Download The Baylis–Hillman reaction is an organic reaction of an aldehyde

Baylis-Hillman Reaction
The Baylis–Hillman reaction is an organic reaction of an aldehyde and an α,β-unsaturated
electron-withdrawing group catalyzed by DABCO (1,4-diazabicyclo[2.2.2]octane) to give an
allylic alcohol. This reaction is also known as the Morita–Baylis–Hillman reaction or MBH
reaction. It is named for the Japanese chemist Ken-ichi Morita, the British chemist Anthony
B. Baylis and the German chemist Melville E. D. Hillman. The Baylis–Hillman reaction, in
the present day version, is an atom-economic carbon-carbon bond formation reaction.
In addition to DABCO, additional nucleophilic amines such as DMAP(4Dimethylaminopyridine) and DBU(1,8-Diazabicycloundec-7-ene) as well as phosphines have
been found to successfully catalyze this reaction.
Reaction mechanism
The nucleophilic addition of DABCO 2 onto the α,β-unsaturated ketone 1 gives a zwitterionic
intermediate 3, which will add to the electrophilic aldehyde producing the keto-alcohol 4.
Elimination of the DABCO gives the desired allylic alcohol 5.
A simple relationship exists between pKa of the base (as its conjugate acids) and the reaction
rate with quinuclidine even more effective than DABCO. Protic additives like methanol,
triethanolamine, formamide, and water also accelerate the reaction.
Scope
The MBH reaction in general is any reaction of electron deficient alkenes and sp2 hybridized
carbon electrophiles such as aldehydes, ketones and aldimines catalyzed by a nucleophile.
Under special reaction conditions the reaction is also found to extend to alkyl halides as the
electrophilic reagent.
The Baylis–Hillman adducts and their derivatives have been extensively utilized for the
generation of heterocycles and other cyclic frameworks.
Limitations
The MBH reaction of phenyl vinyl ketone with benzaldehyde and DABCO in DMF is not
limited to the monoadduct because the MBH adduct reacts with a second molecule of phenyl
vinyl ketone in a nucleophilic conjugate addition.
For aryl aldehydes under polar, nonpolar, and protic conditions, it has been determined that
the rate-determining step is second-order in aldehyde and first-order in DABCO and acrylate.
Henry Reaction
The Henry Reaction (also referred to as the nitro-aldol reaction) is a classic carbon–carbon
bond formation reaction in organic chemistry. Discovered in 1895 by L. Henry, it is the
combination of a nitroalkane and an aldehyde or ketone in the presence of a base to form βNitro alcohols
The Henry Reaction is a base-catalyzed C-C bond-forming reaction between nitroalkanes and
aldehydes or ketones. It is similar to the Aldol Addition, and also referred to as the Nitro
Aldol Reaction.
If acidic protons are available (i.e. when R = H), the products tend to eliminate water to give
nitroalkenes. Therefore, only small amounts of base should be used if the isolation of the βhydroxy nitro-compounds is desired.
Mechanism of the Henry Reaction
The Henry reaction begins with the deprotonation of the nitroalkane on the α-carbon position
forming a resonance stabilized anion. This is followed by alkylation of the nitroalkane with
the carbonyl containing substrate to form a diastereomeric β-nitro alkoxide. The protonation
of the alkoxide by the previously protonated base will yield the respective β-nitro alcohol as
product.
The Henry reaction is a useful technique in the area organic chemistry due to the synthetic
utility of its corresponding products, as they can be easily converted to other useful synthetic
intermediates. These conversions include subsequent dehydration to yield nitroalkenes,
oxidation of the secondary alcohol to yield α-nitro ketones, or reduction of the nitro group to
yield β-amino alcohols.
Due to a number of factors, including the reversibility of the reaction, as well as the tendency
for easy epimerization of the nitro-substituted carbon atom, the Henry Reaction will typically
produce a mixture of enantiomers or diastereomers. It is for this reason that explanations for
stereoselectivity remain scarce without some modification. In recent years, research focus has
shifted toward modifications of the Henry Reaction to overcome this synthetic challenge.
One of the most frequently employed ways to induce enantio- or diastereoselectivity in the
Henry Reaction has been through the use of chiral metal catalysts in which the nitro group
and carbonyl oxygen coordinate to a metal that is bound to a chiral organic molecule. Some
examples of metals that have been used include Zn, Co, Cu, Mg, and Cr. One of the many
features of the Henry Reaction that makes it synthetically attractive is that it utilizes only a
catalytic amount of base to drive the reaction.
Limitations
One of the main drawbacks of the Henry Reaction is the potential for side reactions
throughout the course of the reaction. Aside from the reversibility of the reaction (RetroHenry) which could prevent the reaction from proceeding, the β-nitro alcohol has the
potential to undergo dehydration, and for sterically hindered substrates it is possible that a
base catalyzed self-condensation (Cannizaro reaction) could occur.
Industrial Application- An enantioselective aldol addition product can be obtained in
asymmetric synthesis by reaction of benzaldehyde with nitromethane and the a catalyst
system consisting of a zinc triflate salt / the base diisopropylethylamine (DIPEA) and as
chiral ligand is the N-methyl derivative of (+)-ephedrine (NME).