubility in THF, LDA is a widely used base for
enolate anion formation. In this application one
equivalent of diisopropylamine is produced along with
the lithium enolate, but this normally does not
interfere with the enolate reactions and is easily
removed from the products by washing with aqueous acid.
Although the reaction of carbonyl compounds with sodium
hydride is heterogeneous and slow, sodium enolates are
formed with the loss of hydrogen, and no other organic
compounds are produced. The following equation provides
examples of electrophilic substitution at both carbon
and oxygen for the enolate anion derived from
cyclohexanone.
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A full analysis of the factors that direct substitution
of enolate anions to carbon or oxygen is beyond the
scope of this text. However, an outline of some
significant characteristics that influence the two
reactions shown above is illustrative.
|
Reactant |
Important Factors |
|
CH3–I |
The negative charge density
is greatest at the oxygen atom (greater
electronegativity), and coordination with
the sodium cation is stronger there. Because
methyl iodide is only a modest electrophile,
the SN2 transition state resembles the products more
than the reactants. Since the C-alkylation
product is thermodynamically more stable
than the O-alkylated enol ether, this is
reflected in the transition state energies. |
|
(CH3)3Si–Cl |
Trimethylsilyl chloride is a
stronger electrophile than methyl iodide
(note the electronegativity difference
between silicon and chlorine). Relative to
the methylation reaction, the SN2
transition state will resemble the reactants
more than the products. Consequently,
reaction at the site of greatest negative
charge (oxygen) will be favored. Also, the
high Si–O bond energy (over 25 kcal/mole
greater than Si–C) thermodynamically favors
the silyl enol ether product. |
B.
Alkylation Reactions of Enolate Anions
The reaction of alkyl halides with enolate anions
presents the same problem of competing SN2
and E2 reaction paths that was encountered earlier in
the
alkyl halide. Since enolate anions are very
strong bases, they will usually cause elimination when
reacted with 2º and 3º-halides. Halides that are
incapable of elimination and/or have enhanced SN2
reactivity are the best electrophilic reactants for this
purpose. Four examples of the C-alkylation of enolate
anions in synthesis are displayed in the following
diagram. The first two employ the versatile strong base
LDA, which is the reagent of choice for most
intermolecular alkylations of simple carbonyl compounds.
The dichloro alkylating agent used in reaction #1 nicely
illustrates the high reactivity of allylic halides and
the unreactive nature of vinylic halides in
SN2
reactions.
The additive effect of carbonyl groups on alpha-hydrogen
acidity is demonstrated by reaction #3. Here the two
hydrogen atoms activated by both carbonyl groups are
over 1010 times more acidic than the methyl hydrogens on the ends of the
carbon chain. Indeed, they are sufficiently acidic (pKa
= 9) to allow
complete
conversion
to the enolate anion in aqueous or alcoholic
solutions. As shown (in blue), the negative charge of
the enolate anion is delocalized over both oxygen atoms
and the central carbon. The oxygens are hydrogen bonded
to solvent molecules, so the kinetically favored SN2
reaction occurs at the carbon. The monoalkylated product
shown in the equation still has an acidic hydrogen on
the central carbon, and another alkyl group may be
attached there by repeating this sequence.The last
example (reaction #4) is an interesting case of
intramolecular alkylation of an enolate anion. Since
alkylation reactions are irreversible, it is possible to
form small highly strained rings if the reactive sites
are in close proximity. Reversible bond-forming
reactions, such as the aldol reaction, cannot be used
for this purpose. The use of aqueous base in this
reaction is also remarkable, in view of the very low
enolate anion concentration
noted earlier for such systems. It is the rapid
intramolecular nature of the alkylation that allows
these unfavorable conditions to be used.
The five-carbon chain of the dichloroketone can adopt
many conformations, two of which are approximated in the
preceding diagram. Although conformer II of the enolate
anion could generate a stable five-membered ring by an
intramolecular SN2
reaction, assuming proper orientation of the α and γ'
carbon atoms, the concentration of this ideally coiled
structure will be very low. On the other hand,
conformations in which the α and γ-carbons are properly
aligned for three-membered ring formation are much more
numerous, the result being that as fast as the enolate
base is formed it undergoes rapid and irreversible
cyclization.Ring closures to four, five, six and
seven-membered are also possible by intramolecular
enolate alkylation, as illustrated by the following
example. In general, five and six-membered rings are
thermodynamically most stable, whereas three-membered
ring formation is favored kinetically.
Aldehyde Ketone
Reaction Summary
Preparation
Commonly by
oxidation of 1º & 2º-alcohols by chromium+6
reagents (e.g. PCC and Jones' reagent).
Reactions
Aldehydes are
oxidized to carboxylic acids by Jones' reagent or
Tollens' reagent. Ketones are not.
Both classes undergo the following chemical
transformations:
Acetals and
hemiacetals by reversible addition-elimination of
alcohols. (acetals require removal of water)
Imines and
enamines by reversible addition-elimination of 1º &
2º-amines respectively. (removal of water is necessary)
Cyanohydrins by
reversible addition-elimination of HCN.
Reduction to1º &
2º-alcohols by NaBH4
and LiAlH4 (irreversible hydride addition).
Reduction to
alkanes by Wolff-Kishner or Clemmensen conditions.
Formation of 1º,
2º or 3º-alcohols by addition of organometallic reagents
to formaldehyde, other aldehydes or ketones.
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©
M.EL-Fellah ,Chemistry
Department, Garyounis University
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