1

Chapter 19: Aldehydes and Ketones:Nucleophilic Addition Reactions The Carbonyl Group

C O

carbon with a double bond to oxygen

it is planarhas bond angles of 120°is permanently polarized

NOMENCLATURE OF ALDEHYDES AND KETONES

IUPAC uses endings on the alkane name to indicate thefunctional group. These ones are easy!

Aldehyde

KetoneH

Br O

12

47

IUPAC rules select the longest chain containing the principal functional group number such that it gets the lowest possible number attach the appropriate ending add all other substituents and stereochemistry as you normally would

E-7-bromo-4,4-dimethyloct-2-enal

Geranialoccurs: as alcohol in essence

of roseuse: perfumery

Benzaldehydeoccurs: almonds, defensive

pheromonesuse: almond extract

Vanillinoccurs: vanilla bean, potato

paringsuse: synthetic vanilla

CHO

CHO

HOOCH3

CHO

NATURAL OCCURRENCE OF ALDEHYDES

2

NATURAL OCCURRENCE OF ALDEHYDES

Retinaloccurs: Vitamin Ause: vision

Glucoseoccurs: foodstuffsuse: energy source/metabolism

CHO

CHO

OHH

OHH

HHO

OHH

CH2OH

Cortisoneoccurs: hormone/adrenal glanduse: relief of inflammation

Camphoroccurs: in the camphor

treeuse: perfumery, explosives

H

H

O OH

H

O

O

OH

O

NATURAL OCCURRENCE OF KETONES

Honeybee pheromoneuse: attractive substance of Queen bee

Fructoseoccurs: in sugar (sucrose)use: sweetener

CH2OH

O

OHH

HHO

OHH

CH2OH

HOOCO

NATURAL OCCURRENCE OF KETONES

PREPARATION OF ALDEHYDES

OH PCC

78%

H

O

CH2Cl2

OH O

H99%

Swernoxidation

NH

CrO3ClDMSO(COCl)2CH2Cl2

then Et3N

-60°PCC Swern

reducing conditions required in the second stage to produce the aldehyde

this can be Zn / HOAc or Me2S

as well as a selective oxidation of 1° alcohols, we could performa selective reduction from acid derivatives:

3

OH OK2Cr2O7

H2SO4, H2O∆

96%

OH OKMnO4

HOAc, H2O∆ 96%

PREPARATION OF KETONES

OXIDATIONS OF ALDEHYDES REACTIONS OF ALDEHYDES & KETONES

This leads naturally to their reactions with nucleophiles

Carbonyl groups are polar and have a dipole moment:

RR1

O RR1

O

RR1

ORR1

O

NuNu

4

what kind of nucleophiles are we talking about?

Steric effect

Electronic effect

Let us deal with mechanism first, then the substituent effect

Base catalysis

5

Acidcatalysis

+R'

RO

R'

R OHOHH2O

K

R R’ K

H H 2.2 x 103

H CH3 1H (CH2)2CH3 0.5H CH(CH3)2 0.5 - 1H Ph 0.3 x 10-3

CH3 CH3 1.4 x 10-3

CH3 Ph 6.6 x 10-6

Ph Ph 1.2 x 10-7

H ClCH2 37H CCl3 2.8 x 104

ClCH2 ClCH2 10CF3 CF3 too large to measure

+R'

RO

R'

R OHOHH2O

K

R R’ K

H H 2.2 x 103

H CH3 1H (CH2)2CH3 0.5H CH(CH3)2 0.5 - 1H Ph 0.3 x 10-3

CH3 CH3 1.4 x 10-3

CH3 Ph 6.6 x 10-6

Ph Ph 1.2 x 10-7

H ClCH2 37H CCl3 2.8 x 104

ClCH2 ClCH2 10CF3 CF3 too large to measure

+R'

RO

R'

R OHOHH2O

K

R R’ K

H H 2.2 x 103

H CH3 1H (CH2)2CH3 0.5H CH(CH3)2 0.5 - 1H Ph 0.3 x 10-3

CH3 CH3 1.4 x 10-3

CH3 Ph 6.6 x 10-6

Ph Ph 1.2 x 10-7

H ClCH2 37H CCl3 2.8 x 104

ClCH2 ClCH2 10CF3 CF3 too large to measure

+R'

RO

R'

R OHOHH2O

K

R R’ K

H H 2.2 x 103

H CH3 1H (CH2)2CH3 0.5H CH(CH3)2 0.5 - 1H Ph 0.3 x 10-3

CH3 CH3 1.4 x 10-3

CH3 Ph 6.6 x 10-6

Ph Ph 1.2 x 10-7

H ClCH2 37H CCl3 2.8 x 104

ClCH2 ClCH2 10CF3 CF3 too large to measure

some adducts are just not stable:

6

CYANOHYDRINS IN NATURE

Amygdalin / Laetrileoccurs in pits of apricots, plums, bitteralmonds, lima beans, casava

Mandelonitrilea defensive secretion in the millipede Apheloria corrugata

O

CN

OOO

HOOH

OHOH

OHHO

OH

OH

CN

Addition of organometallic reagents to aldehydes & ketones

H H

OR MgXR Li R OH

H H primary alcohol withone added carbon

R' H

OR MgXR Li R OH

R' H secondary alcohol

R' R'

OR MgXR Li R OH

R' R' tertiary alcohol

O R MgXR Li R

primary alcohol withtwo added carbonsOH

Depending on the starting material, different types of targetsmay be synthesized

SM reagent target comments

7

Retrosynthetic analysis for a secondary alcohol

OH

O

M

X

O

M

X

M = MgBr, Li

X = Br, Cl, I

Retrosynthetic analysis for a tertiary alcoholHO

O

M

M

O

M

M

O

M

M

M = MgBr, Li

X = Br, Cl, I

Addition of nitrogen nucleophiles to the carbonyl groupi the addition phase

CH3C

H

O

H B+

CH3 H

O

RN

H

CH3 H

OH

RNH

Bnucleophilic attackon carbonyl carbon

protonation and deprotonation

HR

NHH

addition compound

this, and the following slide, are a re-write of the text – Fig 19.8

Addition of nitrogen nucleophiles to the carbonyl groupii the elimination phase

CH3 H

OH

RNH

H B+

CH3 H

OH2

RNH

CH3 H

H2O

RN

HB

CH3 H

RN

protonation ofhydroxyl group

loss of water deprotonationimine

NH2 H

O

+KOH

NH

83%

O

+NH2

H+

N 95%

Enamines formwhen the reagenthas only one Hwhich may beeliminated

8

we can see the difference here:1° amine yields an imine2° amine gives the enamine

Transamination

OHO

O

deaminase

L-amino acid sythetase

phenylpyruvate

OHNH2

O

pyridoxal phosphate

L-phenylalanine

pyridoxamine

N

CH2NH2

OH

CH3

PO

N

CHOOH

CH3

PO

P = phosphate

Where is this important???

COOH

NH2

H

PO

P = the rest of the cofactor

COOH

H

PN

imine 1

H

H+

COOH

H

PN

imine 2H

COOH

H

P

O

H

H2N

A useful extension of this type of reactionis the Wolff-Kischner Reduction

solvent DMSO

for those of you who want to know what’s going on:

CH3 H

OH B+

CH3C

H

OH

CH3O

H

CH3 H

OH

CH3O

H

B

B

CH3

H OH

CH3O

protonation ofthe carbonyl group

nucleophilic attackon carbonyl carbon

deprotonation

a hemiacetal -- one OH, one OR

Sequence of events:protonateattackdeprotonate

Addition of alcohols: formation of hemiacetals and acetals

this one can be acid or base catalyzed

9

Conversion of a hemiacetal to an acetal

H B+

CH3

H OH

OCH3

protonation ofthehydroxyl group

loss of water

CH3

H OH2+

OCH3 CH3

HOCH3

CH3

HOCH3

resonance stabilizedcarbocation

CH3C

HOCH3

CH3O

H

nucleophilic attackon carbonyl carbon

CH3 H

OCH3

CH3O

HB

CH3

H OCH3

OCH3

deprotonation an acetal -- two OR groups

this one can be only be acid catalyzed

Glucose as a hemiacetal

OHHOHO

OH

CH2OH

O

glucose in its openchain conformation

glucose cyclized asa hemiacetal

OHOHO

OH

CH2OH

OH

new chiral centre:two diastereomersformed

see text p 954

Maltose is both an acetal and a hemiacetal

OHOHO

OH

CH2OH

OOHO

OH

CH2OH

OH

acetal

hemiacetal

4-O-(α-D-glucopyranosyl)-β-D-glucopyranose

β−OH and CH2OH are cis

α−OR and CH2OH are trans

see p 967

Sucrose is an acetal in both rings

see p 969

OHOHO

OH

CH2OH

O

CH2OH

acetal

β-D-fructofuranosyl-α-D-glucopyranoside

OHO

OH

HOCH2

pyranose = 6-membered ringfuranose = 5-membered ring

acetal

Acetals as protecting groups

OOH

OOEt

O

The text deals with the following example

We will do a different one. Suppose you want to make the compound below

OOH OO

BrMg

the logical disconnection is one of the C-C bonds on the alcohol carbon,and it makes most sense for this not to be one of the ring bonds.

but, what is wrong with this?

O

BrMgwhat is wrong, of course, is that the twofunctional groups in this molecule are incompatible

so, we must protect the ketone before making the Grignard

O

BrOHHO

H+ Br

OO Mg

dry Et2O BrMg

OO

remember, these arestable to base and Nu

O

BrMg

OO+dry Et2O

H3O+OOH

dilute acid work-up not onlyhydrolyzes the Mg salts off,but also cleaves the acetal

10

The Wittig reaction

H3C I

PPh3

Ph3P CH2

H Bu LiTHF

IPh3P CH2 + BuH + LiI

Ph3P CH2

nucleophilic P displacesleaving group I

base pulls offacidic protonα to P+

Wittig reagent is stabilized by resonance

This is the reaction of a carbanionic component with a carbonylcomponent to produce a new alkene.The carbanionic component is readily formed using triphenylphosphine

The huge advantage is that you know exactly where, in the molecule,the new double fond forms. An example:

Retrosynthetic analysis in a Wittig-based reaction

Target:

OPh3P

PPh3O

the normal Wittig reagent is primary, so one would by preference choose the blue route

There is one further aspect of this reaction which makes it evenmore synthetically useful – one can control the stereochemistryof the resulting alkene to be E- or Z-

This target has two alkenes, which we can stereoselectively produceby simple modification of the Wittig reaction conditions

Prostaglandin F2α

HO

HO

OH

CO2HAcO

H

O

O

OAcO

O

O

Ostereoselection for E-alkenedue to stabilized ylide

Na CH2SOCH3

C5H11P

(OEt)2

O O

for the lower side chain:

11

for the upper side chain:

THPO

O

OH

C5H11

OTHP

THPO

HO

OTHP

CO2H

stereoselection for Z-alkenenormal non-stabilized ylide

Br– Ph3P+(CH2)4CO2H

Na CH2SOCH3

We have previously looked at conjugated dienes, now let us look at conjugated carbonyl systems: enones and enals

once again, this reacts like a single functional group:

both carbonyl carbon and β-carbonare electrophilic

Essentially this means that this type of double bond is reactivetowards electrophiles, whereas a normal double bond would not be

When the addition occurs to the β-carbon, it is called conjugate addition

Amines add readily:

O

H2O O

O

60%

Ph Ph

O KCN

HOAc Ph Ph

O

93%

OH

OH5°

CN

Other adducts:

12

Organometallics can add in a conjugate fashion, but they mustbe modified from the normal Mg or Li reagent: which then leads to regioselectivity:

Once again, there are good synthetic possibilities.Let us go back to prostaglandins and see what we might do.

HO

HO

OH

CO2H

ROR2

R1

HO

ROR2

R1O

RO

O

R2 Exclusively 3,4-trans

O

TBDMSO

O

RO OR

OR

Li

TBDMS = t-Butyldimethylsilyl

Me2Zn

normally we use copper to effect the Michael addition of an organometallic, but many other metals can be used. In this case, Noyori found that zinc worked very well:

and, notice that the large group adjacent to thereacting site completely governs the face of thedouble bond which is attacked

-78 ºC 1h.

71% only productexclusively trans- anti

OR

Li

RO OR

O- Me2ZnLi+O

TBDMSO

CO2EtI

O

ROOR

CO2Et

HMPA, -78ºC to -40ºC

Me2Zn

It turns out that the intermediate in this first addition is an enolate-- we can take advantage of that to introduce the second side chain