Download Orbitals

John E. McMurry
http://www.cengage.com/chemistry/mcmurry
Chapter 14
Aldehydes and Ketones:
Nucleophilic Additions Reactions
Richard Morrison • University of Georgia, Athens
Aldehydes and Ketones
Aldehydes (RCHO) and Ketones (R2CO) are among the most widely
occurring of all compounds
• Required by living organisms
•
•
•
Pyridoxal phosphate (PLP) is common coenzyme
Hydrocortisone is steroid hormone secreted by adrenal glands
Solvents and starting materials in chemical industry
•
•
1.9 million tons of formaldehyde, H2C=O, produced each year for insulation
materials and resins
1.5 million tons of acetone, ((CH3)2C=O), produced each year for use as
industrial solvent
14.1 Naming Aldehydes and Ketones
Aldehydes named by replacing terminal –e of corresponding
alkane name with –al
• Parent chain must contain the –CHO group
•
See Appendix A and Table A.2 for naming polyfunctional
organic compounds containing an aldehyde
• – CHO carbon is numbered as C1
Naming Aldehydes and Ketones
Carbaldehyde suffix is used for cyclic aldehydes
Naming Aldehydes and Ketones
Naming Aldehydes and Ketones
Ketones named by replacing terminal –e of corresponding
alkane name with –one
• Parent chain is longest chain containing ketone group
• Numbering begins at end of chain nearer the carbonyl
carbon
Naming Aldehydes and Ketones
Some common names accepted by IUPAC
Naming Aldehydes and Ketones
If R-C=O is a substituent the name acyl (a-sil) group is used and name
ending –yl is attached
The prefix oxo- is used if ketone is not highest priority functional group and
the carbonyl is considered a substituent on the parent chain
•
See Appendix A and Table A.2 for naming polyfunctional
organic compounds containing a ketone
What is the IUPAC name of the following
compound?
a. 3-methyl-3-phenylpropanol
b. 3-phenylbutanal
c. 3-phenyl-1-butanone
d. 3-phenylbutanoic acid
What is the IUPAC name of the following
compound?
a. 4-phenylhexan-3-one
b. 3-phenylhexan-4-one
c. 1,2-diethyl-2-phenylethanal
d. 1-methyl-1-phenylbutan-2-one
14.2 Preparing Aldehydes and Ketones
Aldehydes from oxidation of primary alcohols using the DessMartin periodinane reagent
Preparing Aldehydes and Ketones
Aldehydes from reduction of carboxylic esters using
diisobutylaluminum hydride (DIBAH)
Preparing Aldehydes and Ketones
Secondary alcohols are oxidized by variety of chromium-based
reagents to give ketones
Aryl ketones from Friedel-Crafts acylation reactions
Preparing Aldehydes and Ketones
• Ketones are also prepared from carboxylic acid derivatives
14.3 Oxidation of Aldehydes
Aldehydes easily oxidized to carboxylic acids but ketones are
relatively inert toward oxidation
• –CHO hydrogen abstracted during oxidation
• CrO3 most common oxidizing agent
• KMnO4 and hot HNO3 occasionally used
Oxidation of Aldehydes
Oxidation of aldehydes proceeds through intermediate 1,1-diols
called hydrates
• Hydrates formed by reversible nucleophilic addition of water
to carbonyl group (section 14.5)
14.4 Nucleophilic Addition Reactions of
Aldehydes and Ketones
Nucleophilic addition
reaction
•
•
•
•
:Nu– approaches C=O bond at
75° angle and adds to
electrophilic C=O carbon
Carbonyl carbon rehybridizes
to sp3
Electron pair moves from C=O
bond to electronegative
oxygen atom producing
tetrahedral alkoxide ion
intermediate
Intermediate is protonated to
give neutral alcohol product
Nucleophilic Addition Reactions of Aldehydes
and Ketones
Nucleophiles can be either negatively charged (:Nu-) or neutral
(:Nu)
• If neutral, the nucleophile usually carries a hydrogen atom
that can be subsequently eliminated
Nucleophilic Addition Reactions of Aldehydes
and Ketones
Two products can arise from the tetrahedral alkoxide ion
intermediate
• Protonation by water or acid gives an alcohol
• The carbonyl oxygen atom can be protonated and then
eliminated as HO- or H2O to give a product with a C=Nu
double bond
Nucleophilic Addition Reactions of Aldehydes
and Ketones
Aldehydes more reactive toward nucleophilic addition than
ketones
• Aldehydes (a) are less sterically hindered than ketones (b)
Nucleophilic Addition Reactions of Aldehydes
and Ketones
• Aldehydes are more reactive than ketones due to electronic
factors
•
C=O of aldehyde more polarized than C=O of ketone
Nucleophilic Addition Reactions of Aldehydes
and Ketones
• Aromatic aldehydes are less reactive in nucleophilic addition
reactions than aliphatic aldehydes because the electrondonating resonance effect of the aromatic ring makes the
carbonyl group less electrophilic
14.5 Nucleophilic Addition of H2O: Hydration
Aldehydes and ketones react reversibly with water to give 1,1diols, or geminal (gem) diols
• Equilibrium favors carbonyl compound for steric reasons with
the exception of formaldehyde
Nucleophilic Addition of H2O: Hydration
Nucleophilic addition of water to aldehyde or ketone is slow
under neutral conditions but catalyzed by both acid and
base
• Base-catalyzed hydration mechanism
•
Hydroxide ion is good nucleophile
Nucleophilic Addition of H2O: Hydration
• Acid-catalyzed mechanism
• Protonated carbonyl oxygen is a better
electrophile
Nucleophilic Addition of H2O: Hydration
In general, equilibrium favors the carbonyl-containing aldehyde
or ketone reactant for nucleophiles such as H2O, CH3OH,
HCl, HBr, or H2SO4
Many nucleophilic addition reactions of
aldehydes and ketones are catalyzed by acid
or base. Bases catalyze hydration by:
a. making the carbonyl group more
electrophilic
b. shifting the equilibrium of the reaction
c. making the carbonyl group less electrophilic
d. converting the water to hydroxide ion, a
much better nucleophile
14.6 Nucleophilic Addition of Grignard and
Hydride Reagents: Alcohol Formation
Grignard reagent reacts with aldehyde or ketone C=O to give
tetrahedral magnesium alkoxide intermediate
Intermediate is hydrolyzed to produce neutral alcohol
Grignard reagent reacts like a carbon anion, or carbanion
• Reaction mechanism involves radicals but can be
represented as proceeding through a nucleophilic addition of
a carbanion to the C=O carbon
Nucleophilic Addition of Grignard and Hydride
Reagents: Alcohol Formation
Mechanism of Grignard
Reaction
Nucleophilic Addition of Grignard and Hydride
Reagents: Alcohol Formation
In an analogous manner the reaction of aldehydes and
ketones with hydride reagents may be represented as
proceeding through a nucleophilic addition of a hydride ion
(:H–) to the C=O carbon
• LiAlH4 and NaBH4 act as if they are donors of hydride ion
14.7 Nucleophilic Addition of Amines: Imine
and Enamine Formation
Primary amines, RNH2, add to aldehydes and ketones to yield
imines, R2C=NR
Secondary amines, R2NH, add similarly to yield enamines,
R2N-CR=CR2
Nucleophilic Addition of Amines: Imine and
Enamine Formation
Imines are common biological intermediates where they are
often called Schiff bases
Nucleophilic Addition of Amines: Imine and
Enamine Formation
Mechanism of imine formation
•
•
Nucleophilic addition of primary
amine to give carbinolamine
tetrahedral intermediate
Elimination of water to form new
C=Nu bond
Nucleophilic Addition of Amines: Imine and
Enamine Formation
Mechanism of enamine formation:
•
•
•
Nucleophilic addition of secondary
amine to give carbinolamine
tetrahedral intermediate
Elimination of water yields iminium
ion
Loss of proton from a-carbon atom
yields enamine
Nucleophilic Addition of Amines: Imine and
Enamine Formation
Imine and enamine formations reach maximum rate
around pH = 4 to 5
• Slow at pH > 5 because there is insufficient H+ present in
solution to protonate intermediate carbinolamine –OH to
yield the better leaving group –OH2+
• Slow at pH < 4 because the basic amine nucleophile is
protonated and initial nucleophilic addition cannot occur
Worked Example 14.1
Predicting the Product of Reaction between a
Ketone and an Amine
Show the products you would obtain by acid-catalyzed
reaction of pentan-3-one with methylamine, CH3NH2,
and with dimethylamine, (CH3)2NH
Worked Example 14.1
Predicting the Product of Reaction between a
Ketone and an Amine
Strategy
• An aldehyde or ketone reacts with a primary amine, RNH2, to
yield an imine, in which the carbonyl oxygen atom has been
replaced by the =N-R group of the amine
• Reaction of the same aldehyde or ketone with a secondary
amine, R2NH, yields an enamine, in which the oxygen atom
has been replaced by the –NR2 group of the amine and the
double bond has moved to a position between the former
carbonyl carbon and the neighboring carbon
Worked Example 14.1
Predicting the Product of Reaction between a
Ketone and an Amine
14.8 Nucleophilic Addition of Alcohols:
Acetal Formation
Aldehydes and ketones react reversibly with two equivalents of an alcohol in
the presence of an acid catalyst to yield acetals, R2C(OR′)2, sometimes
called ketals if derived from a ketone
Nucleophilic Addition of Alcohols: Acetal
Formation
Mechanism of acetal
formation:
•
Acetal formation is acidcatalyzed
• Reversible nucleophilic
addition of alcohol to the
carbonyl group yields a
hemiacetal
•
•
Hemiacetal is a hydroxy
ether analogous to gem diol
formed by water addition
Acid catalyst protonates
hydroxyl group forming better
leaving group, –OH2+
Nucleophilic Addition of Alcohols: Acetal
Formation
Mechanism of acetal
formation:
Loss of –OH2+ leads to
an oxonium ion,
R2C=OR+
• Nucleophilic addition of
second alcohol gives
protonated acetal
• Deprotonation of
protonated acetal yields
neutral acetal
•
Nucleophilic Addition of Alcohols: Acetal
Formation
One equivalent of diol such as ethylene glycol yields a cyclic
acetal
• Cyclic acetals are protecting groups for aldehydes and
ketones
Nucleophilic Addition of Alcohols: Acetal
Formation
Reduction of the ester group of ethyl 4-oxopentanoate is
complicated by the presence of the ketone group
Protection of the ketone group as a cyclic acetal allows the ester
group to be selectively reduced
Nucleophilic Addition of Alcohols: Acetal
Formation
Acetal and hemiacetal groups are common in carbohydrate
chemistry
• Glucose, a polyhydroxy aldehyde, undergoes intramolecular
nucleophilic addition
• Exists primarily as a cyclic hemiacetal
Worked Example 14.2
Predicting the Product of Reaction between a
Ketone and an Alcohol
Show the structure of the acetal you would obtain by
acid-catalyzed reaction of pentan-2-one with
propane-1,3-diol
Worked Example 14.2
Predicting the Product of Reaction between a
Ketone and an Alcohol
Strategy
• Acid-catalyzed reaction of an aldehyde or ketone
with 2 equivalents of a monoalcohol or 1 equivalent
of a diol yields an acetal, in which the carbonyl
oxygen atom is replaced by two –OR groups from
the alcohol
Worked Example 14.2
Predicting the Product of Reaction between a
Ketone and an Alcohol
Solution
The substance formed on addition of
water to an aldehyde or ketone is
called a hydrate or a:
a.
b.
c.
d.
vicinal diol
geminal diol
acetal
ketal
Ch. 14.5
Many nucleophilic addition reactions
of aldehydes and ketones are
catalyzed by acid or base. Bases
catalyze hydration by:
Ch. 14.5
a. making the carbonyl group more
electrophilic
b. shifting the equilibrium of the reaction
c. making the carbonyl group less electrophilic
d. converting the water to hydroxide ion, a
much better nucleophile
The reaction of an aldehyde with hydrogen
cyanide is an example of ________ reaction.
a.
b.
c.
d.
a nucleophilic substitution
an electrophilic addition
an electrophilic substitution
a nucleophilic addition
Ch. 14.4
The product of this reaction is called:
a.
b.
c.
d.
an ylide
an acetal
a gem diol
a hydrate
Ch. 14.8
The Nucleophile in this reaction is:
A
b. B
c. C
d. D
a.
© 2006 Thomson Higher Education
The catalyst in this reaction is :
a. A
b. B
c. C
d. D
© 2006 Thomson Higher Education
Choose the BEST reagent for carrying out each
of the following conversions.
A. LiAlH4, THF
B. NaBH4, ethanol
C. 1. DIBAH, toluene
2. H3O+
D. All of the above work well
14.9 Nucleophilic Addition of Phosphorus Ylides:
The Wittig Reaction
Wittig reaction
• Converts aldehydes and ketones into alkenes
• Phosphorus ylide, R2C–P(C6H5)3, adds to aldehyde or
+
ketone to yield dipolar, alkoxide ion intermediate
•
Ylide (pronounced ill-id) is a neutral, dipolar compound with
adjacent positive and negative charges
• Also called a phosphorane and written in the resonance form
R2C=P(C6H5)3
• Dipolar intermediate spontaneously decomposes through a
four-membered ring to yield alkene and triphenylphosphine
oxide, (Ph)3P=O
• Wittig reaction results in replacement of carbonyl oxygen
with R2C= group of original phosphorane
Nucleophilic Addition of Phosphorus Ylides:
The Wittig Reaction
Wittig reaction mechanism
Nucleophilic Addition of Phosphorus Ylides:
The Wittig Reaction
• Phosphorus ylides are prepared by SN2 reaction of
primary and some secondary alkyl halides with
triphenylphosphine, (Ph)3P, followed by treatment with
base
Nucleophilic Addition of Phosphorus Ylides:
The Wittig Reaction
Wittig reaction yields a single, pure alkene of defined
structure
• Grignard reaction yields two products
• Most-substituted double bond is the major product
• Wittig reaction yields only one product
• Less-substituted double bond is the sole product
Nucleophilic Addition of Phosphorus Ylides:
The Wittig Reaction
Wittig reactions used commercially to synthesize numerous
pharmaceuticals
Worked Example 14.3
Synthesizing an Alkene Using a Wittig Reaction
What carbonyl compound and what phosphorus ylide
might you use to prepare 3-ethylpent-2-ene?
Worked Example 14.3
Synthesizing an Alkene Using a Wittig Reaction
Strategy
• An aldehyde or ketone reacts with a phosphorus ylide to
yield an alkene in which the oxygen atom of the carbonyl
reactant is replaced by the =CR2 of the ylide
• Preparation of the phosphorus ylide itself usually involves
SN2 reaction of a primary alkyl halide with
triphenylphosphine, so the ylide is typically primary,
RCH=P(Ph)3
• Disubstituted alkene carbon in product comes from carbonyl
reactant, while the monosubstituted alkene carbon comes
from the ylide
Worked Example 14.3
Synthesizing an Alkene Using a Wittig Reaction
Solution
Choose the BEST reagent for
carrying out each of the following
conversions
A. 1. PhMgBr, ether
B. 1. PhCH2MgBr, ether
2. H3O+
C. (C6H5)3P=CHC6H5, THF
D. Li(C6H5)2Cu, ether
14.10 Biological Reductions
Nucleophilic addition reactions are characteristic of aldehydes
and ketones
• Tetrahedral intermediate produced by addition of nucleophile
cannot expel a stable leaving group
Biological Reductions
Cannizzaro reaction is a nucleophilic acyl substitution reaction
of aldehydes and ketones
•
•
•
OH¯ adds to aldehyde to give tetrahedral intermediate
H:¯ ion is transferred to a second aldehyde
The aldehyde accepting the H:¯ ion is reduced and the aldehyde
transferring the H:¯ is oxidized
Biological Reductions
Cannizzaro reaction mechanism is analogous to biological reduction
in living organisms by nicotinamide adenine dinucleotide, NADH
•
NADH donates H:¯ to aldehydes and ketones, similar to tetrahedral
alkoxide intermediate in Cannizzaro reaction
Choose the BEST reagent for
carrying out each of the following
conversions
A. NaBH4, ethanol, H3O+
B. 1. LiAlH4, ether
2. H3O+
C. NaOH, H2O
D. All of the above
Ch. 14.10
14.11 Conjugate Nucleophilic Addition to α,βUnsaturated Aldehydes and Ketones
Nucleophiles can add directly to carbonyl group of aldehydes
and ketones, called 1,2-addition
Nucleophiles can also add to conjugated C=C bond adjacent
to carbonyl group of aldehydes and ketones, called
conjugate addition or 1,4- addition
• Carbon atom adjacent to carbonyl carbon is the a carbon
atom and the next one is the b carbon atom
• Initial product of conjugate addition is a resonance-stabilized
enolate ion
Conjugate Nucleophilic Addition to α,βUnsaturated Aldehydes and Ketones
Comparison of direct and conjugate additions
Conjugate Nucleophilic Addition to α,βUnsaturated Aldehydes and Ketones
Conjugate addition occurs because the nucleophile can add to
either one of two electrophilic carbons of the a,b-unsaturated
aldehyde or ketone
Conjugate Nucleophilic Addition to α,βUnsaturated Aldehydes and Ketones
Conjugated double bond of a,b-unsaturated carbonyl is
activated by carbonyl group of the aldehyde or ketone
• C=C double bond is not activated for addition in absence of
carbonyl group
Conjugate Nucleophilic Addition to α,βUnsaturated Aldehydes and Ketones
Primary and secondary amines add to a,b-unsaturated
aldehydes and ketones to yield b-amino aldehydes and
ketones
•
Both 1,2- and 1,4-addition occur
• Additions are reversible
• More stable conjugate addition product accumulates
Conjugate Nucleophilic Addition to α,βUnsaturated Aldehydes and Ketones
Related biological addition of water to an a,b-unsaturated
carboxylic acid in citric acid cycle
•
Cis-aconitate is converted to isocitrate
Conjugate Nucleophilic Addition to α,βUnsaturated Aldehydes and Ketones
Conjugate addition of an alkyl or other organic group to an a,bunsaturated ketone (but not aldehyde) is a useful 1,4addition reaction
Conjugate Nucleophilic Addition to α,βUnsaturated Aldehydes and Ketones
Conjugate addition of alkyl groups to an a,b-unsaturated
ketone (not aldehyde) is accomplished with a lithium
diorganocopper reagent, R2CuLi (Gilman reagent)
•
Lithium diorganocopper reagent is prepared by reaction of 1
equivalent of copper(I) iodide and 2 equivalents of an
organolithium reagent, RLi
• Organolithium reagent is prepared by reaction of lithium metal with
an organohalide
Conjugate Nucleophilic Addition to α,βUnsaturated Aldehydes and Ketones
Primary, secondary, and even tertiary alkyl groups undergo
conjugate addition
•
Alkynyl groups react poorly
• Grignard reagents and organolithium reagents normally give direct
carbonyl addition to a,b-unsaturated ketones
Conjugate Nucleophilic Addition to α,βUnsaturated Aldehydes and Ketones
Mechanism of conjugate addition is thought to involve
nucleophilic addition of the diorganocopper anion, R2Cu• R2Cu- adds to the unsaturated ketone to give coppercontaining intermediate
• R group is transferred from copper to carbon
• Subsequent elimination of a neutral copper species gives
product
Worked Example 14.4
Using a Conjugate Addition Reaction
How might you use a conjugate addition reaction to
prepare 2-methyl-3-propylcyclopentanone?
Worked Example 14.4
Using a Conjugate Addition Reaction
Strategy
•
•
A ketone with a substituent group in its b position
might be prepared by a conjugate addition of that
group to an a,b-unsaturated ketone
Propyl substituent on the b carbon might be
prepared from 2-methylcyclopenten-2-one by
reaction with lithium dipropylcopper
Worked Example 14.4
Using a Conjugate Addition Reaction
Solution
This reaction is called a _________ reaction.
a.
b.
c.
d.
conjugate addition.
electrophilic addition.
direct addition
1,2-addition.
Ch. 14.11
Choose the BEST reagent for carrying out
each of the following conversions
A. NaBH4, ethanol
B. 1. LiAlH4, ether
2. H3O+
C. HCHO, NaOH, H2O
D. All of the above
Ch. 14.10
14.12 Spectroscopy of Aldehydes and Ketones
• C=O bond absorption in IR
region from 1660 to 1770
cm-1 is diagnostic of the
nature of the carbonyl group
• Aldehydes show two
characteristic C-H
absorptions in the range
2720 to 2820 cm-1
Spectroscopy of Aldehydes and Ketones
Spectroscopy of Aldehydes and Ketones
Aldehyde protons (RCHO) absorb near 10 d in the 1H NMR
• Aldehyde proton shows spin-spin coupling with protons on
the neighboring carbon, with coupling constant J ≈ 3 Hz
• Hydrogens on carbon next to a carbonyl group are slightly
deshielded and absorb near to 2.0 to 2.3 d
Spectroscopy of Aldehydes and Ketones
Carbonyl-group carbon atoms of aldehydes and ketones have
characteristic 13C NMR resonances in the range of 190 to
215 d
Spectroscopy of Aldehydes and Ketones
• Aldehydes and ketones with (g) carbon atoms undergo
McLafferty rearrangement
• Aldehydes and ketones also fragment by a cleavage
Spectroscopy of Aldehydes and Ketones