Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 1 of 11. Date: February 20, 2012

Chapter 14 Aldehydes and Ketones: Addition Reactions at Electrophilic Carbons

Overview of Chapter 14 1. Structures of aldehydes and ketones

CR

R'O R, R' = alkyl, aryl: ketonesR = alkyl, aryl; R' = H: aldehydesδ

δ

electrophilic CAldehyde C=O carbons are lesssterically hindered and more electrophilic compared with the corresponding ketone carbons (i.e., with the same R)

lone pair: more basic than C=O π

2. Reactions of aldehydes and ketones with an electrophile and a nucleophile

CR'

RO

σ−frameworklone pairs

all of these sigma-bonds and lone pairs on thesame plane

El+with this trajectory

π-bonding

Highest occupied molecular orbitals

(HOMOs) of the C=O group

CR'

RO

emptyanti-bondingorbitals

Lowest unoccupied molecular orbital

(LUMO)

Nu:

trajectory ofa nucleophileapproach

trajectory angle of 107°

CR'

RO

Nu

CR'R

O

Nu

sp3between sp2 and sp3;on its way to sp3

CR

R'O

El

all atoms including Elon the same plane

Two lone pairs:

3. Activation of RR’C=Z (Z = O and N) with H-A or a Lewis acid → activates C=O toward a nucleophilic addition

O OH A

becomes even more δ ; i.e., more electrophilic

OH A

H A

Lewis acid (L.A.)

OL.A. O

L.A.O

M

(if M+ is used)or

Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 2 of 11. Date: February 20, 2012 Chapter 14: Overview (continued) 4. Four categories of nucleophilic addition reactions Two classes of nucleophiles: reversible and irreversible

O

Reversible Nu: Irreversible Nu:

Type 1H M

O HM H3O

H2O

HO H

Type 2R O RM HO R

RO OR HO OR

HO N

or

e.g.,RLi,RMgX(Grignard reagent)

Type 3divalent Nu:

e.g.,ROH, RSH

SN1

N RH

RE1

Type 4

Trivalent Nu:

e.g., R-NH2

H3O

H2Oor

==============================================================

I. Nucleophilic Addition Reactions of RR’C=Z (Z: electronegative atom)

Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 3 of 11. Date: February 20, 2012 I-1 (1) Hydride reducing agents (cont’d)

OO

H

AlH

HH

Li

H3O OH

H+ LiOH + Al(OH)3

All of these three Hs could be used in the reduction of a ketone.

Reduction with LiAlH4:

LiAlH4

OLi

H AlH

HH

OLi

AlHHH

note: O-Al bond stronger than O-Li

hydrolysis*

*This acid-hydrolysis step may be quite complex, depending upon the stoichiometry betweena ketone and LiAlH4. However, all of those hydrolysis step should involve

O

H

AlX

XX

H

anhyd. aproticsolvent (e.g., THF)

X: OH or ORReduction with NaBH4:

OOH

H

NaBH4usually in a protic

solvent (e.g., ethanol)O

NaH B

HH

H

ONa

H OR

+ BH3 reacts with the solvent 3 x RO-H to formB(OR)3 and 3 x H2

Reduction with DIBAL (Al in DIBAL quite Lewis acidic):

OO

H

Al H3O OH

H+ Al(OH)3 + 2 (H3C)3CH

DIBAL

OAl

hydrolysisanhyd. aproticsolvent (e.g., THF)

AlH

H

O

H

AlO

H

AlC

HOH2O H2O

H2O

H3O

HH

HO

HH

Li AlH4

Na BH4Na OR

O

not very favorable;Na+ not much Lewis acidic

Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 4 of 11. Date: February 20, 2012 I-1. Irreversible nucleophiles (cont’d)

+

+

++

(b) R nucleophiles: Type 2

O

Could be sp3, sp2, sp carbanions

Grignard reagents (R-MgX)

alkyllithium (R-Li) or sodium (R-Na)

alkenyl lithium (C=CHLi)

alkynyl lithium/sodium or lithium/sodium acetylide (C C-Li; C C-Na)

R Manhydrous

aprotic solvent

O

R

M H3Ohydrolysis

O

R

H

M(OH)

Grignard reagents: R-MgX (X is usually Br or I, sometimes X=Cl)

H3C BrMg*

anhydrousTHF or etherδ δ

δ δH3C Mg Br

δH3C Mg Br

2

Formally equivalent to:

polarization reversal

* R X Mg R• •Mg-Xoxidation #: 0 oxiudation #: +2

Prepration of Grignard reagents:(i) Alkyl Grignard reagents from R-X

(ii) Alkynyl Grignard reagents:

CH3C C HpKa ~26

H3CCH2MgBr CH3C C MgBr

CH3C C MgBr

H3C CH

HH

pKa ~50

+

CH3C C Hnote:

Na, liq NH3or NaNH2, liq NH3

CH3C C Na

Br MgBr

(iii) Alkenyl and aryl grignard reagents from their halide precursors

Mgusually in anhydrous

THF

Br MgBrMg

anhydrousTHF or ether

note:

Li Li-Br

2 Li

alkenyllithiumCyanide carbanion - often reversible nucleophile

ONaCNH2O

O

CN

Na H3O OH

CN

electronegativity values: C (2.5); H (2.1); Li (1.0); Na (0.9); Mg (1.2); Al (1.5); Br (2.8)

R-Mg-X

Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 5 of 11. Date: February 20, 2012

Chapter 14 I-1. Irreversible nucleophiles

δ

δ+ Mg(OH)2

(b) R M (Type 2; organometallic reagents) (cont'd)Note: Reactions with epoxides

OH PhMgBr OH

Ph

OHH

Ph

MgBr

PhSN2!

work-upwith

aq NH4Cl*

*NH4Cl: weakly acdic; pKa ~9.7; commonly used for the work-up of organometallic reactions; the only exception is the work-up of a carboxylate product (you need to acdity the solution to pH~1-2).

Ph MgBr OMgBr

CO

PhO

CO

Ph CO

O HH3OpH 1-2

+ Br

pKa 4.2

Not with aq NH4Cl!

I-2. Reversible nucleophiles

Type 3: Divalent nucleophiles (ROH & RSH); requires an acid catalyst Type 4:

Trivalent nucleophiles (R-NH2 & RR'NH); w/o activation by an acid

+O

ketone

oxygen atom

ROH, H or L.A. OH

OR

OR

OR

ROH, H or L.A.H2O

+H

O

aldehyde

oxygen atom

ROH, H or L.A.

H

OH

OR H

OR

OR

ROH, H or L.A.H2O

hemiketal

hemiacetal

ketal

acetal

Tend to be unsatble intermediates!

+O

ketone

oxygen atom

RSH, H or L.A. OH

SR

SR

SR

RSH, H or L.A.H2O

+H

O

aldehyde

oxygen atom

RSH, H or L.A.

H

OH

SR H

SR

SR

RSH, H or L.A.H2O

hemithioketal

hemithioacetal

thioketal

thioacetal

(a) ROH (alcohols)

(b) RSH (thiols or mercaptans)

meaning"mercury capturers"

Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 6 of 11. Date: February 20, 2012

Chapter 14: I-2. Reversible nucleophiles (cont’d)

+

(c) Mechanism (similar for both ROH and RSH nucleophile additions)

O H3CO OCH3H2O

CH3OH, p-TsOH (catalytic)

SHSH

BF3•O(CH2CH3)2(catalytic) + H2O

SS*p-TsOH (or TsOH) para-toluenesufonic acid; strong, organicsolvent-soluble acid.

H3C S OO

OH

pKa ~-1

**

*

OBFF

F

**boron trifluoride diethey etherate;gives better yields of thioketals & thioacetals than p-TsOH

Ts Not a base!

-------------------------------------

Since ROH and RSH are not nucleophilic enough to add to a C=O, the C=O has to be activated by the use of H+ or a Lewis acid. Incidentally, their conjugate bases, RO-/RS- can add (quite easily as being highly nucleophilic) to the C=O, but the adducts are less stable than the original C=O, thus reverse back to the C=O and RO- /RS-.

Mechanism using H-B for the acid catalyst, p-TsOH:

+

O

H3CO OCH3

H BO

B

HO

B

H

HO

CH3O

H

OH

CH3

B

OH

OCH3

HBO

H

OCH3

H

lone pair-assistedionization!!

H2O

H2O

O CH3

O CH3

SN1!

resonance-stabilizedoxoniom

ionHO

CH3

OCH3

OCH3

HB

H B

BB

dimethyl ketal

Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 7 of 11. Date: February 20, 2012

Chapter 14: I-2. Reversible nucleophiles: Mechanism (cont’d)

Comments:1. The ketalization and acetalization reactions from ketone and aldehyde, respectively, under acid- catalyzed conditions are reversible. High yields of ketals and acetals can be achieved by the use of excess alcohols and/or continuous removal of the resulting water (using, e.g., a Dean-Stark apparatus).2. Conversely, if a ketone or aldehyde is desired from its corresponding ketal or acetal, a large excess of water needs to be added to the solution of ketal of acetal in the presence of an acid catalyst.3. Throughout the mechanism for the acid-catalized ketalization and acetalization, DO NOT involve negatively-charged intermediates. The only negatively charged species allowed is the conjugate base (:B-) of a strong acid catalyst.Lastly,

OH

OCH3

HH3CO OCH3

Does not involve an SN2 step!

OH

OCH3

H

H O CH3

x

Representative reactions:

+

+

H

O

OH

OH(excess)

p-TsOH(catalytic)

ΔH

O OH2O

(1) cyclic acetal formation

(2) cyclic thioacetal formation

+H

O

SH

SH(excess)

BF3•O(CH2CH3)2(catalytic)

Δ

HS S

H2O

(3) cyclic ketal formation from diols: acetonide formation

OH

OH H3C

H3CO

acetone

(excess)

O

O CH3

CH3H2O

p-TsOH(catalytic)

Δ

+H3C

H3C

(excess)

O

O CH3

CH3p-TsOH(catalytic)

+H2C

H3CO

(excess)

O

O CH3

CH3p-TsOH(catalytic)

OO

CH3CH3

O CH3H2

CH3

O CH3H

milderreaction

conditions

called (5-membered) acetonide (i.e., acetone adduct)

Mechanism?

Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 8 of 11. Date: February 20, 2012 Chapter 14: I-2 reversible nucleophiles-ROH/RSH Representative reactions (cont’d)

(4) Transketalization reaction: Spiroketal formation

+

OCH3H3CO

OH H

O

DIBAL ( 2 mol equiv)

mild workupwith aq NH4Cl

OCH3H3CO

OHHO

p-TsOH(catalytic)

Δ

O O2 HOCH3

spiro system

By boiling off methanol, this spiroketal can be obtained in high yield.

Mechanism for the spiroketalization step:

(5) Hydrolysis of ketals and acetals - Acid-catalyzed ketal-acetal formation reactions from, respectively, ketones and aldehydes are reversible. Therefore, treatment of ketals or acetals with an acid and excess water should produce their corresponding carbonyl compounds. This process is called “hydrolysis.” Mechanism of the reaction is exactly the same as the formation of ketals and acetals except going to the opposite direction.

O

O

H

extremely acidunstable

p-TsOH(catalytic)

H2O(excess)

This reaction does not need to be heated!

OH

OH

H

O+

Mechanism for the hydrolysis shown on the next page.

Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 9 of 11. Date: February 20, 2012 Chapter 14: I-2 reversible nucleophiles-ROH/RSH Representative reactions (cont’d)

(5) Hydrolysis of ketals and acetals:

Mechanism:

O

O

HH B

O

O

HH

O

OH

HHO H O

OH

H

O

H

H

B

O

OH

H

O H

HB

O

OH

H

O H

H

OH

OH

H

O

+

H

B

H

O

lone pair-assistedionization!

lone pair-assistedionization!

============================================ The “take-home message:”

Lone pair-assisted ionization!

O OR'R

O OR'R

HO O

R'R

HH B +

SN1!

O OR''R

HOR"

Not an SN2!!

Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 10 of 11. Date: February 20, 2012

Chapter 14 I-2. Reversible nucleophiles (cont’d)

Type 4 nucleophiles: Trivalent nucleophiles

Amines are sufficiently nucleophilic enough to add to ketone and aldehyde C=O carbons without activation of the C=O oxygen atom by an acid. However, the last dehydration step from the aminol intermediates requires an activation of the hydroxyl oxygen atom (by H+ or L.A.). (1) Imine formation [from a ketone/aldehyde and a 1°-amine]

+O

HH2N CH3

N

H

CH3+ H2O

imine1°-aminealdehyde

Δ

or H+

Mechanism:

O

HH2N CH3

O

H N CH3H H

H BOH

H N CH3H

H BO

H N CH3

H

H

H B

O

HN CH3

H

HH

aminol

H

NCH3

H

B

N

HCH3

imine

These two steps may be reversed in order.

Those RR’C=N-Z formation reactions from RR’C=Os have the optimum rate at around pH = 4.7. If the conditions are too acidic, the formation of such derivatives becomes slow, presumably due to the exclusive protonation of an amine, thus depriving the nucleophilicity of an amine. Although the protonation is required for the dehydration from the aminol intermediate, the formation of these RR’C=N-Z compounds can be achieved even without adding an acid catalyst, especially when the reaction involves an aldehyde (often heating is required to complete the reaction, though). Amazingly, the formation of hydrazones (RR’C=NNH2) can be achieved under basic conditions with strong heating.

Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 11 of 11. Date: February 20, 2012

Chapter 14 I-2. Reversible nucleophiles: Type 4 nucleophiles (trivalent nucleophiles) (cont’d)

(2) Oxime formation

O H2N NOH

+ +Δ

or Δ, H+

oxime

H2O

(3) Hydrazone formation

O NNH2

+ +Δ

H2Oor Δ, H+

OHhydroxylamine

H2N NH2hydrazine

hydrazone Application: Wolff-Kishner reduction Reduction of RR’C=O to RR’CH2

O

H2N NH2KOH, Δ

H H

NN

HH

hydrazone

OHN

NH

H OH NN

H

H

OH

H H OH

N2 (gas)

ketone methylene

An alternative method for the formation of a methylene group from a C=O:

Reduction of thioacetal/thioketal derivatives with Raney Ni.

OS

S

H

H

HS

HSBF3•O(CH2CH3)2

Raney Niethanol, Δ

thioketal

Type 3 reversible nucleophile!