Hydrogen Transfer Redox Reactions

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. A table listing these reagents and the conditions under which they are best used is available by clicking here.
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.

By clicking on the above diagram, a second example of MVP reduction, which demonstrates the stereoselectivity of the reduction will be presented.
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 sulfides. 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 -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 by clicking on the diagram. 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.
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Haloform Oxidation
The Haloform Reaction
Exhaustive base-catalyzed halogenation of methyl ketones is accompanied by CC bond cleavage, yielding a carboxylate salt and haloform ( X3CH ).
As shown in the diagram, an enolate conjugate base reacts with elemental halogen to form an -halo ketone. This process is repeated until the -site
is fully halogenated. The trihalo derivatives formed from methyl ketones are then cleaved by base attack at the carbonyl group, reflecting the relative

stability of the trihalomethyl anion as a leaving group.

Before nmr became an essential tool for structure elucidation, a variant of the haloform reaction called the iodoform test was used to identify methyl
ketones, as well as alcohols that gave methyl ketones when oxidized. By clicking on the diagram an illustration of this test will appear as reaction 1.
The iodoform product is an easily identifiable, bright yellow, water-insoluble solid with a characteristic odor.
The haloform reaction has also been used to prepare carboxylic acids, as in the synthesis of trimethylacetic acid from acetone shown in reaction 2.
Dissolving metal reduction of acetone gives the diol pinacol, which then undergoes acid-catalyzed rearrangement to the methyl ketone pinacolone.
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Aldol Reactions
Directed Aldol Reactions

The aldol reaction is potentially a powerful synthetic tool. As demonstrated by the following equation, a directed aldol reaction between different
aldehydes would produce a single crossed aldol product (the new bond is colored maroon) and create two new stereogenic centers (colored blue).
However, conducting this reaction with aqueous NaOH usually generates a mixture of four different adducts, and frequently -elimination of water
when possible.

R1CH2CHO
Carbonyl Acceptor

+ R2CH2CHO
Enolate Donor

base

R1CH2CH(OH)CH(R2)CHO
One Crossed Aldol Product

In this section methods of controlling the enolate donor and carbonyl acceptor reactants to produce a single aldol product will be described and
discussed. Several important principles must be taken into consideration for this purpose.
The conventional aldol reaction is reversible. (aqueous base at room temperature)
The initial aldol product may undergo beta-elimination of water, depending on reaction conditions.
Regioselective enolate anion formation may be achieved by using differences in kinetic vs. equilibrium acidities of -hydrogens.
Enolate anions may be trapped as silyl ethers and used subsequently for controlled aldol reactions.
Enolate-like species may be used for aldol-like reactions with carbonyl compounds, and hydrolyzed later to aldol products.
Metal cations or other electrophilic moieties may act to orient the reactants in specific ways.
The reversibility of conventional aldol reactions is illustrated by the crossed aldol condensation of 2-butanone with benzaldehyde, illustrated below.
The methyl hydrogens are kinetically more acidic than the methylene hydrogens, so the '-enolate is generated more rapidly than the more substituted
-enolate. As a rule, ketone enolate bases react more rapidly with aldehydes than with ketones, so self condensation of the ketone is minimal. Both
enolate anions add reversibly to benzaldehyde to form -hydroxy ketones; however, the -enolate product (on the left) reverts to reactants faster than
it eliminates water. In contrast, the isomeric '-enolate product (on the right) undergoes rapid -elimination to the observed 5-phenyl-4-penten-3-one
final product.
The significance of aldol reversibility is dramatically demonstrated by the base-catalyzed isomerization of 2-methyl-1-acetylcyclobutene, a reaction that
will be outlined below by clicking on the diagram.

Acid catalysis of the 2-butanone-benzaldehyde reaction gives the isomer, 3-methyl-4-phenyl-3-buten-2-one, as the chief product, thanks to the
predominance of the more substituted -enol as an intermediate. In this case both -hydroxy ketone intermediates undergo reversible dehydration.

1. Regioselective Enolate Formation and Diastereoselectivity

Lithium enolate derivatives of aldehydes or ketones may be formed at low temperature by slow addition of the carbonyl compound to an excess of
LDA in THF (-78 C). In this procedure self aldolization is avoided, because freshly introduced aldehyde (or ketone) reacts with the powerful LDA base
more rapidly than with any less basic enolate already present. In the following example, a preformed lithium enolate of 2-pentanone is reacted with
propanal at low temperature, ca. -15 C. Only the desired aldol addition takes place, with very little enolate exchange occurring by proton transfer.
Both enolate formation and aldol addition are essentially irreversible, with a forward to reverse rate difference of roughly ten powers of ten (based on
pKa values). The lithium salt of the final adduct is quenched in dilute acid to give the -hydroxyketone. A new stereogenic center is created in this
reaction, resulting in a racemic mixture of products.

Aldol reactions at an -methylene group generally create two new stereogenic centers, thus producing diastereomeric pairs of enantiomers. These
diastereomers are called syn and anti, as described in an earlier section. The ability to control the configurational outcome of such reactions is vital to
the use of aldol reactions in complex synthesis, and considerable effort has been directed toward achieving this end. The three reactions shown in the
following diagram illustrate some of the factors to be considered. If the preformed lithium enolate of cyclohexanone reacts with benzaldehyde under
rate controlling conditions (irreversible addition), the anti isomer is the preferential product (eq. 1). Under equilibrating conditions, the two
diastereomers are produced in nearly equal quantity. Magnesium and zinc enolates may be prepared by reacting -bromo carbonyl compounds with
these metals, as illustrated in equation 2. The aldol addition in such cases usually requires a higher temperature. In all these examples the reactants
are achiral and the products are racemic.
Moderately sized cyclic ketones can only generate one enolate stereoisomer (configuration E), but acyclic ketones may give E or Z-enolates. In the
case of 2,2-dimethyl-3-hexanone, reaction with LDA gives the lithium Z-enolate (98%), as shown in equation 3. Here, the rate controlled aldol reaction
strongly favors the syn-diastereomer, but under equilibrium control the anti-isomer is the dominant product. The size of ketone substituents also
influences the isomer distribution of aldol products, as illustrated by the E-enolate reactions of the two compounds in equation 4.

From these examples it is clear that kinetic selectivity in the aldol reaction depends in large part on the configuration of the enolate reactant. The first
of the following tables illustrates the dramatic influence of the accompanying carbonyl substituent (R) on the Z to E ratio of enolate species formed by
reaction of a CH3CH2C=O moiety with LDA. The second table demonstrates how the amide base used for enolate formation may direct reaction
exclusively to an E or Z-product, provided the other carbonyl substituent does not exert a controlling influence (e.g. tert-butyl). Identification of enolate
species is usually achieved by trapping them as their silyl enol ethers.

Enolate Distribution from Reaction of RCOCH2CH3 with LDA in THF (78 C)

R=

C2 H5

(CH3)2CH

(CH3)3C

C6 H5

CH3O

(CH3)2N

Z:E Ratio

23:77

60:40

99:1

98:2

5:95

97:3

Enolate Distribution from Reaction of 3-Pentanone with Lithium Amide Bases

Base

LDA

LTMP

LTMP + LiBr

LHMDS

(Et3Si)2NLi

[Ph(CH3)2Si]2NLi

Z:E Ratio

23:77

15:85

1:99

66:34

99:1

100:0

LDA = lithium diisopropylamide

LTMP = lithium 2,2,6,6-tetramethylpiperidide

LHMDS = lithium hexamethyldisilazide

An explanation for these interesting and useful characteristics requires consideration of the transition state for base induced enolate formation. Two
putative transition states are displayed at the top of the following diagram. An early state that resembles reactants is on the left, while a late state
resembling products is on the right. The product from each transition state is the enolate drawn in the green shaded box between them. Dialkylamide
bases such as LDA and LTMP are powerful bases that react rapidly with simple aldehydes and ketones, presumably by an early transition state. The
chief steric interactions (orange circles) are between R & R1 in the substrate, and between R 2 & L (a substituent on the nitrogen base). The former is
particularly strong in tert-butyl ketones, resulting in predominate Z-enolate formation (the oxygen group is smaller than tert-butyl). For less sterically
demanding R groups, the R2:L interaction acts to favor the E-enolate, and may dominate when L is large (i.e. LTMP). This tendency is enhanced by
added LiBr.
In contrast, hexaalkyldisilazide bases such as LHMDS, (Et3Si)2NLi, and [Ph(CH3)2Si]2NLi are much weaker bases (at least a million times) and will
probably react by a later transition state. Here the SiN bonds are longer than the CN bonds of the amide bases, and the entire L 2NH moiety is
shifted away from the enolate substrate. Consequently, the L:R2 interaction is relatively unimportant, leading to a preference for Z-enolates.

Extensive study of aldol reactions with aldehyde acceptors has led to the general rule: Z-enolates favor syn-products and E-enolates favor anti
products. To explain this stereoselectivity a chair-like transition state, called the Zimmerman-Traxler model, has been proposed, and examples are
drawn beneath the enolization transition states in the above diagram. The lower energy transition state for the Z-enolate aldol has a gauche
relationship between the phenyl and R2 groups, and this leads to the syn-product. Rotating the aldehyde 180 about the C=O creates an equivalent
transition state for the anti-isomer, which suffers from a destabilizing 1,3-diaxial hinderance between the phenyl and R1 groups. The favored transition
state for an E-enolate aldol has a similar gauche interaction, but leads to the anti-product. Once the new CC bond has formed, the aldol product can
relax into a chair-like chelate structure (drawn in the brown box on the right). In the case of the anti-product, all substituents are equatorial. The
equivalent structure for the syn-isomer has an axial R2 group. In general, anti-aldols are more stable than their syn analogs. A link to a model for the
chair-like transition state is provided below.
Three additional aldol reactions will be displayed above by clicking on the diagram. Reaction 5 demonstrates that a very bulky substituent on the -

carbon of a Z-enolate can dramatically change the stereoselectivity from syn to anti. A similar effect has been reported for E-enolate reactions. Two
modifications of the idealized chair transition state, the twisted chair and boat models drawn in the box at the upper right, have been suggested to
accommodate these facts. Note that different faces of the carbonyl group bond to the enolate species in these structures, with the re(si)-face in the
twisted boat bonding to the re(si)-face of the Z-enolate to yield the anti-diastereomer.
Reaction 6 demonstrates stereoelectronic control in the bonding of the carbonyl reactant to the enolate intermediate. The bulky t-butyl substituent
maintains an equatorial orientation on the six-membered ring, disclosing axial attack of benzaldehyde at the -carbon. Finally, reaction 7 shows an
intramolecular Tischenko reaction following an aldol reaction, the result being stereoselective construction of a 2-methyl-1,3-diol. The hydride transfer
step is rate determining, so the aldol intermediate is the thermodynamically favored anti-diastereomer. A six-membered chair-like transition state
accounts for the selective reduction of the carbonyl group.
A cautionary point must be made regarding these models and mechanisms. The lithium cation associated with the amide base and the enolates is
organized in oligomeric clusters of substrate and solvent species that are much larger than the atoms (or groups) shown here. These amide and
enolate ion clusters have variable compositions, and are presumably in rapid equilibrium with other clusters of the same type.

2. Silyl Enol Ethers as Enolate Reactants

Enolate anions may be trapped, purified and stored as silyl enol ethers. The most commonly used silyl group is trimethylsilyl (TMS), but other useful
derivatives are the tert-butyldimethylsilyl (TBDMS), dimethylphenylsilyl (DMPS) and triisopropylsilyl (TIPS) analogs. As a rule, silyl enol ethers are not
as reactive as their anion precursors, but under suitable conditions may be induced to give aldol products when reacted with carbonyl acceptor
compounds. The equations above the heavy horizontal line in the following diagram illustrate how mixtures of TMS enol ethers may be prepared under
mild conditions, separated by distillation or chromatography, and then used to generate isomerically pure lithium enolates. As expected, the enolates
react regioselectively with electrophilic reagents.

Mixing silyl enol ethers with aldehydes or ketones does not normally result in any reaction, even at elevated temperatures. In order to effect an aldollike transformation, it is necessary to increase the electrophilicity of the carbonyl group by adding a Lewis acid catalyst. Four examples of such
reactions, known as the Mukaiyama aldol, are displayed below the horizontal line. Reactions 1 and 2 generate a mixture of syn and anti
diastereomers. Although there is a preference for the syn-isomer from both E and Z-enol ethers, this diastereoselectivity is less pronounced than that
of lithium enolates. In contrast to the closed cyclic transition states proposed for the latter, the acid-catalyzed reactions of the silyl enol ethers are
presumed to take place by way of an open, less organized transition state, which favors syn-products regardless of the enolate configuration.
Aldehydes are the most common co-reactants with silyl enol ethers, but catalyzed aldol reactions with ketones have also been reported, as shown in
reaction 3. Reaction 4 is an interesting case in which the catalyzed aldol is followed by an acetal exchange involving the new hydroxyl group. The
bulky tert-butyl substituent blocks cis-attack of formaldehyde on the enolate, directing the new bond formation trans to that group.

3. Enolborinate Intermediates
The aldol diastereoselectivity of lithium enolates has been attributed to a structurally organized closed transition state, in which the two oxygen atoms
are coordinated to the metal cation. Since lithium is not an exceptionally strong chelating agent, replacing it with a larger and stronger electrophile
should improve the diastereoselectivity of this important synthetic method. To this end, enolborinates have proven to be particularly effective. The
comparatively short BO bond of a dialkyl boron enolate, together with the electrophilic character of trivalent boron provides a tighter, more highly
organized transition state, and in most cases leads to enhanced diastereoselectivity.
A model of the cyclic aldol transition state may be examined by

Clicking Here .

The preparation of suitable enolborinates is accomplished by reacting a ketone, ester or amide with a dialkylchloroborane (or equivalent triflate) and a
3-amine base, as outlined in the following equation.. The alkyl substituents on boron are usually n-butyl, cyclopentyl (Cpen), cyclohexyl (Chex) or the
C8H14 substituent of a 9-borobicyclononane moiety (shown in the diagram). The 3-amine base is most commonly triethyl amine (Et3N), Nethyldiisopropylamine (Hnig's base) or 2,6-dimethylpyridine (lutidine). Less hindered amines (e.g. pyridine and DABCO) are ineffective, possibly due
to irreversible complexation with the boron reagent.

R1COCH2R2 +
Ketone

R2B-Z
Z=Cl or OTf

3 amine

R1C(OZ)=CHR2
E or Z-Enolborinate

Some examples of the selective formation of enolborinate derivatives from ketones, and their diastereoselective reaction with aldehydes are displayed

in the following diagram. In most cases the enolborinate is generated in ether solution at 78 C, and may either be reacted directly with an aldehyde
acceptor or converted to a TMS silyl ether for spectroscopic identification. By judicious selection of the boron reagent and base, it is clear that specific
syn or anti-isomers may be prepared in high purity and good yield from simple acyclic ketones.
These procedures also effect regioselective enolborination of unsymmetrical ketones, as demonstrated by the examples displayed by clicking on the
diagram. The dominant enolborinate in all cases is that derived from the kinetically favored enolate anion.

Example 5 suggests that steric factors are important, since the -carbons have identical substitution. The last example (#7) illustrates the influence of
boron substituents (R) and the leaving group (X) on reactions of 2-methyl-3-pentanone. From the data presented in the following table, it is clear that
more reactive borinating reagents ( OTf > OMs > I > Br > Cl ) favor formation of Z-enol derivatives, as does the 9-BBN moiety. The iodine reagents are
anomalous, and often give Z-enolborinates, even when other reagents act to form the E-isomer.
Variation in Z : E Enolborinate Formation in 2-Methyl-3-Pentanone
R

Chex

Chex

Chex

Chex

Chex

OTf

OMs

Br

Cl

Z : E 25 : 75 23 : 77 32 : 68 11 : 89

3 : 97

9-BBN 9-BBN 9-BBN 9-BBN 9-BBN

OTf

OMs

Br

Cl

88 : 12 82 : 18 73 : 27 57 : 43 56 : 44

By clicking on the diagram a second time, a mechanism model for these reactions will appear. The favored chair transition state, T1 or T4, is that in
which steric crowding of R1 and R2 is avoided. Large substituents (R) on boron enhance this steric control. Curiously, cyclic ketones which are
restricted to E-enolborinate intermediates do not exhibit as large a specificity toward anti-aldol products as do their acyclic counterparts. The
cyclohexanone example shown below the horizontal line is typical. The stereospecificity of these aldol reactions is improved by using nonpolar
solvents, possibly because the structure of the transition state is tightened due to lack of competitive coordination with boron.
It is not a simple task to write a single mechanism that rationalizes all the experimental results concerning enolborinate formation. Among the variables
that must be accommodated are the nature and size of the carbonyl substituents. Thus, tert-butyl ethyl ketones give Z enolates under kinetic control,
whereas tert-butyl esters of propanoic acid give E-enolates. Other critical variables are the size and orientation of the alkyl substituents on the R2BX
reagent, the nature of the leaving group X, the size of the 3-amine base, and solvent polarity. A sequence of events that may influence the course of
these enolizations is proposed here:
Some Events Associated with Enolborinate Formation
Acyclic ketones such as 3-pentanone generally adopt a zig-zag conformation. Least motion enolization would give a Z-enol.
The nucleophilic oxygen of the ketone coordinates reversibly with the boron reagent. C=O + R2BX C=OBR 2X
A bulky boron moiety may shift the conformer equilibrium of the complexed ketone to gauche forms, favoring an E-enol. [ R=Chex > R=9BBN in size ]
The BX bond ionizes to X(). This increases the BO bond strength and the acidity of the -hydrogens. [ reactivity X=OTf > X=Cl ]
The 3-amine base removes an -proton, forming the enolborinate. Hnig's base is more hindered and reacts more slowly than triethylamine.
(Note that the last two events may be concerted, as in an E2 elimination.)

4. Chlorotitanium Enolates
A convenient procedure for preparing Z-titanium enolate derivatives has been reported by D. A. Evans (Harvard). As shown in the following illustration,
these intermediates react with aldehydes to give syn-isomers with high diastereoselectivity. A cyclic transition state similar to that proposed for the
enolborinate reactions is suggested.

5. Imine and Enamine Intermediates

Examples of imine and enamine analogs of enolate species are well known. The following diagram gives two examples of metalated imine and
hydrazone intermediates in carbon bond forming reactions at an -carbon. The first is an aldol reaction which would be difficult to accomplish directly.
Although the -hydrogen acidity of aldehydes and ketones do not differ appreciably, aldehydes are much better enolate acceptors than are ketones.
By using a preformed tert-butylimine of acetaldehyde as the enolate donor source, the ketone is forced to react as a nucleophile acceptor. Hydrolysis
of the imine product generates a disubstituted -hydroxyaldehyde. In cyclic systems the electrophile bonds preferentially in an axial orientation.

Enamines have been proposed as enolate donors in some aldol reactions. The intramolecular cyclization shown in equation 1 below may be induced
by acid or base catalysis or by heating with a 2-amine such as pyrrolidine. A few drops of acetic acid appear to enhance this catalysis, which
probably takes place by the mechanism drawn in the colored box. If the 2-amine and carboxylic acid functions are incorporated in the same molecule,
as for example in the amino acid proline, exceptional catalytic action might be expected. This has been realized in a recent study reported by Alan B.
Northrup and David W. C. MacMillan from Cal. Tech. As shown in equation 2, catalytic pyrrolidine effects the homo-condensation of propanal to anti-3hydroxy-2-methylpentanal under mild conditions. Apparently -hydroxyaldehydes resist enamine formation, since there is no further reaction of this
product. In contrast, alkali metal hydroxides cause polymerization of this aldehyde. Of particular value in this reaction is its' high enantioselectivity. The
previously described aldol reactions generate racemic mixtures of stereoisomers from achiral reactants. In this case, enantiomerically pure (S)-proline
(the natural amino acid) produces anti-(2S,3S)-3-hydroxy-2-methylpentanal in 99% enantiomeric excess. As expected, (R)-proline catalyzes formation
of the enantiomer.

Since the rate of enamine formation from aldehydes is retarded by bulky substituents, cross condensations with 2-propanal are possible, provided this
donor aldehyde is added slowly to the acceptor-catalyst mixture. Three examples are shown in equation 3. A mechanism for these stereoselective
reactions is drawn in the colored box to the right of equation 2. Proline transfer from the iminium aldol species to a new aldehyde molecule may be
assisted by the small amounts of water produced in the initial enamine formation.
This transformation is similar to the aldol-retroaldol processes catalyzed by a family of enzymes called aldolases.By clicking on the diagram a series
of equations illustrating the biosynthesis of 2-deoxyribose-5-phosphate from glyceraldehyde-3-phosphate by action of the bacterial enzyme DERA will
be displayed. Lysine and aspartic acid functions have been identified in the active site of this enzyme. Configurations of the reactants and
intermediates are not indicated, but these transformations are highly stereospecific. Antibodies that mimic this enzymatic catalysis have been
prepared and used effectively in enantioselective synthesis.
For information about the influence of chiral reactants on the stereoselectivity of the aldol reaction;
and the development of enantioselective catalyst systems for this reaction. Click Here.

The aldol reaction of aldehydes was first reported in 1872 by C.A. Wurtz at the Sorbonne. Over the past quarter century many chemists have
contributed to the development of the aldol reaction into the powerful synthetic tool it is now recognized to be. The interested reader should consult
the original literature describing their work. Prominent among these are:

H.C. Brown, Purdue

D.A. Evans, Harvard
C.H. Heathcock, Berkeley
S. Masamune, MIT
T. Mukaiyama, Tokyo
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Mannich Reaction
The Mannich Reaction
The Mannich reaction is similar to a crossed aldol reaction in that a nucleophilic enol-donor forms a carbon-carbon bond to an electrophilic iminiumacceptor. This assembly is outlined at the top of the following diagram, using a methyl ketone as the enol precursor and an aldehyde iminium
electrophile. Formaldehyde is a commonly used aldehyde reactant, as shown in the example below the mechanism. The Mannich base product is a aminoketone, usually formed as a mineral acid salt. These bases find use as stable precursors of reactive ,-unsaturated carbonyl compounds, as
illustrated in the same example. Eschenmoser's salt is a particularly useful source of formaldehyde for Mannich reactions.

By clicking on the diagram, three additional examples of Mannich reactions will be displayed. The first is a straightforward reaction involving the
kinetically favored enol of a cyclic ketone. The second shows the reaction of Eschenmoser's salt with a preformed lithium enolate. Such reactions
produce the free base directly. In order to effect the -elimination of the amine, it is first converted to a quaternary ammonium salt by methylation.
Subsequent elimination is very rapid. The last example is an unconventional case in which an intramolecular Mannich precursor is generated in situ by
an azaCope rearrangement.
By clicking on the diagram a second time, a remarkable synthesis of the bicyclic aminoketone tropinone will appear above. This double Mannich
sequence is known as the Robinson-Schopf synthesis in honor of the two chemists who first reported it in the first quarter of the 20th century. The
reaction takes place in water under physiological conditions (pH and temperature), and in high yield.
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