Download organometallic reagents

8-7
Organometallic Reagents: Sources of Nucleophilic
Carbon for Alcohol Synthesis
If the carbonyl carbon of an aldehyde or ketone could be attacked
by a nucleophilic carbon atom, R:-, instead of a hydride ion, both
an alcohol and a new carbon-carbon bond would be formed.
The class of compounds called organometallic reagents are
strong bases and good nucleophiles and are useful in this kind of
synthesis.
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Alkyllithium and alkylmagnesium reagents are
prepared from haloalkanes.
Alkyllithium and alkylmagnesium compounds can be prepared
by reaction of alkyl halides with lithium or magnesium in
ethoxyethane (diethylether) or oxacyclopentane (THF).
The order of reactivity of the haloalkane is:
Cl < Br < I
(CH3CH2 )2 O, 0o  10o C
CH3Br + 2 Li  CH3Li + LiBr
Methyl-lithium
Grignard reagents, RMgX, can be formed from primary,
secondary, and tertiary haloalkane, as well as from haloalkenes
and halobenzenes.
Grignard reagents are very sensitive to moisture and air and are
formed in solution and used immediately.
The metal atoms in a Grignard reagent are electron-deficient and
become coordinated to two solvent molecules:
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The alkylmetal bond is strongly polar.
The carbon-lithium bond in CH3Li has about 40% ionic character,
and the carbon-magnesium bond in CH3MgCl has about 35% ionic
character.
The metal atom is strongly electropositive and is at the positive
end of the dipole.
The formation of a Grignard reagent is an example of reverse
polarization. In the haloalkane, the carbon atom attached to the
halogen was electrophilic. In the Grignard reagent, the carbon
atom has become nucleophilic.
The alkyl group in alkylmetals is strongly basic.
Carbanions are the conjugate bases of alkanes (estimated pKa’s of
about 50), and as a result are extremely basic, much more so
than amines or alkoxides.
Because of their basicity, carbanions are extremely sensitive to
moisture or other acidic functional groups.
This reaction is one method which can be used to convert
alkylhalides into alkanes.
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A more direct way of producing an alkane from a haloalkane is by
an SN2 displacement of the halide by a hydride ion from LiAlH4.
NaBH4 is not reactive enough to carry out this displacement.
A deuterium atom can be introduced into an alkane by the
reaction of D2O with an organometallic reagent:
8-8
Organometallic Reagents in the Synthesis of
Alcohols
Useful reactions of organometallic reagents are to react aldehydes
and ketones giving an alcohol containing a new C-C bond.
Reaction with
formaldehyde
produces a
primary
alcohol.
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Aldehydes other than formaldehyde form secondary alcohols.
Ketones react to form tertiary alcohols.
Alkyllithium and Grignard reagents cannot be used to displace
halide ions from haloalkanes as the reaction is too slow.
8-9
Complex Alcohols: An Introduction to
Synthetic Strategy
Mechanisms help in predicting the outcome of a
reaction.
Bromide is a better leaving group than fluoride.
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Example 2: How does a Grignard reagent add to a carbonyl
group?
The negatively polarized alkyl group in the organometallic reagent
attacks the positively polarized carbonyl carbon in the carbonyl
group.
Example 3: What is the product of the radical halogenation of
methylcyclohexane?
The tertiary bond is weaker than a primary or secondary C-H
bond. Br2 is very selective in radical halogenations.
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New reactions lead to new synthetic methods.
We now have several synthetic methods at our disposal:
Each of the products formed by these reactions can be altered by
further chemical reactions leading to more and more complicated
molecules.
Finding suitable starting materials and an efficient synthetic path
to a desired target molecule is a problem called total synthesis.
A successful synthesis is characterized by:
• Brevity
• High overall yield
• Readily available starting materials (commercially available
and inexpensive)
• Reagents should be relatively nontoxic and easy to handle.
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Retrosynthetic analysis simplifies synthesis
problems.
The most frequent synthetic task is building up larger, more
complicated molecules from smaller simple fragments.
The best approach in designing a synthetic route to a desired
product is to work the synthesis backwards on paper.
This approach is called retrosynthetic analysis.
In this approach, strategic C-C bonds in the target molecule are
broken at points where bond formation seems possible.
The reason that retrosynthetic analysis is useful is that fewer
possible reactions need to be considered compared to an analysis
starting with large numbers of possible starting materials and
chemical reactions.
An analogy would be to start at the tip of a branch of a tree and
work backwards to the main trunk. If you started at the trunk and
tried to find a particular branch, you would encounter many dead
end paths and would have to constantly backtrack.
Consider the retrosynthetic analysis of 3-hexanol:
The double-shafted arrow indicates a strategic disconnection.
Two inferior retrosynthetic analyses are:
These strategies are inferior to the first because they do not
simplify the target structure: no C-C bonds are broken.
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Retrosynthetic analysis aids in alcohol construction.
Consider the retrosynthetic analysis of the preparation of
4-ethyl-4-nonanol.
The strategic bonds are around the functional group.
Of the three paths, a,b, and c, is best:
The building blocks are almost equal in size (5 and 6 carbon
fragments), providing the greatest simplification in structure.
The 3-hexanone can also be subjected to retrosynthetic analysis:
The 3-hexanol was subjected to an earlier retrosynthetic analysis.
The complete synthetic scheme will be:
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Watch out for pitfalls in planning syntheses.
Try to minimize the total number of transformations required to
convert the initial starting material into the desired product.
A seven-step synthesis with a yield of 85% at each step gives
an overall efficiency of conversion of 32%.
A four-step synthesis with three yields at 95% and one at
45% gives an overall efficiency of conversion of 39%.
A convergent synthesis of the same number of steps is
preferable to a linear synthesis.
Do not use reagents having functional groups that would
interfere with the desired reaction.
This problem could be overcome by using two equivalents of a
Grignard reagent, or by protecting the hydroxy functionality in
the form of an ether.
Do not try to make a Grignard reagent from a bromoketone. It
will react with its own or another molecule’s ketone group.
It is possible to protect the ketone group in this case.
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Take into account any mechanistic and structural constraints
affecting the reactions under consideration:
• Radical brominations are more selective than chlorinations.
• Remember the structural limitations on nucleophilic
reactions.
• Remember the lack of reactivity of the 2,2-dimethyl-1halopropanes.
• These hindered systems form organometallic reagents and
may be modified in this manner.
• Tertiary haloalkanes do not undergo SN2 reactions, but
eliminate in the presence of bases:
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Important Concepts
1. Alcohols are alkanols (IUPAC) – Names
derived from stem prefixed by alkyl and halo
substituents
Alcohols Have Polar and Short O-H Bond –
2.
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•
•
•
Hydroxy group is hydrophilic (hydrogen bonding)
Unusually high boiling points
Appreciable water solubility
Alkyl part is hydrophobic
3. Alcohols Are Amphoteric –
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•
•
•
Deprotonation by bases whose conjugate acids are
weaker than the alcohol
Protonation yields alkyloxonium ions
Acidity: primary > secondary > tertiary alcohol
Electron-withdrawing substituents increase acidity
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Important Concepts
4. Reverse Polarization – i.e., conversion of the
alkyl group in a haloalkane, Cδ+-Xδ-, into its
nucleophilic analog in an organometallic compound,
Cδ--Mδ+.
5. Aldehyde and Ketone Carbonyl Carbons
are Electrophilic – C=O carbon is subject to attack
by hydride hydrogens or organometallic alkyl groups.
Aqueous workup yields alcohols.
6. Oxidation of Alcohols – Yields aldehydes and
7.
ketones (Chromium IV reagents).
Retrosynthetic Analysis – Identifies efficient
sequence of reactions by identifying strategic bonds.