electrophile (lewis acid) nucleophile (lewis base) free …psbeauchamp/pdf/315_arrow_pushing… ·...

$: Electrophile (Lewis Acid) Nucleophile (Lewis Base) Free …psbeauchamp/pdf/315_arrow_pushing… · · 2013-11-191 y:\files\classes\315\315 Handouts\arrow pushing mechs & rxn summary.doc$
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y:\files\classes\315\315 Handouts\arrow pushing mechs & rxn summary.doc

Electrophile (Lewis Acid) = electron loving = any general electron pair acceptor (can also be an acidic proton = Bronsted acid)

Nucleophile (Lewis Base) = nucleus/positive loving = any general electron pair donor (can also be donated to an acidic proton = Bronsted base) Free Radicals = one electron transfers, only limited examples are emphasized in our course (free radical substitution at sp3 C-H, anti-Markovnikov free radical addition reactions to pi bonds and some reactions with metals),

Problems - Supply the lone pairs, formal charge and the curved arrows to show how the electrons move for each step of a reaction mechanism. Be able to identify nucleophiles and electrophiles in each step of the reactions below. Our two free radical mechanisms (substitution at sp3 C-H and anti-Markovnikov addition to pi bonds) are at the end. Check your mechanisms against the examples provided.

SN2 and E2 Mechanisms (strong base/nucleophile competition reacting at a carbon or reacting at a proton)

1. Hydroxide (available as NaOH, KOH or LiOH)

CC

BrNa

H3C H

S

OHH

H CH3

Problem

H2CC

BrNa

H3C H

H3C

OC

CH2

H3C H

CH3

SR

OH

H

CC

BrNa

H3C H

S

OH H

H CH3

CC

H

H3C

CH3

H

CC

H3C

H

CH3

H CC

H

CH2

H

H

H3C

methyl RBr = only SN2primary RBr = SN2 > E2secondary RBr = E2 > SN2tertiary RBr = only E2

E2

SN2alcohols

2. Alkoxide (make with ROH + NaH or make ROH + Na )

CC

Br Na

H3C H

S

OH3CH

H CH3

Problem

H2CC

BrNa

H3C H

H3C

OC

CH2

H3C H

CH3

SR

OH3C

H3C

CC

BrNa

H3C H

S

OH3C H

H CH3

CC

H

H3C

CH3

H

CC

H3C

H

CH3

H CC

H

CH2

H

H

H3C

methyl RBr = only SN2primary RBr = SN2 > E2secondary RBr = E2 > SN2tertiary RBr = only E2SN2

E2

ethers

2


3. Carboxylates (make with RCO2H + NaOH)

4. Potassium t-butoxide (make with (CH3)3COH + KH)

3


5. Sodium azide (available as NaN3)

Problem

H2CC

BrNa

H3C H

H3C

NC

CH2

H3C H

CH3

S RN

Follow up reaction = SN2 reaction at nitrogen, followed by workup (protonates nitrogen)

NN

N N

methyl RBr = only SN2primary RBr = mainly SN2secondary RBr = mainly SN2tertiary RBr = only E2

NR

NN

Al H

H

H

HLi

NR

NNH

LiO H

H

H

2. workup

NR

H

H

azido compounds

Na

NN

NH2C

CBr

H3C H

H3C

1o amines

Can also usethe Gabrielamine synthesis(next).

2. LiAlH4

3. workup

SN2

SN2

resonance

1.

azido compounds 1o amines

6. Phthalimidate (make from phthalimide + NaOH or KOH), Also called the Gabriel amine synthesis.

Problem

Na

H2CC

Br

H3C H

H3C

H2CC

Br

Na

H3C H

H3C

CCH2

H3C H

CH3SR


N

O

O

N

O

O

Follow up reaction = acyl substitution (twice) to make primary amines

alkyl imide

Na

O H N

O

R

O O

N

O

R

O

OH

N

O

R

O

O

H

OH

N

O

R

O

O

H

O

H

N R

O

OH

O

OH

O

O

O

ON R

H

H

primary amine(also made by1. NaN3

2. LiAlH4

3. workup)

throw away

N

O

O

R

Hacylsubstitution

(twice)

alkyl imide

SN2

N

O

O

acidbase

acidbase

acylsubstitution

T.I.

T.I.

4


7. Sodium hydrogensulfide (available as NaSH)

ProblemH2C

CBr

H3C H

H3C

Na

SH

H2CC

BrNa

H3C H

H3C

SC

CH2

H3C H

CH3

SR

SH

H


SN2thiol

8. Sodium alkylsulfide (make from RSH + NaOH)

ProblemH2C

CBr

H3C H

H3C

Na

SH3C

9. Cyanide (available as NaCN)

5


10. Terminal acetylides (make from terminal alkynes, RCCH + NaNR2)

zipper reaction – moves an internal triple bond (CC) to the end position in unbranched chains where the negative charge is the most stable (in sp orbital).

6


11. Enolates (make from carbonyl compounds or nitriles + LDA, -78oC to prevent side reactions)

ProblemH2C

CBr

H3C H

H3C

H2CC

O

H3C

H2CC

Br

H3C H

H3C

S

CCH2

H3C H

CH3H2C

C

O

H3C methyl RBr = only SN2primary RBr = mainly SN2secondary RBr = mainly SN2tertiary RBr = only E2

H2CC

O

O

H2CC

Br

H3C H

H3C

S

CCH2

H3C H

CH3H2C

C

O

OR R

H2CC

H2CC

Br

H3C H

H3C

S

CCH2

H3C H

CH3H2CN

CN

ketone enolate

ester enolate

nitrile enolate

Li

Li

Li

H2CC

O

H3C

Li

There are many variations ofthis reaction on the enolatecomponent and on theelectrophilic component.

SN2

SN2

SN2

-78oC

-78oC

-78oC

-78oC

S

R

R

R

12. Dithiane anion (made from dithiane + n-butyl lithium)

Problem H2CC

Br

H3C H

H3C

Li

H2CC

Br

Li

H3C H

H3C

CCH2

H3C H

CH3S

R


C

S

S

Follow up reaction = hydrolysis to carbonyl compound to make aldehydes or ketones.

R

O

H

aldehydeor

ketone

SC

S

H R

3. workup

Hg+2S

CS

H R

Hg SC

H R

S

HgO

H H

SC

R

S

Hg

OH

H

HH2O

SC

R

S

Hg

OH

H

SHg

S

CH

OR

H

SHg

S

CH

O

HO

H H

H2O

S

C

S

H

S

C

S

HH

hydrolysis

discard

RThink of Hg+2

as a giant proton

for sulfur.

SN2

Can repeatone moretime.

resonance

7


13. Cuprates (made from RBr/Li RLi + CuBr R2Cu-- + R’Br R-R’)

ProblemH2C

CBr

H3C H

H3C

Li

H2CC

BrLi

H3C H

H3C

CCH2

H3C H

CH3

S R methyl RBr = only SN2primary RBr = mainly SN2secondary RBr = mainly SN2tertiary RBr = only E2Cu

R

R

R

CuR

R

SN2(for us)

8


SN1 / E1 possibilities –extra complications at Cβ positions of 2o RX, rearrangement to more stable 3o R+ considered

9


E1 product from left C carbon atom (without rearrangement)

HC

CC

H2C

CH3

H H

H

CH3

Br

H

HC

CC

H2C

CH3

H H CH3H

H

Redrawn

(3S)

(achiral)

CCH

C

H

HH

H2O

CCH

CH

HH

H2O

same first stepfor SN1/E1

add nuclephile (top/bottom) = SN1

lose -H (top/bottom) = E1

"H" parallel toempty 2p orbitalon top

"H" parallel toempty 2p orbitalon bottom

C C

H H

H C

H2C

CH3

H2O

CH3CH

C

H

CH2H3C

CH3

CH3CH

C

"H" parallel toempty 2p orbitalon top

"H" parallel toempty 2p orbitalon bottom

3Z-alkene

3E-alkene

OH2

H

CH3

OH2

C

C CH2

H3C

H3C

H

CH3

C

C CH3

H3C

H2C

H

CH3

OH2

CH3CH

C

OH2

H2O

a

b

SN1 product (a. add from top and b. add from bottom), (without rearrangement), usually SN1 > E1 (in our course)

CH3C

C

H

O

HH

H2C

CH3

CH3C

H

C

O

HH

a

b

OH2

OH2

CH3C

C

H

O

H

H2C

CH3

CH3C

H

C

O

H (2S,3S)

diastereomers

acid/baseproton transfer

acid/baseproton transfer

E1 product from right C carbon atom (without rearrangement)

H2C

H3C

(2R,3S)

(2R,3S)

H2C

CH3

CH3H CH3H

H2C

CH3

CH3H

H2C

CH3

H CH3 CH3H2C

CH3

CH3H

H H

H

H2C

CH3

CH3

CH3

(3S)

(3S)

(3S)

(3S)

(3S)

diastereomers

same alkene

3R stereochemistry is lost

(2R,3S)

(2S,3S)

rearrangement to similar or

more stable carbocation (R+)

(start all over)carbocation

choices

rotate bond

rotate bond

rotate bond

(rearrangement on next page)

E1

E1

E1

E1

SN1

Both chiralcenters aredestroyed.

(3S)

10


After rearrangement to 3o carbocation (R+)

11


1. Water as a weak nucleophile/base with R-Br (or RX), makes alcohols by SN1 (No reaction at methyl and 1o RBr)

Br H

HO

H

HH

HH rearrangement

H2O

OH2

a = back

b = frontc

H O

O HH

H

H H

SN1

SN1

E1

H

H

OH2

OH2

H2O

OH H

OH2

OH

SN1E1

H O H

O H

H

2S

2R

2S

H

de

f

a

b

c = f

a

b

c

c' = not shownd

d

ef = c

Problem

Br H

HO

H2S

(2o to 3o)

achiral (top attack = bottom attack)

2. Alcohols as weak nucleophile/bases, makes ethers with R-Br (or RX) by SN1 (No reaction at methyl and 1o RBr)

Problem

Br H

HO

CH32S

Br H

HO

CH3

HH

HH

rearrangement

a

b

c

H O

O HH3C

H

SN1

SN1

E1

CH3

H

OH3C H

OH3C

SN1E1

H O CH3

O H

CH3

2S

2R

2S

achiral

HO

CH3HO

H3C

HO

CH3

HO

CH3

HO

H3C

HO

CH3

H H

H

de

f

a

b

c = f

c = f e

d

c' = not shownc

b

a

12


3. Carboxylic acids as weak nucleophile/bases, makes esters with R-Br (or RX) by SN1

Alcohol reactions in strong acid (HCl, HBr, HI, H2SO4, TsOH are available): (HBr = SN2 and SN1), (H2SO4/ = E1) in our course. 1. Methyl and primary alcohols + HBr SN2 reactions (no rearrangement)

13


2. Secondary and tertiary alcohols + HBr SN1 reactions (possible rearrangement)

3. Methyl and primary alcohols + PCl3 or PBr3 SN2 reactions (no rearrangement) (PX3 Lewis acids are available)

4. Secondary and tertiary alcohols + PCl3 or PBr3 SN1 reactions (possible rearrangement)

14


5. Methyl and primary alcohols + SOCl2 or SOBr2 SN2 reactions (no rearrangement) (SOX2 Lewis acids are available)

6. Secondary and tertiary alcohols + SOCl2 or SOBr2 SN1 reactions (possible rearrangement)

Problem

OH O

S

O Br

Br

OS

O

H

O

SBr

O

H

SN1 at secondary and tertiary alcohols

synthesis of an alkyl chloride from an alcohol + thionyl chloride (SOCl2) [can also make RBr from SOBr2]

O

SBr

O

H

BrH

RR

R

RR

acyl-like substitution

SBr

O

Br

Br

Br

OH

RS

Br

O

Br

BrBrtop/bottom attack

S

7. How to avoid rearrangement at secondary ROH RBr (two steps, a. TsCl/pyridine b. NaBr = SN2)

15


8. Alcohols + H2SO4/ = E1 (alkene products, possible rearrangements)

16


9. Alcohols + CrO3/C5H6N (PCC) (oxidizes primary ROH to aldehyde and secondary ROH to ketone)

17


10. Alcohols + CrO3/H2O (Jones) (oxidizes primary ROH to carboxylic acid and secondary ROH to ketone)

ProblemH3C

CH2

CH

OH

H

Cr

O

OO

H3CCH2

CCH3

OH

H

Cr

O

OO

HO

H HO

H

H3CCH2

CH

OH

H

H3CCH2

CH

O

Jones = CrO3 / H2O / acidprimary alcohols oxidize to carboxylic acids(acidic water hydrates the carbonyl group,

which oxidizes a second time )

primary alcohols

aldehydes (continue in water)

HO

HH

OH

H

H3CCH2

CH

OH

H3CCH2

CH

OH

HO

H

H3CCH2

C

OH

O

H

H

H

HO

HH3C

CH2

C

O

O

H H

H

HO

H

HO

H

H3CCH2

C

O

OH

hydration ofthe aldehyde

second oxidation of the carbonyl hydrate

H

O

H

resonance

carboxylic acids

Cr

O

OOH3C

CH2

CH

OH

H

Cr

O

O

O

H3CCH2

CH

O

H

Cr

O

O

O

Cr

O

O

O

HO

H

H

HO

H

H

Cr

O

OO H3CCH2

CO

O

H

Cr

O

O

O

H

H

H3CCH2

CO

O

H

Cr

O

O

O

H

HO

H

H

Cr

O

O

O

HO

H

H

E2

18


11. THP protection of alcohols, ROH + DHP (TsOH cat.) THP ether, which can be deprotected with H2SO4/H2O

Problem

O

OOTsH

O

DHP = dihydropyran

resonance

OO O

HO

RH

O O

THP = tetrahydropyranprotected alcohol

OTHP

=

THP ethers do not react under strongbase/nucleophiles and neutral conditions(protected). They are hydrolyzed backto the alcohol under acid conditions

(deprotected).

a. protection conditions - alkene addition reaction

O

O

OTsH

THP protected alcohol

H3OH2O

regenerated alcohol

b. deprotection conditions - aqueous acid conditions hydrolyzes acetal back to alcohol

O O

OHH

H

OHH

O O

H

OO

OHH

etc.

H

desired alcohol

THP = tetrahydropyranprotected alcohol

H

H

O

H

OH

discard

Epoxides in Strong Base/Nucleophile mixtures: backside attack at least hindered carbon. 1. Hydroxide

19


2. Alkoxides

3. Organometallics (Li and Mg)

4. Terminal acetylides

Problem SH2C

C

O

CH3H

Na

CCRS

H2CC

O

CH3H R

CC

H2C

CO

H3C H

S OH2H

RC

C

H2C

CO

H3C H

H

Na

CCR 2. workup

chiral centerdid not invert

S

5. Cyanide

20


6. Lithium aluminum hydride and sodium borohydride (or deuterides)

7. Dithiane anion

8. Enolates

21


9. Reactions with LDA (lithium diisopropylamide = strong, bulky base removes a proton, made from diisopropylamine + n-butyl lithium)

Epoxides in Strong Acid/Electrophile mixtures 1. Aqueous acid

2. Alcohol + TsOH

22


Carbonyl Groups in Strong Base/Nucleophile mixtures Aldehydes 1. Hydroxide – hydration

Problem

HC

CH3

O

OC

O

CH3

HO

H

HO

C

O

CH3

H

H

attack from both faces R and S

OH

Na

H H

Na

equilibriumfavors C=O equilibrium

favors C=O

carbonylhydrate

HC

CH3

O

OH

Na

H2O

2. Alkoxide – hemi-acetal formation

Problem

HC

CH3

O

OH3C

Na

CH3OH

HC

CH3

O

OC

O

CH3

HO

H

CH3 OC

O

CH3

H

H


OH3C

Na

H3C H3C

Na


favors C=O

hemi-acetal

3. Organometallics (Li and Mg reagents)

23



5. Cyanide

Problem

HC

CH3

ONa

HC

CH3

O

Na

CNC

N

C

O

CH3

HO

H

H H

CN

C

O

CH3

H

H


CN 2. workup

6. Lithium aluminum hydride or sodium borohydride (or deuteride)

7. Enolates (with various electrophiles)

Problem

Li

N

HC

CH2

O

H

2.

2.

2.

3. workup

Br

O

H

O

3. workup

24


8. Dithiane anion - reacts with various electrophiles, can react once (make aldehydes) or twice (make ketones)

Problem

Li

S

C

S

H

2.

2.

2.

Br

O

H

O

3. HgCl2/H2O

3. HgCl2/H2O

3. HgCl2/H2O

25


9. Sulfur ylid (make from a. diphenylsulfide + RBr (SN2) b. sulfur salt + n-butyl lithium c. carbonyl compound)

ProblemH

CCH3

O

PhS

C

Ph

PhS H2C

Ph

Br

PhS

HC

PhBr

CH3CH3

H CH2

Li CH3

H

HC

CH3

O

PhS H

C

Ph

CHO

PhS

Ph

O

CH3

CH3

trans is preferred

PhS

Ph

H2CBr

CH3n-butyl lithium

1 2

3

3

2

1

SN2

sulfur salt

sulfur ylid

10. Phosphorous ylid (Wittig reaction = make from a. triphenylphosphine + RBr (SN2) b. phosphorous salt + n-butyl

lithium c. carbonyl compound)

26


11. Wittig reaction that makes alkynes from aldehydes. (J.O.C., 1982, 47, 1837-1845)

Problem HC

R

O

Br

CH2

Li

n-butyl lithium

1

2

1

(H3CO)P

O(H3CO)

phosphorous salt

CN

N

H H

O

H R(H3CO)

P

O(H3CO)

CN

N

H

(H3CO)P

O(H3CO)

CN

N

C

O

H

R

H

N

C

P(H3CO)

(H3CO) O

CH

O

HR

N

C C

N R

HH

N

P(H3CO)

(H3CO) O

O

C RCH

terminal alkyne

(H3CO)P

O(H3CO)

CN

N

H H terminal alkyne

27


Ketones (and carbon dioxide) 1. Hydroxide – hydration

2. Hydroxide with carbon dioxide makes bicarbonate makes carbonic acid (an inorganic example)

OC

OProblem

OC

O

O

H

H

attack from both faces

OH

Na Na


favors C=O

OH

Na

H2O acidify

OC

O

OH

bicarbonate

H

OC

O

OH

H

carbonic acid 3. Alkoxide – makes hemi-ketal

Problem

H3CC

CH2

O

OC

O

CH2

O

H

HO

C

O

CH2

H


OH3C

Na

H3C H3C

Na


favors C=O

hemi-ketal

H3CC

CH2

O

OH3C

Na

H2OCH3

CH3CH3

CH3

CH3

CH3


28


5. Organometallics (Li and Mg reagents) + CO2 (special carbonyl) 2. workup


7. Cyanide

8. Lithium aluminum hydride (more reactive) or sodium borohydride (less reactive) (…or deuterides)

29


9. Enolates - many variations

Problem

Li

N

CH3

CCH2

O

H

2.

2.

2.

3. workup

Br

O

H

O

3. workup-78oC

2. workup

H3CC

CH2

O

H N

Li

H3CC

CH2

O

resonance

Br

O

CH

O

CH3

H3CC

CH2

O

H2C

CH3

2.

2.

H3CC

CH2

O

H3CC

CH2

O

H2C

CH2

O

3. workup

OH2H

H3CC

CH2

OH2C

CH2

OH

H3CC

CH2

O

H3CC

CH2

O

CHCH3

O

3. workup

OH2H

H3CC

CH2

O

CHCH3

OH

-78oC

10. Dithiane anion – many variations

Problem

Li

S

C

S

H

2.

2.

2.

Br

O

CH3C

O

CH3

3. HgCl2/H2O

3. HgCl2/H2O

3. HgCl2/H2O

30


11. Sulfur ylid (make from a. diphenylsulfide + RBr (SN2) b. sulfur salt + n-butyl lithium c. carbonyl compound)

12. Phosphorous ylid (Wittig reaction = make from a. triphenylphosphine + RBr (SN2) b. phosphorous salt + n-butyl

lithium c. carbonyl compound)

31


Esters (and carbonates) 1. Hydroxide (hydrolysis is also called saponification = soap making)

Problem

ester

R'

O

OR R'

O

O

O

tetrahedral intermediate = (T.I.)

R

H

OH

RO

R'

O

elimination

overall = acyl substitution

OH

addition

ester

R'

O

OR

OH

RO

R'

O

O

H

2. Alkoxide (Transesterification)

Problem

ester

R'

O

OR R'

O

O

O

tetrahedral intermediate = (T.I.)

R

H3C

the nucleophileattacks theelectrophileO

H3CR

O

R'

O

elimination


OH3C

addition

ester

R'

O

OR

OH3C


ester

R

O

O R

O

O

tetrahedral intermediate(T.I.)

the nucleophile attacks the electrophile

CH2

H3C O

ketone is more reactivethan the ester

ethoxidesimilar energy

to T.I. intermediate

R

Oreaction

option notpossible toaldehydes

and ketones

elimination


CH2

H3C

R

O

H2O H

2. workup

R

OH

3o alcohol with two identical groups at alcohol carbon.

32


4. Lithium aluminum hydride or sodium borohydride (or deuteride)

Problem

esterR'

O

OR

ester

R

O

O R

O

O

Dtetrahedral intermediate

(T.I.)

O

aldehyde is more reactivethan the ester

R

O

Delimination


R

O

DD

H2O H

2. workup

R

O

DD

H1o alcohol with two identical groups at alcohol carbon.

Al DD

D

D

Li

addition

Al DD

D

DLi

2. workup

LiAlD4

5. Diisobutylaluminium hydride (DIBAH)

6. Amines

7. Lithium diisopropylamide (LDA), run at -78oC

33


8. Cuprate reactions – three variations for us that complement the lithium and magnesium organometallics

34


Carbonyls (aldehydes, ketones, esters, amides, nitriles) in Strong Acid/Electrophile mixtures 1. Aqueous acid makes carbonyl hydrates

Problem

CH3

C

O

H3C

C

O

H3C CH3

C

O

C

O

H3C CH3

O

HOH H

C

O

H3C CH3

H H

H3C CH3H

OH

H H

HO

H

C

O

H3C CH3

O

H

H

O H H3O

H

H2SO4H2O

H

2. Carbonyl (aldehyde or ketone) + ROH + TsOH (-H2O) makes hemi-acetals and acetals and hemi-ketals and ketals

Problem

HC

O

H3C

C

O

R HC

O

C

O

R H

O

H

C

O

R H

H H

R HH3C

OH

H3C H

HO

H

C

O

R H

O

H

H3C

hemi-acetal

resonance

OH TsO HTs

C

O

R H

O

H

H3C

H

C

OH3C

HR

resonance

C

OH3C

HR

H3CO

H

C

O

R H

O

H

H3C

H3CCH3

O

HC

O

R H

OH3C

H3C

acetal

remove H2O

TsOHCH3OH

(-H2O)hemi-acetal

TsOHCH3OH acetal

OH TsCH2

OH

several steps

CH3C H

O

hemi-acetal

acetal favored by removal of water

several stepscarbonyl favored by

addition of water

H2C

OH

CH3C H

OOC

H3C H

OOH

O

H

35


HOOH

OTsH

OTs

OH

O

OH

TsO H

OH

O

OH

HOH

O

O

H

O OH

O O

H

OHH

OHH

H

H

OH

O

OH

O

O

H

ketone

hemi-ketal

Making a ketal (acetals are similar)

resonance

water controls the direction of equilibrium

OO

HO

H

resonance

ketal

ProblemHO

OH

O OTsH

Problem

OO

Hydrolysis of a ketal back to a ketone and ethylene glycol (acetals are similar and go back to aldehydes and ethylene glycol)

(H2SO4/H2O)

HH

O O

OHH

H OOH

OHH

O

O

H

O

O

H OH

O

OH

H

OHH

OHH

OHH

H

OH

O

OH

OH

O

OH

H

OH

OH

resonance

OHH

OHH

H

O

ketal

ketone

O O H3OH2O

36


3. Carbonyl (aldehyde or ketone) + RNH2 + TsOH (-H2O) / pH = 5, makes imines that can be reduced (a. NaH3BCN b. workup) to amines.

Problem

TsOH(-H2O)

N

OTsH

OTs

OH

N

TsO H

OH

N

HOH

N

H

H

OH

N

N

ketone oraldehyde

Making an imine from a ketone or aldehyde and NH3, RNH2 or R2NH. Then making the imine into a 1o, 2o or 3o amine using NaH3BCN and workup.

resonance

water controls the direction of equilibrium

O OH

OH

resonance

imine

HH

HHH

pH 5(-H2O)

NH3, RNH2 or R2NH

RH2N

N

remove to for imine

N

Reduce imine to amine with 1. sodium cyanoborohydride and 2. workup

BH

H

H

C N

NaN

H

Na

2. workup

OH2HN

H

H

TransformationsC=O + NH3 primary aminesC=O + 1o amines secondary aminesC=O + 2o amines tertiary amines

imineamine

O

NH2

1. NaH3BCN2. workup

H

H

37


4. Carbonyl (aldehyde or ketone) + R2NH + TsOH (-H2O) / pH = 5, makes enamine that can be alkylated and hydrolyzed back to a ketone

38


5. Fischer esterification (RCO2H + R’OH RCO2R’ + H2O using TsOH as acid catalyst)

Problem

(-H2O)

TsOHCH3OH

C

O

R O

C

O

R O

O

H

C

O

R O

H

H3CO

H

H3C H

C

O

R O

O

H

H3C

carboxylic acid

T.I.

resonance

equilibrium is controlled by water, removing water shifts it to the right and adding water shifts it to the left

OH Ts

O HTs

C

O

R O

O

H

H3C

H

= B

= C

H H C

O

R O

H

H

resonance

C

O

R O

H

H

H

O Ts

HH

C

O

R O

H

CH3

resonance

C

O

R O

H

CH3

resonance

C

O

R O

H

CH3

HO

H

O Ts

C

O

R OCH3

ester

water can be distilled out and removedfrom the equilibrium

C

O

R OH H3C

OH

alcohol

6.

39


Acid chlorides (and chloroformates, phosgene and equivalents, sulfur, nitrogen and phosphorous)

1. Making an acid chloride (from RCO2H + SOCl2)

2. Alcohols make esters

3. Amines make amides

40


4. Organometallics (Li and Mg reagents) make tertiary alcohols

5. Lithium aluminum hydride or sodium borohydride make primary alcohols

6. Diisobutylaluminium hydride (DIBAH) makes ketones

7. Carboxylic acids make anhydrides

8. Water remakes the carboxylic acid (not desired)

9. Aromatics + AlCl3 makes aromatic ketones

10. Cuprates make ketones

Anhydrides (organic and mixed) 1. Hydroxide

2. Alkoxide


4. Lithium aluminum hydride or sodium borohydride


6. Amines

7. Lithium diisopropylamide (LDA)

8.

Acids 1. Hydroxide

2. Alkoxide




6. Amines


8.

41


Amides (primary, secondary and tertiary) 1. Hydroxide

2. Alkoxide




6. Amines


8.

Nitriles 1. Hydroxide

2. Alkoxide




6. Amines


8.

Carbonyl Groups in Strong Protic or Lewis Acid Conditions 7. Aldehydes

8. Ketones (and carbon dioxide)

9. Esters (and carbonates)

10. Acid chlorides (and chloroformates, phosgene and equivalents, sulfur, nitrogen and phosphorous)

11. Anhydrides (organic and mixed)

12. Acids

42


13. Amides (primary, secondary and tertiary)

14. Nitriles

15.

Miscellaneous (Various name reactions) 1. Baeyer Villigar reaction

2. Iodoform reaction

3. Nitrile synthesis from primary amide and SOCl2

CR

O

NH resonance Base

BaseH

CR NCR N

resonance

H

H HCR N

ClH

synthesis of a nitrile from an 1o amide + thionyl chloride (SOCl2)

resonance

resonanceS

Cl

O

ClC

R

O

NH

S

O Cl

Cl

H

CR

O

NH

S

O Cl

Cl

CR

O

NH

S

O Cl

Cl

HH

CR

O

N

S

O Cl

Cl

HCl

OS

O

Cl

CR

O

N

SCl

O

H

43


4. Hydrolysis of nitriles (moderate acid makes 1o amide, strong acid/heat makes carboxylic acids)

H3CC

N

H3CC

N CNH3C

O

HH

CN

H

H3C

OH

CN

H

HH3C

OH

CN

H

HH3C

OH

CN

H

HH3C

O

HO

H

HCl / H2O hydrolysis of a nitrile to an amide (in H2SO4 / H2O / hydrolysis continues on to a carboxylic acid)

H

O

H

H HH3C

CN

H

OH H

H

H

O

H

CN

H

HH3C

OH

O

H

H H

stop here in HCl/H2O(continue on in H2SO4/H2O)

O

H

H HC

N

H

HH3C

OH

see resonance structuresdirectly above

H

O

HC

N

H

HH3C

OH

O H

H H

O

H

CN

H

HH3C

OH

O

HO

H

H H

CN

H

HH3C

OH

O

H

HC N

H

H

H3C

OH

H

H3CC

OH

O

H

H3CC

OH

O

H

N

H

H

H H3CC

OH

ON

H

H

H

H

most stable cation drivesequilibrium to completion

resonance

resonanceresonance

resonance

resonance

hydroxamic acid

1o amides

OH

carboxylic acids (in H2SO4/)

O

H

H H

5. Ritter reaction

44


6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19. Cuprates DIBAH Nitriles Thionyl chloride

45


CN

OH

OH3C methyl RBr = only SN2primary RBr = mainly SN2secondary RBr = mainly SN2tertiary RBr = only E2

methyl RBr = only SN2primary RBr = SN2 > E2secondary RBr = E2 > SN2tertiary RBr = only E2

methyl RBr = only SN2primary RBr = SN2 > E2secondary RBr = SN2 > E2tertiary RBr = only E2

methyl RBr = only SN2primary RBr = SN2 > E2secondary RBr = SN2 > E2tertiary RBr = only E2

Li

S

CCR

H3C

H2C CH2

O H

BrH

primary alcoholH3C

H2C CH2

O H

H

Br

H3C

H2C CH2

O

H

H

BrSN2

no rearrangement

BrH

O

H

H H

primary bromoalkane

Br

pKa = -9

water is a good leaving group

H2CC

O

CH3H

SH2C

C

O

CH3H

CH2

H2C

CO

H3C H

S OH2H

CH2

H2C

CO

H3C H

H

RNa

2. workup

OH

S

Al D

D

D

D

Li

S

S

H3CC

CH2

O

H3CC

CH2

O

CH3C

O

C

O

H3C

46


IBrIBr CN

I

IC

N

a b

O Br

Br I

IO

c dH H2O

O

O O

H

eO

CH3

Li

O

CH3

Li 2. workup

OH2H

O

CH3

HH2O

Cl

Li

Cl

f

H

O Na

H

O

C

2. workup

OH2H

H2O

Cl

LiCl

C N

N

Na

H

O

C N

H

C CH

2. workup

OH2H

OO O

HH2Og Na Na

h H

CH3

ClH

H

H

CH3Cl

H

H

Cl

CH3

47


H3CC

CH

OH

H

H H3CC

C

H

H

O

H

H

CC

H

HH3C

O

H

O

H

H

H

CC

H

HH3C

OH

OH

H

HCC

H

HH3C

OH

H

CC

H

HH3C

OH

H

CC

H

HH3C

O

H

OH

H

HH

OH

There isn't any lone pair, so you have to use the pi electrons as the nucleophile.i

BrBrBr

Br

jBra little tricky,

requires 3 arrowsto make bridge

Br

BrBr Br

O

k Bra little tricky,requires 3 arrows

H

O

H HH

H

O

H

Br

OH

OH2HBr

O

O

O

O

HO

H

O

OH

O

H

O

OH

H

O

OOO

HO O

H

O

HHO

HH

H

common name = ________________

Remove H2O shifts equilibrium to the _________________

Adding H2O shifts equilibrium to the _________________

functional group = _____________

H

O

H

O

OH

Hydrolysis of a ketal back to a ketone and ethylene glycol (acetals are similar and go back to aldehydes and ethylene glycol)l

(H2SO4/H2O)

O

O

H

O

HH

O

HH

H

O

HO

HH

O

HHH

H

O

HH

H

48


Na

O H

R

C

O

O

H

O

H

R

H

O

H

CR

O

O

R

O

H

R

C

O

O

H

O R

H

O

R

R

C

O

O2. workup(neutralize carboxylate)

R

C

O

O

H

H

ester

alcohol

carboxylic acid

Na Na

NaR

C

O

O

m ester base hydrolysis = saponification

R

C

O

Cl

R

O

H

CR

O

O

R

ClR

C

O

O

R

acid chloride

n ester synthesis from acyl substition at an acid chloride with an alcohol

H

H

Cl

R

C

O

O

R

ClH

R

C

O

Cl

R

N

H

CR

O

N

R

Cl

R

C

O

N

R

acid chloride

o secondary amide synthesis from acyl substition at an acid chloride with a primary amine

H

HCl

R

C

O

N

R

ClH

H H

H H

C

R

O

O

H S

Cl

O

Cl C

R

O

O

H

S

O Cl

Clresonance

C

R

O

O

H

S

O Cl

Cl

C

R

O

O

H

S

O Cl

Cl

Base

C

R

O

O

S

O Cl

Cl

BaseH

C

R

O

O

SCl

O

Cl

OS

Cl

O

CR OCR O

resonance

C

R

Cl

O

p synthesis of an acid chloride from an acid + thionyl chloride (SOCl2)

acylium ion

49


H2C

R O

H S

Cl

O

Cl

H2C

R O

S

O Cl

Cl

BaseH

OS

Cl

O

H Base

H2C

R O

S

O Cl

Cl

H2C

R O

SCl

O

Cl

CH2

R

Cl

q synthesis of an alkyl chloride from an alcohol + thionyl chloride (SOCl2) [can also make RBr from SOBr2]

SN2 at methyl and primary alcohols

CH

R O

H S

Cl

O

Cl

CH

R O

S

O Cl

Cl

BaseH

OS

Cl

O

H Base

CH

R O

S

O Cl

Cl

CH

R O

SCl

OCl

C

R

R

RR

R

R

H

C

R

R

H

ClSN1 at secondary and tertiary alcohols

r synthesis of an alkyl chloride from an alcohol + thionyl chloride (SOCl2) [can also make RBr from SOBr2]

C

R

O

N

H S

Cl

O

Cl C

R

O

N

H

S

O Cl

Clresonance

C

R

O

N

H

S

O Cl

Cl

C

R

O

N

H

S

O Cl

Cl

Base

C

R

O

N

S

O Cl

Cl

BaseH

C

R

O

N

SCl

O

Cl

OS

Cl

O

CR NCR N

resonance

HH H H

H

H

H HCR N

ClH

r synthesis of a nitrile from an 1o amide + thionyl chloride (SOCl2)

50


There isn't any lone pair, so you have to use the pi electrons as the nucleophile.s

HC

CH2

CH2

H3C C

CH2

CH3

H3C

H

C

CH2

CH3

H3C

H

OH

H

C

CH2

CH3

H3C

H

O

H

O

H

H H

O H

OH H

O

H

H HH

hydration of an alkene with aqueous acidform most stable carbocation

( rearrangements are possible )

There isn't any lone pair, so you have to use the pi electrons as the nucleophile.t

HC

CH CH2

H3C C

C CH3

H3C

H

C

C CH3

H3C

O

H

H H

O HO

H

H H

H



CH3 CH3

H

HH

CH3

C

C CH3

H3C

HH

O

HH

H3C

OH

H

C

C CH3

H3C

HH

O

H

H3C

There isn't any lone pair, so you have to use the pi electrons as the nucleophile.s

HC

CH2

CH2

H3C C

CH2

CH3

H3C

H

C

CH2

CH3

H3C

H

OH

CH3

C

CH2

CH3

H3C

H

O

CH3

O

H

H CH3

O CH3

OH CH3

O

H

H CH3H



(CH3OH / TsOH)

51


There isn't any lone pair, so you have to use the pi electrons as the nucleophile.t

HC

CH CH2

H3C C

C CH3

H3C

H

C

C CH3

H3C

O

H

H3C H

O HO

H

H CH3

H3C

ether synthesis from an alkene with alcoholic acidform most stable carbocation


CH3 CH3

H

HH

CH3

C

C CH3

H3C

HH

O

HCH3

H3C

OH3C

H

C

C CH3

H3C

HH

O

CH3

H3C

(CH3OH / TsOH)

O

O

O

O

HO

H

O

OH

O

H

O

OH

H

O

OOO

HO O

H

O

HHO

HH

H

common name = ________________

Remove H2O shifts equilibrium to the _________________



H

O

H

O

OH

Hydrolysis of a ketal back to a ketone and ethylene glycol (acetals are similar and go back to aldehydes and ethylene glycol)l

(H2SO4/H2O)

O

O

H

O

HH

O

HH

H

O

HO

HH

O

HHH

H

O

HH

H

52


H3CC

N

H3CC

N CNH3C

O

HH

CN

H

H3C

OH

OH

H

H

CN

H

HH3C

OH

CN

H

HH3C

OH

CC

H

HH3C

O

H

HO

H

HCl / H2O hydrolysis of a nitrile to an amide (in H2SO4 / H2O hydrolysis continues on to a carboxylic acid)i

H

O

H

H HH3C

CN

H

OH H

H

H

O

H

CN

H

HH3C

OH

O

H

H H

stop here in HCl/H2O(continue on in H2SO4/H2O)

O

H

H HC

N

H

HH3C

OH

see resonance structuresdirectly above

H

O

HC

N

H

HH3C

OH

O H

H H

O

H

CN

H

HH3C

OH

O

HO

H

H H

CN

H

HH3C

OH

O

H

H

C N

H

H

H3C

OH

O

H

H

H3C

C

O

H

O

H

H3C

C

O

H

O

H

N

H

H

H H3C

C

O

H

O N

H

H

H

H

most stable cation drivesequilibrium to completion

53


H3C

CH2

C

H

O

H

H

Cr

O

OO H3C

CH2

C

H

O

H

H

Cr

O

O

O

H3C

CH2

C

H

O

H

Cr

O

O

ON

N H

N

H3C

CH2

C

H

OCr

O

O

O

N H

PCC = pyridinium chlorochromate oxidation of primary alcohol to an aldehyde (no water to hydrate the carbonyl group)

primary alcohols

aldehydes

H3C

CH2

C

CH3

O

H

H

Cr

O

OO H3C

CH2

C

CH3

O

H

H

Cr

O

O

O

H3C

CH2

C

CH3

O

H

Cr

O

O

ON

N H

N

H3C

CH2

C

CH3

OCr

O

O

O

N H

PCC = pyridinium chlorochromate oxidation of secondary alcohol to a ketone

secondary alcohols

ketones

54


H3C

CH2

C

H

O

H

H

Cr

O

OO H3C

CH2

C

H

O

H

H

Cr

O

O

O

H3C

CH2

C

H

O

H

Cr

O

O

O

H3C

CH2

C

H

OCr

O

O

O

Jones = CrO3 / H2O / acid primary alcohols oxidize to carboxylic acids

(water hydrates the carbonyl group, which oxidizes a second time )

primary alcohols

aldehydes

H

O

HH

O

H

H

H

O

H

H

H3C

CH2

C

H

O

H

H3C

CH2

C

H

O

H

H

O

H

H3C

CH2

C

O

H

O

H

H

H

H

O

HH3C

CH2

C

O

O

H H

H

O

H

H

Cr

O

OO

H

H3C

CH2

C

O

O

H H

H Cr

O

O

O

H

O

H

H3C

CH2

C

O

O

H H

Cr

O

O

O

H

O

H

H

H

O

H

H3C

CH2

C

O

OH

H

O

H

H

Cr

O

O

O

hydration of the aldehyde

second oxidation of the carbonyl hydrate

55


Na

CN

H3CCH2

BrC

N

H2C

CH3

H2CC

O

CH3H

HC

CH3

O

Na

CN

Na

CN

CN

H2C

CO

H3C H

CN

C

O

CH3

H

O

H

H H

O

H

H H

CN

H2C

CO

H3C H

CN

C

O

CH3

H

H

H

Na

CHC

H3CCH2

BrC

HC

H2C

CH3

H2CC

O

CH3H

HC

CH3

O

Na

CHC

Na

CHC

CHC

H2C

CO

H3C H

CHC

C

O

CH3

H

O

H

H H

O

H

H H

CHC

H2C

CO

H3C H

CHC

C

O

CH3

H

H

H

CH2

Li

C

Li

H3CCH2

Br

H2CC

O

CH3H

HC

CH3

O

CH2

H2C

CO

H3C H

CC

O

CH3

H

O

H

H H

O

H

H H

too many side reactionspoor yields

H2C

CH2

H3C CH2

H2C

CO

H3C H

H2C

CH2

H3C

H

C

Li

CC

O

CH3

H

H

56


Al

D

DD

D

B

D

DD

D

Na

Li

H3CCH2

BrD

H2C

CH3

H2CC

O

CH3H

HC

CH3

O

D

H2C

CO

H3C H

DC

O

CH3

H

O

H

H H

O

H

H H

D

H2C

CO

H3C H

DC

O

CH3

H

H

H

Al

D

DD

D

Li

H3CCH2

CH

O

Reaction continues with aldehydes, IF in water (= Jones).

O

H

H HH3C

CH2

CH

OH

resonance

OH H

H3CCH2

CH

O

H

O

H HOH2

H3CCH2

CH

O

H

O

H

Cr

O

OO

H3CCH2

CH

O

O

H

H

CrO

O O

H2O

H3CCH2

CH

O

O

H

CrO

O O

OH2

Cr

O

O

O

H3C

H2C

CO

O

H

carbonylhydrate

aldehyde(from 1o alcohol)

carboxylic acids

H3C

CH2

C

H

O

H

H

Cr

O

OO H3C

CH2

C

H

O

H

H

Cr

O

O

O

H3C

CH2

C

H

O

H

Cr

O

O

ON

N H

N

H3C

CH2

C

H

OCr

O

O

O

N H

PCC = pyridinium chlorochromate oxidation of primary alcohol to an aldehyde (no water to hydrate the carbonyl group)

PCC: base = pyridine

Jones: base = water

primary alcohols

aldehydes

57


Possible Keys –Check for mistakes. I often make a few with all of the necessary computer clicks.

IBrIBr CN

I

IC

N

a b

HO Br

Br I

I

Oc dH H2O

O

OO

e

O

CH3

Li

O

CH3

Li 2. workup O

CH3

H

Cl

H2O

Li

Cl

OH2H

f

H

O Na

H

O

C

2. workup

OH2H

H2O

ClLiC N

N

Na

H

O

C N

H

Cl

C CH

2. workup

OH2H

O

O OH H2Og

H

CH3

ClH

H

H

CH3

H

H

CH3

ClCl

h

from best R+

58


H3CC

CH

OH

H

H H3CC

C

H

H

O

H

H

CC

H

HH

O

H

O

H

H

H

CC

H

HH

OH

OH

H

H

CC

H

HH

OH

H

CC

H

HH

OH

H

CC

H

HH

O

H

OH

H

HH

OH

resonance

There isn't any lone pair, so you have to use the pi electrons as the nucleophile.i

Br

Br

ja little tricky,

requires 3 arrowsto make bridgeBrBr

Br

Br

BrBr Br

O

k Bra little tricky,requires 3 arrows

H

O

H HH

H

O

H

Br

OH

OH2HBr

water is better than bromide

O

HO

OH

OTsHO

H

OTs

O

H

O

OH

TsO H

O

H

O

OH

HO

H

O

O

H

O OH

O O

H

O

HHO

HH

H

common name = ________________

common name = ________________ Remove H2O shifts equilibrium to the _________________



H

O

H

O

OH

O

H

O

O

H

ketal

ketone

hemi-ketal

right

left

Making a ketal (acetals are similar)l

59


Na

O H

R

C

O

O

H

O

H

R

H

O

H

CR

O

O

R

O

H

R

C

O

O

H

O R

H

O

R

R

C

O

O2. workup(neutralize carboxylate)

R

C

O

O

H

H

ester

alcohol

carboxylic acid

Na Na

NaR

C

O

O

resonance

m ester base hydrolysis = saponification

R

C

O

Cl

R

O

H

CR

O

O

R

ClR

C

O

O

R

acid chloride

n ester synthesis from acyl substition at an acid chloride with an alcohol

H

H

Cl

R

C

O

O

R

ClH

ester

R

N

H

CR

O

N

R

Cl

R

C

O

N

R

acid chloride

o secondary amide synthesis from acyl substition at an acid chloride with a primary amine

H

H

R

C

O

N

R

ClH

H H

H H

Cl

R

C

O

Cl

2o amide

C

R

O

O

H S

Cl

O

Cl C

R

O

O

H

S

O Cl

Clresonance

C

R

O

O

H

S

O Cl

Cl

C

R

O

O

H

S

O Cl

Cl

Base

C

R

O

O

S

O Cl

Cl

BaseH

C

R

O

O

SCl

O

Cl

OS

O

CR OCR O

resonanceC

R

Cl

O

p synthesis of an acid chloride from an acid + thionyl chloride (SOCl2)

acylium ion

Cl

60


Problem - Identify the nucleophile (Lewis base) and the electrophile (Lewis acid) in each equation and show the products of the following reactions. Add the curved arrows to show how each reaction proceeds.

a

b

c

d

CN Br

O I

NH2H3C BrH3C

SH I

e

f

g

OH IH3C

O

O

Br

O

Cl

61


h

OH

H

CH2C

H3C

CH3

Hreact with carbon

i

OH

H CH2C

H3C

CH3

H

react with proton

j

k

l

m

n

OH CH3C

H3C

O

CH2

NH3C H

HH

CH C HCH2H3C

OH CH3CH3C

O

CH2

CH3C CH3

O

OH S

O

O

OH

Problem - Which of the structures below can be a Lewis acid (show an arrow pushing reaction with base B:), a Lewis base (show a reaction with acid HA) or both an acid and a base (show both reactions)?

NH3 H2O CH4 Cl CH3OHO

H C

O

O

62


1. Mechanism for free radical substitution of alkane sp3 C-H bonds to form sp3 C-Br bonds at weakest C-H position

H3C

H2C

CH3 H3CCH

CH3

Br

BrBr

overall reactionh

BrH

1. initiation

BrBrh BrBr H = 46 kcal/mole

weakest bond ruptures first

2b propagation

H3CC

CH3

H

BrBrH3C

CCH3

H Br

BrH = -22 kcal/mole (overall)

BE = +46 kcal/moleBE = -68 kcal/mole

2a propagation

H3CC

CH3

H H

Br BrH

H3CC

CH3

H

H = +7 kcal/mole (overall)


H = -15

both steps

3. termination = combination of two free radicals - relatively rare because free radicals are at low concentrations

BrH3C

CCH3

H

H3CC

CH3

H Br

H3CC

CH3

H

CH3

CH3C

H

CH

CH3

H3C CHCH3

CH3

H = -68 kcal/mole

H = -80 kcal/mole

very minor product

2. Free radical addition mechanism of H-Br alkene pi bonds (alkenes can be made from E2 or E1 reactions at this point in course) (anti-Markovnikov addition to alkenes)

H3C

H2C

CH2

Br

H3C

HC

CH2

HBrR2O2 (cat.)

h

overall reaction

1. initiation (two steps)

RO

OR h R

OO

R

BrHR

O RO

H Br

H = 40 kcal/mole

H = -23 kcal/mole


(cat.)

reagent

2a propagation

H3C

HC

CH2Br

H3CC

CH2

Br

H

H = -5 kcal/mole

BE = +63 kcal/mole BE = -68 kcal/mole

63


H = -15

both steps(2a + 2b)

2b propagation

H3CC

CH2

Br

H

BrH H3C

H2C

CH2

BrBr

H = -10 kcal/mole

BE = +88 kcal/mole BE = -98 kcal/mole

Na

CN

CH2

Li

CCH

Na

N

H3CCH2

Br

HC

H

O

C

H2CC

O

O

H

H HLi

CH3H

Al

H

HH

H

B

H

HH

H

Na

Li

Cr

O

O

O

electrophile (lewis acid) nucleophile (lewis base) free …psbeauchamp/pdf/315_arrow_pushing… ·...

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