Industrial Organic Chemistry

Chapter 19.

Aldehydes and Ketones:

Nucleophilic Addition Reactions

Instructor: Prof. Junhwan Choi

 Introduction
• Aldehydes (RCHO) and ketones (R2CO) are among the most widely occurring
of all compounds.
• Formaldehyde (H2C=O): use in building insulation and the adhesive resins.
• Acetone ((CH3)2C=O): widely used as an industrial solvent.
• Formaldehyde is synthesized industrially by catalytic oxidation of methanol and
acetone preparation involves oxidation of 2-propanol.
 19-1. Naming Aldehydes and Ketones
• Aldehydes: named by replacing the terminal –e with –al.
• The parent chain must contain the –CHO group (–CHO carbon: carbon 1).
• The longest chain in 2-ethyl-4-methylpentanal is a hexane, but is not parent
because it does not include –CHO group.

• –CHO group is directly attached to a ring: –carbaldehyde.

 19-1. Naming Aldehydes and Ketones
• A few simple and well-known aldehydes have common names.
 19-1. Naming Aldehydes and Ketones
• Ketones: named by replacing the terminal –e with –one.
• The parent chain is the longest one that includes the ketone group.
• The numbering begins at the end nearer the carbonyl carbon.

• A few ketones have their common names.

 19-1. Naming Aldehydes and Ketones
• When it is necessary to refer to the , the name acyl
group is used and the name ending –yl is attached.
• 3 is an acetyl formyl COAr is an aroyl group

6H5 is a benzoyl group.

• If the double-bonded oxygen is considered as a substituent on a parent chain,

the prefix oxo- is used.
 19-2. Preparing Aldehydes and Ketones
Preparing Aldehydes
• Aldehyde synthesis: by oxidation of primary alcohols using Dess-Martin
periodinane reagent.

• Certain carboxylic acid derivatives (ex. esters) can be partially reduced to yield
aldehydes (Chapter 21).
 19-2. Preparing Aldehydes and Ketones
Preparing Ketones
• Secondary alcohols are oxidized to give ketones.
• Either Dess-Martin periodinane or Cr (VI) reagents such as CrO3 can be used.

• The ozonolysis of alkenes can yield ketones in which one of the unsaturated
carbon atoms is disubstituted.
 19-2. Preparing Aldehydes and Ketones
• Friedel-Crafts acylation of an aromatic ring (with an acid chloride in the
presence of AlCl3) can also yield ketones.

• Just as aldehydes can, ketones can also be prepared from certain carboxylic
acid derivatives between an acid chloride and a lithium diorganocopper reagent
(Chapter 21).
 19-3. Oxidation of Aldehydes and Ketones
• Aldehydes are easily oxidized to yield carboxylic acids, but ketones are
generally inert toward oxidation.
• Structural difference: aldehydes have a –CHO proton (abstracted during
oxidation), but ketones do not.

• CrO3 is the most common oxidizing agents for aldehyde oxidation, to yield
carboxylic acid.
 19-3. Oxidation of Aldehydes and Ketones
• Aldehyde oxidations occur through intermediate (1,1-diols or hydrates) which
are formed by a reversible nucleophilic addition of water to carbonyl group.
• The hydrate is oxidized to a carboxylic acid.

• Ketones can undergo a slow cleavage reaction

carbonyl group when treated with hot alkaline KMnO4 (not often used).
19-4. Nucleophilic Addition Reactions of Aldehydes and Ketones
• Most general reaction of aldehydes & ketones: nucleophilic addition reaction.

• A nucleophile, :Nu approaches the carbonyl group

from an angle of ~75° opposite the carbonyl oxygen
and forms a bond to the electrophilic C=O carbon.
• Rehybridization of the carbonyl carbon (from sp2
to sp3) occurs.
• An electron pair from the C=O bond moves toward
the electronegative oxygen atom and a
tetrahedral alkoxide ion intermediate is produced.
• Protonation of the alkoxide by addition of acid
then gives an alcohol.
19-4. Nucleophilic Addition Reactions of Aldehydes and Ketones
• The nucleophile in nucleophilic addition reactions can be either negatively
charged (:Nu ) or neutral (:Nu).
• If it is neutral (:Nu), it carries a hydrogen atom that can subsequently be
eliminated
19-4. Nucleophilic Addition Reactions of Aldehydes and Ketones
• Two general variation after forming alkoxide ion intermediate.
(1) The tetrahedral intermediate is protonated by water or acid to give an
alcohol as the final product.
(2) The carbonyl oxygen atom is protonated and then eliminated as HO or
H2O to give a product with a C=Nu double bond.
19-4. Nucleophilic Addition Reactions of Aldehydes and Ketones
• Aldehydes are generally more reactive than ketones in nucleophilic addition
reactions: (1) steric reason, (2) electronic reason.
• Sterically, there is only one large substituent bonded to the C=O carbon in an
aldehyde vs. two large substituents in a ketone.
• This means that a nucleophile is able to approach an aldehyde more readily.

An aldehyde A ketone
19-4. Nucleophilic Addition Reactions of Aldehydes and Ketones
• Electronic reason: greater polarization of aldehyde carbonyl groups.
• A primary carbocation is more reactive (less stable) than a secondary one.
• Similarly, alkyl group in carbonyl compound can inductively stabilize the
partial positive charge on the carbonyl carbon.
• An aldehyde has only one alkyl group, which makes carbonyl carbon more
electrophilic and therefore, more reactive than a ketone.
19-4. Nucleophilic Addition Reactions of Aldehydes and Ketones
• Aromatic aldehydes are less reactive than aliphatic aldehydes in nucleophilic
addition reactions: the electron-donating resonance effect of the aromatic ring
makes the carbonyl group less electrophilic.
19-4. Nucleophilic Addition Reactions of Aldehydes and Ketones
• Example: Treatment of an aldehyde or ketone with cyanide ion (
by protonation of the tetrahedral alkoxide ion intermediate, gives a cyanohydrin.
Show the structure of the cyanohydrin obtained from cyclohexanone.

• Adding a nucleophile to the carbonyl carbon gives a tetrahedral alkoxide ion

intermediate.
• The protonation of the tetrahedral intermediate (or subsequent elimination of
carbonyl oxygen) gives the final product.
19-4. Nucleophilic Addition Reactions of Aldehydes and Ketones
• Example: Treatment of an aldehyde or ketone with cyanide ion (
by protonation of the tetrahedral alkoxide ion intermediate, gives a cyanohydrin.
Show the structure of the cyanohydrin obtained from cyclohexanone.
 19-5. Nucleophilic Addition of H2O: Hydration
• Aldehydes and ketones react with water to yield 1,1-diols, or geminal (gem) diols.

• The hydration reaction is reversible: the position of the equilibrium depends on

the structure of the carbonyl compound.
• Equilibrium generally favors the carbonyl compound for steric reason, but
the gem diol is favored for a few simple aldehydes.

• The hydration is slow under neutral conditions but is catalyzed by base and acid.
 19-5. Nucleophilic Addition of H2O: Hydration
• Under basic conditions, the nucleophile
is negatively charge (OH ) and it forms
a bond to the electrophilic carbon.
• The C=O carbon rehybridizes from sp2
to sp3 and two electrons from the C=O
bond are pushed onto the oxygen,
giving alkoxide ion.
• Protonation of the alkoxide ion by
water yields a neutral addition product
(gem diol) (+ regenerated OH ).
 19-5. Nucleophilic Addition of H2O: Hydration
• Under acidic conditions, the carbonyl
oxygen atom is first protonated by H3O+ to
make the carbonyl carbon more electrophilic.
• A neutral nucleophile, H2O forms a bond to
the carbon and two electrons from the C=O
bond move onto the oxygen.
• The positive charge on oxygen is neutralized,
while the nucleophile gains a positive
charge.
• Deprotonation by water gives the neutral
addition product (gem diol) (+ regenerated
H3O+ catalyst).
 19-5. Nucleophilic Addition of H2O: Hydration
• Base-catalyzed hydration vs. acid-catalyzed hydration.
• The base-catalyzed reaction: water is converted into hydroxide ion, a much
better nucleophile.
• The acid-catalyzed reaction: carbonyl compound is converted into a much
better electrophile (by protonation).
• The hydration reaction happens when an aldehyde or ketone is treated with a
( and can stabilize a negative
charge such as oxygen, halogen or sulfur).

• Such nucleophilic addition is reversible with the equilibrium generally

favoring the carbonyl reactant (rather than the tetrahedral addition product).
 19-5. Nucleophilic Addition of H2O: Hydration
• Example: When dissolved in water, trichloroacetaldehyde exists primarily as its
hydrate, called chloral hydrate. Show the structure of chloral hydrate.

• Aldehydes can undergo nucleophilic addition reaction with H2O.

• Addition of nucleophile onto carbonyl carbon gives alkoxide ion.
• Protonation of alkoxide ion yields a neutral addition product (gem diol).
 19-5. Nucleophilic Addition of H2O: Hydration
• Example: When dissolved in water, trichloroacetaldehyde exists primarily as its
hydrate, called chloral hydrate. Show the structure of chloral hydrate.
19-6. Nucleophilic Addition of HCN: Cyanohydrin Formation
• Aldehydes and unhindered ketones undergo a nucleophilic addition reaction
with HCN to yield .
• Reaction occurs slowly when pure HCN is used, but rapidly when a small
amount of base is added to generate the nucleophilic cyanide ion, CN .
• Addition of CN yields a tetrahedral intermediate that is protonated by HCN to
give cyanohydrin (+ regenerated CN ).
19-6. Nucleophilic Addition of HCN: Cyanohydrin Formation
• Protic acids such as H2O, HBr, HCl and H2SO4 do not normally yield carbonyl
addition products because the equilibrium constants are unfavored.
• However, with HCN, equilibrium favors the cyanohydrin adduct.
• Cyanohydrin is useful because of further chemistry
reduced to yield a primary amine or can be hydrolyzed to yield a carboxylic acid.
19-7. Nucleophilic Addition of Hydride and Grignard Reagents
Addition of Hydride Reagents: Reduction
• Aldehydes are reduced to give primary alcohols and ketones are reduced to
give secondary alcohols (Chapter 17).

• NaBH4 and LiAlH4 act as donors of hydride ion nucleophile (:H ) and the
initially formed alkoxide ion intermediate is then protonated by acid.
19-7. Nucleophilic Addition of Hydride and Grignard Reagents
Addition of Grignard Reagents, RMgX
• Aldehydes give secondary alcohols with Grignard reagents and ketones give
tertiary alcohols.
19-7. Nucleophilic Addition of Hydride and Grignard Reagents
• An acid-base complexation of
Mg2+ makes the carbonyl carbon
a better electrophile.
• Nucleophilic addition of R:
produces a tetrahedral
magnesium alkoxide
intermediate.
• Protonation by water or acid
yields the neutral alcohol.
 19-8. Nucleophilic Addition of Amines
• Primary amines, RNH2, add to aldehydes and ketones to yield imines, R2C=NR.
• Secondary amines, R2NH, add to yield enamines, R2 2.

• Imine formation and enamine formation seem different because one leads to a
product with a C=N bond and the other leads to a product with a C=C bond.
• However, the reactions are quite similar: nucleophilic addition reactions, water
is eliminated from the tetrahedral intermediate and a new C=Nu double bond
is formed.
 19-8. Nucleophilic Addition of Amines
• Imine formation: begins with
nucleophilic addition of the primary
amine to the carbonyl group.
• Transfer of a proton from nitrogen to
oxygen yields a carbinolamine.
• Protonation of the carbinolamine
a better

2 ) and loss of
+

water produces iminium ion.

• Loss of proton from nitrogen gives a
final imine product (+regenerated acid
catalyst).
 19-8. Nucleophilic Addition of Amines
• Reaction of an aldehyde or ketone with
a secondary amine, R2NH yields an
enamine.
• The process is identical to imine:
carbinolamine and iminium ion
formation.
• Difference: there is no proton on
nitrogen in iminium ion.
• Instead, a proton is lost from the
neighboring carbon (the carbon),
yielding an enamine.
 19-8. Nucleophilic Addition of Amines
• Imine and enamine formation are slow at both high pH and low pH but reach a
maximum rate at a weakly acidic pH around 4 to 5.
• An acid catalyst is required to protonate the intermediate carbinolamine thereby
slow at high pH.
• If too much acid is present, the basic amine nucleophile is completely protonated:
initial nucleophilic addition can not occur at low pH.

• A pH of ~4.5 represents a compromise between

the need for some acid but not too much acid
to avoid the complete protonation of the amine.
 19-8. Nucleophilic Addition of Amines
• Example: Show the products you would obtain by acid-catalyzed reaction of 3-
pentanone with methylamine, CH3NH2, and with dimethylamine, (CH3)2NH.

• An aldehyde or ketone reacts with a primary amine to yield an imine, where

the carbonyl oxygen atom is replaced by the of the amine.
• Reaction with a secondary amine yields an enamine, where the oxygen atom
is replaced by 2 group of the amine, and the double bond moves to former
carbonyl carbon and the neighboring carbon.
 19-8. Nucleophilic Addition of Amines
• Example: Show the products you would obtain by acid-catalyzed reaction of 3-
pentanone with methylamine, CH3NH2, and with dimethylamine, (CH3)2NH.

• Drawing the reaction mechanism to yield both products should be practiced.

 19-9. Nucleophilic Addition of Hydrazine
• The treatment of an aldehyde or ketone with hydrazine, H2NNH2, in the
presence of KOH, called the Wolff-Kishner reaction, is a useful method for
converting an aldehyde or ketone into an alkane, R2 2CH2.
 19-9. Nucleophilic Addition of Hydrazine
• The treatment of an aldehyde or ketone with hydrazine,
H2NNH2, forms hydrazone intermediate, R2C=NNH2.
• Base-catalyzed double bond migration: a base removes
one of the weakly acidic NH protons to generate
hydrazone anion, which has an allylic resonance
structure that places the double bond between
nitrogens and the negative charge on carbon.
Reprotonation occurs on carbon to generate double-
bond rearrangement product.
• Loss of N2 gas to give carbanion: driven by the large
thermodynamic stability of the N2 molecule.
• Protonation of an alkyl anion gives the alkane product.
 19-10. Nucleophilic Addition of Alcohols
• Aldehydes and ketones react with 2 equivalents of an alcohol in the presence
of an acid catalyst to yield acetals, R2C(OR’)2.

• Alcohols are weak nucleophiles slowly under neutral conditions.

• Under acidic conditions, the reactivity of the carbonyl group is increased by
protonation, so addition of an alcohol occurs rapidly.
 19-10. Nucleophilic Addition of Alcohols
• Nucleophilic addition of an
alcohol to the carbonyl group
initially yields a hydroxy ether
called a hemiacetal.
• ,
followed by E1-like loss of water
leads to an oxonium ion,
R2C=OR+.
• The oxonium ion undergoes a
second nucleophilic addition
of alcohol to yield the acetal.
 19-10. Nucleophilic Addition of Alcohols
• Example: Show the structure of the acetal you would obtain by acid-catalyzed
reaction of 2-pentanone with 1,3-propanediol.

• Acid-catalyzed reaction of an aldehyde or ketone with 2 equivalents of an alcohol

yields an acetal.
• But, in this case, diol is used, so reaction with 1 equivalent of a diol will yield an
acetal.
 19-10. Nucleophilic Addition of Alcohols
• Example: Show the structure of the acetal you would obtain by acid-catalyzed
reaction of 2-pentanone with 1,3-propanediol.

• It is often convenient to use 1 equivalent of a diol to form a cyclic acetal.

 19-10. Nucleophilic Addition of Alcohols
• All the steps in acetal formation are reversible.
• The acetal formation reaction can be driven either forward (from carbonyl
compound to acetal) or backward (from acetal to carbonyl compound).
• The forward reaction is favored by removing water.

• Acetals are useful because they can act as protecting group for aldehydes
and ketones ( trimethylsilyl (TMS) ethers for alcohol protection).
• If we wanted to reduce only the ester group of ethyl 4-oxopentanoate, the ketone
would interfere.
 19-10. Nucleophilic Addition of Alcohols
• By protecting the keto group as an acetal, the problem can be circumvented.
• Like other ethers, acetals are unreactive to bases, hydride reducing agents,
Grignard reagents, but they are cleaved by acid.
• The selective reduction of the ester group by first converting the keto group to an
acetal, then reducing the ester with LiAlH4, and then removing the acetal by
treatment with aqueous acid.
 19-
• Aldehydes and ketones are converted into alkenes by a nucleophilic addition
called the Wittig reaction.
• A triphenylphosphorus ylide, R2C +PPh
3 (also called a phosphorane) in the
resonance form R2C=P(Ph)3, adds to an aldehyde or ketone to yield a four-
membered cyclic intermediate called an oxaphosphetane.
• The oxaphosphetane spontaneously decomposes to give an alkene and
triphenylphosphine oxide, O=PPh3.
• The oxygen atom of the aldehyde or ketone and the R2C= bonded to
phosphorus exchange places.
 19-
• Nucleophilic addition of phosphorus ylides: different pathways.
• One pathway involves a one-step cycloaddition process ( Diels-Alder rxn).
• The other pathway involves a nucleophilic addition to give a dipolar intermediate
(betaine), which undergoes ring closure.
 19-
• The phosphorus ylides are easily prepared by SN2 reaction of primary (or
sometimes secondary) alkyl halides with triphenylphosphine, (Ph)3P, followed
by treatment with base.

• Because of the positive charge on phosphorus, the hydrogen on the neighboring

carbon is weakly acidic.
• It can be removed by strong base to generate neutral ylide.
 19-
• Many monosubstituted, disubstituted and trisubstituted alkenes can be prepared
from the combination of phosphorane and aldehyde or ketone (tetrasubstituted
alkenes can not be prepared because of steric hinderance).
• The real value of the Wittig reaction is that it yields a pure alkene.
• The C=C bond in the product is always exactly where the C=O group, and no
alkene isomers are formed.
 19-
• Example: What carbonyl compound and what phosphorus ylide might you use to
prepare 3-ethyl-2-pentene?

• Nucleophilic addition of phosphorus ylides: an alkene where the oxygen atom of

the carbonyl reactant is replaced by the =CR2.
• Preparation of the phosphorus ylides involves SN2 reaction of a primary alkyl
halide, so the ylide is typically RCH=P(Ph)3.
• Disubstituted alkene carbon comes from the carbonyl reactant, while the
monosubstituted alkene carbon comes from the ylide.
 19-
• Example: What carbonyl compound and what phosphorus ylide might you use to
prepare 3-ethyl-2-pentene?
19-13. Conjugate Nucleophilic Addition to , -Unsaturated A. & K.
• So far, a nucleophile directly adds to the carbonyl group (1,2-addition).

• Conjugate addition or 1,4-addition: nucleophile adds to the C=C bond of an

, -unsaturated aldehyde or ketone.
• The carbon next to a carbonyl group is carbon, and the next carbon is the
carbon. Thus, an , -unsaturated aldehyde or ketone has a double bond
conjugated with the carbonyl group.
19-13. Conjugate Nucleophilic Addition to , -Unsaturated A. & K.
• Conjugate addition or 1,4-addition: nucleophile adds to the C=C bond of an
, -unsaturated aldehyde or ketone.
• The initial product is a resonance-stabilized enolate ion, which typically
undergoes protonation on the carbon to give a saturated aldehyde or ketone.
19-13. Conjugate Nucleophilic Addition to , -Unsaturated A. & K.
• The electronegative oxygen atom of the , -unsaturated carbonyl compound
withdraws electrons from the carbon, making it electron-poor and more
electrophilic.
19-13. Conjugate Nucleophilic Addition to , -Unsaturated A. & K.
• The net effect is addition of the nucleophile to the C=C bond, with the carbonyl
group itself unchanged.
• However, the carbonyl group is crucial to the success of the reaction. Without
carbonyl group, the C=C bond would not be activated for addition, and no
reaction would occur.
19-13. Conjugate Nucleophilic Addition to , -Unsaturated A. & K.
Conjugate Addition of Amines
• Both primary and secondary amines add to , -unsaturated aldehydes and
ketones to yield -amino aldehydes and ketones rather than imines.
• More stable conjugate addition product is obtained with the complete
exclusion of the less stable direct addition product (reactions proceed with
thermodynamic control, not with kinetic control).
19-13. Conjugate Nucleophilic Addition to , -Unsaturated A. & K.
Conjugate Addition of Water
• Water can add reversibly to , -unsaturated aldehydes and ketones to yield -
hydroxy aldehydes and ketones.
• The position of the equilibrium generally favors unsaturated reactant rather than
saturated adduct.
19-13. Conjugate Nucleophilic Addition to , -Unsaturated A. & K.
Conjugate Addition of Alkyl Groups: Organocopper Reactions
• The conjugate 1,4-addition of an alkyl or other organic group to an , -
unsaturated ketones (not aldehyde) ( Grignard reaction of 1,2-addition).

• Lithium diorganocopper (Gilman) reagents are prepared by reaction between

copper iodide and an organolithium reagent, RLi, which is formed by reaction of
lithium metal with an organohalide.
19-13. Conjugate Nucleophilic Addition to , -Unsaturated A. & K.
• Conjugate addition of an organic group is carried out by treating the , -
unsaturated ketones with a lithium diorganocopper reagent, R2CuLi.
• Other organometallic reagents (Grignard reagents and organolithiums) result in
direct carbonyl addition on reaction with , -unsaturated ketones.
19-13. Conjugate Nucleophilic Addition to , -Unsaturated A. & K.
• The mechanism involves conjugate nucleophilic addition of the
diorganocopper anion, R2Cu , to the unsaturated ketone to give a copper-
containing intermediate.
• Transfer of an R group from copper to carbon, followed by elimination of a
neutral organocopper species, RCu, gives the final product.
19-13. Conjugate Nucleophilic Addition to , -Unsaturated A. & K.
• Example: How might you use a conjugate addition reaction to prepare 2-methyl-
3- propylcyclopentanone?

• A ketone has a substituent group in its position might be prepared by a

conjugate addition to an -unsaturated ketones.
• The target molecule has a propyl substituent on the carbon, so it might be
prepared from lithium dipropylcopper.
19-13. Conjugate Nucleophilic Addition to , -Unsaturated A. & K.
• Example: How might you use a conjugate addition reaction to prepare 2-methyl-
3- propylcyclopentanone?
 Summary of Chapter 19
The nucleophilic addition reaction for aldehydes and ketones.
• Aldehydes are reduced by NaBH4 or LiAlH4 to yield primary alcohols, and
addition of Grignard reagents to aldehydes gives secondary alcohols.
• Ketones are reduced by NaBH4 or LiAlH4 to yield secondary alcohols, and
addition of Grignard reagents to ketones gives tertiary alcohols.
• Addition of HCN yields cyanohydrins.
• Primary amines add to carbonyl compounds yielding imines and secondary
amines yield enamines.
• Reaction of an aldehyde or ketone with hydrazine and base gives alkane.
• Phosphorus ylides add to aldehyde or ketones to give alkenes.
• Alcohols add to carbonyl group to yield acetals (protecting groups).

• , -Unsaturated aldehydes and ketones react with nucleophiles to give the

product of conjugate addition or 1,4-addition.