The halogenation of alkenes occurs by
anti addition of diatomic halogen (X2) to an alkene through the intermediacy of a
halonium ion in inert solvent. Review halogenation
here.
When this reaction is conducted in hydroxylic solvent
(water, methanol and ethanol, typically), the solvent acts
as the nucleophile to form halohydrins or, in the case of
alcohols, halo ethers. Bromine is used in the
following
examples although chlorine or iodine
may be used as well. The bromonium ion is a rapidly
equilibrating mixture of mirror images (right panel). Water
competes effectively with bromide ion as the nucleophile,
not because it is a better nucleophile but because the
bromide ion is highly solvated by water (less reactive) and
there is much more water than bromide ion present. Water
does an SN2 displacement at the C-Br bond that
leads to a chair cyclohexane in the product. The mirror
image transition states lead to mirror image diaxial
bromohydrins. If water were to attack the bromonium ion at
the alternate C-Br bond, a boat-like cyclohexane would occur
through a transition state that is necessarily higher in
energy than the chair-like transition state. The diaxial
bromohydrins rapidly equilibrate to the more stable
diequatorial conformers as a racemic mixture. When a halohydrin is treated with a
strong base aqueous KOH, methanolic sodium methoxide or
ethanolic sodium ethoxide, proton exchange between the base
and the halohydrin occurs reversibly and faster than
intermolecular SN2 and E2 reactions (see left
panel.) The bromohydrin alkoxide exists in two
conformations: diequatorial and diaxial. While the former
conformation is more populated, it is not suitable for an
intramolecular SN2 reaction because the
equatorial alkoxide cannot reach the rear of the C-Br bond
to accomplish Walden inversion. If this contortional feat
were possible, the epoxide formed would be trans-fused to
the cyclohexane ring, an exceptionally strained ring!
However, the less populated diaxial conformation is
well-suited for rearside displacement to afford a cis-fused,
stable epoxide. The observant student will notice that
the achiral bromonium ion (vide supra) and the
cis-fused epoxides are analogs of one another. They
necessarily both have the configuration R,S. The first
SN2 displacement occurs with water to give
racemic (RR/SS) bromohydrin. The newly installed hydroxyl
group, through the agency of its alkoxide acting as a
nucleophile, inverts the remaining center to the R,S
epoxide. This is an efficient reaction even though
a strained ring is formed. The molar concentration of the
alkoxide and the leaving group are high because they are
proximate to one another with few degrees of freedom for
random motion. Consider the hydroxychlorination of
(E)-2-pentene shown on the right. The racemic
chloronium ion (blue box) can add water at two possible
positions, C2 and C3, leading to the
racemic 3-chloro-2-pentanol or the 2-chloro-3-pentanol.
These structural isomers need not form in equal amounts. The
2-pentanol may be expected to be the predominate product
owing to the less hindered attack of water near the methyl
group as opposed to near the slightly larger ethyl group in
the chloronium ion. There will to equal amounts of each
enantiomer produced and the reaction will only occur by anti
addition of the elements of HOCl. In spite of the formation
of two structurally isomeric chlorohydrins, treatment of the
mixture with base affords a single racemic epoxide. The
ethyl and methyl groups were on opposite sides of the double
bond; they are now on opposite sides of the oxirane ring by
virtue of the double inversion. The R and S convention is used to
designate the absolute stereochemistry of a single
enantiomer. This method can also be used to designate
relative stereochemistry. Consider the enantiomer
(2R,3S)-3-chloro-2-pentanol and its enantiomer
(2S,3R)-3-chloro-2-pentanol. To designate the
racemate and its relative stereochemistry select the carbon
bearing the lowest number assignment (C-2) in theenantiomer
with the R-configuration and assign it as R*. The subsequent
asymmetric carbons follow in kind. Thus, the racemate is
(2R*,3S*)-3-chloro-2-pentanol. The racemic structural
isomer would be (2R*,3S*)-2-chloro-3-pentanol. The
racemic epoxide is designated
(2R*,3R*)-3-ethyl-2-methyloxirane.
When (Z)-2-pentene undergoes the chlorohydrin reaction, there
are likewise two possible racemic chlorohydrins formed, which upon
base treatment, lead to a single, racemic epoxide. The formation of
epoxides by the halohydrin route is stereospecific. Each stereoisomer
of 2-pentene gives a single epoxide. Because there are two
SN2 inversions in going from the alkene to the epoxide,
the (E)-alkene affords the epoxide having the methyl and ethyl
groups on opposite sides of the ring; the (Z)-alkene the same
groups are on the same side of the ring. To see the overall
transformation from another perspective, an oxygen atom has been
added syn to the double bond.
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This transformation is also accomplished through the aegis of a peracid (left, panel a). The peracid transfers an oxygen atom syn to the double bond of a generic (Z)-alkene. The mechanism seems a little busy. The blue arrows account for the transfer of an oxygen to the double bond while the red arrows illustrate the conversion of the peracid to the carboxylic acid. Panel b shows that the peracid serves as a source of an oxygen atom. A simpler understanding of the mechanism (panel c) uses the π-bond of the alkene as a nucleophile to attack oxygen in an "SN2 sense" with the departure of carboxylate anion as the leaving group. The carboxylate anion in turn deprotonates the protonated epoxide. Had an (E)-alkene been employed, the trans-epoxide would have formed. |