Download Chapter 12- Alcohols from Carbonyl Compounds, Redox Reactions

Chapter 12- Alcohols from Carbonyl
Compounds, Redox Reactions and
Organometallic Compounds
Carbonyl Compounds
• Carbonyl Compounds are a broad group of
compounds that include aldehydes, ketones,
carboxylic acids, and esters
• Examples
• We will cover each of this in more detail in
later chapters
• Here, we will only be concerned with how
they can be converted to alcohols.
Structure of the Carbonyl Group
• The carbon-oxygen double consists of a sigma
bond and a pi bond.
• The strongly electronegative oxygen attracts
the electrons of Both the bonds
• This causes both bonds to be polarized
• This leaves the carbon with a substantial
partial positive charge and the oxygen with a
substantial partial negative charge
• We can demonstrate this with resonance
Structures
Structure of the Carbonyl Group
• This substantial partial positive charge leaves the
carbon very electrophilic and susceptible to
nucleophilic attack.
• When the nucleophile attacks the carbonyl carbon
by attacking with its electrons, the double bond to
the oxygen opens, transferring the pi electrons to
the Oxygen
• When this happens, the carbonyl carbon is
transformed from an sp2 , trigonal planar carbon, to
an sp3 , tetrahedral carbon
• Example:
Important Nucleophiles
• Two important nucleophiles that add to
carbonyls are:
– Hydride ions: H- , typically from sodium
borohydride or lithium aluminum hydride; and
– Carbanion like reagents: from organolithium and
grignard reagents
Oxidation-Reduction Reactions
• Another related set of reactions are reactions in
which alcohols and carbonyls are oxidized or
reduced.
• Example
• Reduction reaction: any reaction in which the
number of C-O bonds is decreased and/or the
number of C-H bonds is increased
• Oxidation reaction: any reaction in which the
number of C-O bonds is increased and/or the
number of C-H bonds is decreased
Reduction Examples
• [H] is a generic symbol for a reduction. It is
used to write a general reaction without
specifying what the reducing reagent is.
Oxidation Examples
• Basically the reverse of the reduction examples
• [O] is a generic symbol for an oxidation. It is
used to write a general reaction without
specifying what the oxidizing reagent is.
Synthesis of Alcohols by Reduction of
Carbonyls
• Primary and Secondary alcohols can be
synthesized by the reduction of a variety of
compounds that contain carbonyls
• Carboxylic acids, esters, and aldehydes call all
be reduced to a primary alcohol
• Ketones are reduced to a secondary alcohol
Synthesis of Alcohols by Reduction of
Carbonyls
• Reductions of carboxylic acids are the most
difficult, but they can be reduced with a very
powerful reducing agent, Lithium Aluminum
Hydride, LAH, LiAlH4
• When followed by acid and water, carboxylic
acids are reduced to primary alcohols in
excellent yields
• Example:
Synthesis of Alcohols by Reduction of
Carbonyls
• Esters are also difficult and require LAH.
• Ex
• On an industrial scale, esters are reduced with
hydrogen gas at very high pressure
• Ex
Synthesis of Alcohols by Reduction of
Carbonyls
• Aldehydes and Ketones are much easier to reduce.
• They can be reduced by:
– H2 / M (Pt, Pd, Ni)
– Na in alcohol
– LAH
• The reagent most used, however, is Sodium
Borohydride, NaBH4
• Ex.
Synthesis of Alcohols by Reduction of
Carbonyls
• The key step in the reduction of a carbonyl
compound by either LAH or NaBH4 is the
transfer of a hydride ion from the metal to the
carbonyl carbon.
• Mechanism:
LAH vs NaBH4
• Sodium Borohydride is much less powerful as
a reducing agent than LAH
• While LAH will reduce all carbonyl
compounds, NaBH4 will only reduce
aldehydes and ketones.
• Ex.
Oxidation of Primary Alcohols
• Primary alcohols can be oxidized to both
aldehydes and carboxylic acids
• Ex.
• The oxidation of the aldehyde to the carboxylic
acid is actually easier, thus it is difficult to stop
the oxidation at the aldehyde stage
• Special conditions must be used to prepare
aldehydes from primary alcohols.
Oxidation of Primary Alcohols
• A variety of reagents are available for these
oxidations
• One of the most used is pyridinium
chlorochromate (PCC)
• It is prepared by mixing CrO3 with HCl, then
treating with pyridine
Oxidation of Primary Alcohols
• PCC when dissolved in methylene chloride,
CH2Cl2, will oxidize primary alcohols to an
aldehyde and stop at that stage.
• Ex.
• PCC also does not attack carbon-carbon
double bonds!
Oxidation of Primary Alcohols
• Primary alcohols are easily oxidized to carboxylic
acids by potassium permanganate, (KMnO4)
• The reaction is usually done in a basic, aqueous
solution
• Ex.
Note: 1) Count your carbons!
2) Watch out for reactions with other
functionalities! (alkenes)
Summary
• To get an aldehyde from a primary alcohol,
use PCC in methylene Chloride
• To get a carboxylic acid from a primary
alcohol, use KMnO4 with NaOH/water and
heat, followed by dilute acid.
Oxidation of secondary alcohols to
Ketones
• Secondary alcohols can be oxidized to ketones
• The reaction usually stops at the ketone because
further oxidation would require the breaking of a CC bond
• Example
• Various oxidizing agents based on Chromium IV
have been used for this type of oxidation
• The most common used reagent is Chromic Acid,
H2CrO4
Oxidation of secondary alcohols to
Ketones
• The oxidation of secondary alcohols are
generally carried out in acetone or acetic acid
• Examples
• Note: Chromic acid also oxidizes primary
alcohols to carboxylic acids.
Take Home Quiz
• Show how each of the following
transformations could be accomplished.
Organometallic Compounds
• Compounds that contain carbon-metal bonds
are called organometallic compounds
• The nature of the carbon-metal bond varies
widely, ranging from bonds that are essentially
ionic to those that are primarily covalent
• examples
Organometallic Compounds
• While the organic portion of the
organometallic compound has some effect on
the nature of the C-M bond, but the identity
of the metal is of far greater importance!
• The reactivity of organometallic compounds
increases with the percent ionic character of
the carbon-metal bond
Organometallic Compounds
• Alkyl Sodium and alkyl potassium compounds
are highly reactive and are among the most
powerful bases
• They react explosively with water and burst
into flames when exposed to air
• Organomercury and organolead compounds
are much less reactive and more stable
Organometallic Compounds
• Organometallic compounds of lithium and
magnesium are of great importance in organic
synthesis
• They are relatively stable in ether solutions, but
their carbon-metal bonds have considerable ionic
character
• Due to this ionic character, the carbon atom that is
bonded to the metal of an organolithium or
organomagnesium compound is a strong base and
powerful nucleophile
Preparation of organolithium and
organomagnesium compounds
• Organolithiums are made by reacting alkyl
halides with lithium metal.
• Ex
• Only ether or THF is used as a solvent and
moisture must be avoided!
• Why?
Preparation of organolithium and
organomagnesium compounds
• Order of reactivity:
RI > RBr > RCl
• Flouride are not used.
• Examples:
Preparation of organolithium and
organomagnesium compounds
• Organomagnesium halides are called Grignard
reagents, after the man that discovered them
• They are made by mixing alkyl halides with
magnesium in diethyl ether
• Example:
Preparation of organolithium and
organomagnesium compounds
• Grignard reagents are rarely isolated.
• They are normally used in the same they are
prepared in
• The ether solvent is very important in that it
forms a diether complex with the grignard
reagent that provides its solubility and
stabilizes the reagent.
Reactions of alkyl lithiums and
Grignard reagents
• A) Reactions with compounds that contain
acidic hydrogens
• Alkyl lithiums and grignard reagents are very
strong bases
• They will react with any compound that has a
hydrogen attached to an electronegative atom
such as oxygen, nitrogen, or sulfur
• examples
Reactions of alkyl lithiums and
Grignard reagents
• Not only are these reagents strong bases, they
are also very strong nucleophiles!
• This is very important because it can be used
to make carbon-carbon bonds!
B) Reactions of Grignards with
Oxiranes
• Grignard reagents attack epoxides at the less
substituted carbon.
– Attacks via base catalyzed mechanism
• After adding acid in a second step, we are left
with an alcohol
• Ex.
• Mech.
C) Reactions of Grignard Reagents with
Carbonyl Compounds
• From a synthetic point of view, the most important
reactions of Grignard reagents and organolithium
compounds are those in which these reagents act
as nucleophiles and attack an unsaturated carbon,
especially the carbon of a carbonyl
• We have seen that the carbon of a carbonyl group is
electrophilic and very susceptible to nucleophilic
attack.
• Reaction:
• Mech:
C) Reactions of Grignard Reagents with
Carbonyl Compounds
• Grignard additions to carbonyl compounds are
especially useful because they can be used to
prepared primary, secondary, and tertiary alcohols.
– Grignards + formaldehyde to get primary alcohols
– Grignards + all other aldehydes to get secondary alcohols
– Gignards + ketones to get tertiary alcohols.
– Esters + 2 equivalents of Grignards to get tertiary alcohols
Planning a Grignard Synthesis
• By using the grignard synthesis skillfully, we can
synthesize almost any alcohol we wish
• In planning a gridnard synthesis, we must simply
choose the correct grignard reagent and the correct
aldehyde, ketone, ester or epoxide.
• We do this by examing the alcohol we wish to
prepare and by paying special attention to the
groups attached to the carbon atom baring the –OH
group
Planning a Grignard Synthesis
• Most of the time, there will be more than one
way of carrying out the synthesis
• In those cases, our final choice will probably
be dictated by the starting compounds
available.
Planning a Grignard Synthesis
• Three step process:
1) Locate the carbon attached to the –OH group
2) Examine the other groups bonded to that
carbon
3) Decide which bonds can be made
Note: the C-OH bond used to be the C=O!
Example: Show how to make 3-phenyl-3pentanol using grignard reagents.
Use in a multi-step synthesis
• Problem: Using an alcohol of no more than 4
carbons as your only starting material outline
a synthesis of:
O
Planning a Grignard synthesis
• Reminder: You can also make the bond two
bonds away from the alcohol by using the
appropriate epoxide!
• Example: Synthesis the following starting with
bromobenzene.
O
H
Restrictions on the use of Grignard
Reagents
• Although they are very versatile, they are not
without limitations
• Most limitations arise from the fact that in addition
to being a strong nucleophile, they are also a very
strong base
• It is not possible to prepare a Grignard from an
organic compound that contains an acidic hydrogen
• By acidic Hydrogen, we mean any hydrogen that is
more acidic than the hydrogens on an alkane or
alkene
Restrictions on the use of Grignard
Reagents
• For example, we can not prepare a Grignard
from a compound containing:
-OH, -NH, -SH, -CO2H, -SO3H
• If we tried to do so, when the grignard
formed, it would simply abstract the acidic
hydrogens.
• Note: Remember that protecting groups are
an option for –OH’s!!!
Restrictions on the use of Grignard
Reagents
• Also, since the grignard is a powerful
nucleophile, we cannot prepare them from a
compound that contains a:
Carbonyl, epoxide, nitro, or cyano
• If we were to try, the grignard would only
react with itself!
• Ex.
Restrictions on the use of Grignard
Reagents
• This means that when we prepare grignard
reagents, we are effectively limited to alkyl
halides or to analogous organic halides
containing C-C double bonds, internal triple
bonds, ether linkages, and –NR2 groups
• And remember, when planning to use a
grignard in synthesis, neither the grignard, nor
the Carbonyl compound can have an acidic
hydrogen!
Restrictions on the use of Grignard
Reagents
• Acid/Base reactions will always happen faster
than nucleophilic attack or any other type of
reaction.
• Occasionally, there will be circumstances in
which a chemist will knowingly ignore this rule
and add multiple equivalents of the grignard
reagent
• Example.
Restrictions on the use of Grignard
Reagents
• This occurs when the grignard reagent is
cheap and the electrophile is very expensive!
• This problem can also be overcome with the
use of protecting groups!
• Example
The use of alkyl lithium reagents
• Organolithium reagents react with carbonyl
compounds in the same way as grignard reagents
• This provides another method for preparing
alcohols!
• Example:
• Organolithium reagents have the advantage of
being somewhat more reactive than grignard
reagents.
The Use of Sodium Alkynides
• Sodium alkynides are also considered
organometallic compounds
• They also react with aldehydes and ketones to
yield alcohols.
• Example:
Lithium Dialkylcuprates
• Lithium Dialkylcuprates are a specialty
organometallic compound featured in the CoreyPosner-Whiteside-House synthesis
• The use of lithium dialkylcuprates are a highly
versatile method for the direct synthesis of alkanes
and other hydrocarbons from organic halides
• It does not create a new functional group for use in
further reactions, other than radical halogenations,
but it does provide a method for coupling the alkyl
portions of alkyl halides
Lithium Dialkylcuprates
• Overall reaction:
• The first step in the process is the conversion
of one of the alkyl halides into a lithium
dialkylcuprate (R2CuLi)
• This conversion requires two steps:
– Alkyl halide to alkyl lithium
– Alkyl lithium to lithium dialkylcuprate
Lithium Dialkylcuprates
• Step 1- Alkyl halide to alkyl lithium
– Use the same process we saw earlier
– example
• Step 2- alkyl lithium to lithium dialkylcuprate
– The alkyl lithium is treated with cuprous iodide
(CuI) to form the lithium dialkylcuprate
– example
Lithium Dialkylcuprates
• When the lithium dialkylcuprate complex is
treated with a second alkyl halide, coupling
takes place between one alkyl group of the
dialkylcuprate and the alkyl group of the new
alkyl halide
• Examples:
Lithium Dialkylcuprates
• For the coupling to give a good yield of alkane,
the second alkyl halide added must be a
methyl halide, a primary alkyl halide, or a
secondary cycloalkyl halide
• The alkyl group on the lithium dialkylcuprate
can be methyl, primary, secondary or tertiary.
Lithium Dialkylcuprates
• The two alkyl groups don’t have to be
different
• The overall scheme for the alkane synthesis is:
• Examples