Chemistry Reference
In-Depth Information
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C-H Activation
Much of organic chemistry is based on the manipulation of reactive functional groups, and much of organic
synthesis is about introducing, exploiting and removing these groups, or protecting them when their reactivity
becomes a liability. With very few exemptions, all organic compounds have C-H bonds, but these are rarely
used in organic synthesis unless activated in some way by a nearby functional group. Carbonyl groups, and
other electron-withdrawing groups activate the
-protons towards bases, while alkenes activate the allylic
protons to radical abstraction. Similarly, many of the reactions mediated by transition metals involve functional
groups, such as organic halides or alkenes. C-H activation involves the formation of a carbon-transition-metal
bond, most often a carbon-metal single bond, from a carbon-hydrogen bond.
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The carbon-metal bond can
then be employed in bond-forming reactions with other molecules or functional groups, or even by reaction
with a second carbon-hydrogen bond. The term C-H activation should be reserved for reactions that are
initiated by the breaking of the C-H bond by the metal complex. Reactions, such as the Heck reaction
(Chapter 5), in which the C-H bond is broken late in the mechanism are not considered within this topic.
Efforts at C-H activation can be divided into three broad categories. The first involves C-H bonds of
arenes, heteroarenes and comparable alkenes. In many cases, the formation of the carbon-metal bond may
be viewed as an electrophilic substitution reaction (Scheme 3.1), following the same pathway as metallation
by main-group metals such as mercury, thallium and lead, as well as classical reactions such as bromination
and nitration. This is not, however, always the case.
The second category is C-H functionalization in the allylic position. It is based upon coordination of the
alkene to the metal to form an
2
-complex, followed by oxidative addition to the allylic C-H bond to produce
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-allyl complex (Scheme 3.2).
The third category is the most challenging: C-H activation at an unfunctionalized position, especially at
sp
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-hybridized carbon atoms (Scheme 3.3). Clearly, most organic molecules have a large number of such C-H
bonds. The problem is regioselectivity. The solution is coordination. A metal complex becomes coordinated
to a functional group, Y, often nitrogen or oxygen containing, in the molecule, and is directed to a nearby C-H
bond. The formation of the metal-carbon bond can be through oxidative addition, followed by loss of HX by
reductive elimination, or by sigma-bond metathesis. This mechanism can also operate in aromatic molecules.
A functional group capable of coordinating a metal complex can direct oxidative addition to an
ortho
C-H
bond. A carbonyl or carboxylic group is often involved. Such complexes, including the manganese complex
3.2
, have been isolated
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an
and can undergo further reactions (Scheme 3.4).
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