Acid Catalyzed Reactions Important

1

Z:\classes\316\Organic mechanisms overview\316 arrow pushing practice.doc

Acid catalyzed reactions you should be able to write arrow-pushing mechanisms for.

R

OOTsH

(-H2O)

R

N

ketones & aldehydes

enaminesR = C or H

NH

pyrrolidine

OH

OH3C

OH S

O

O

OH

∆ (-H2O)

OH S

O

O

OH

∆ (-H2O)

OH

OH S

O

O

OH

∆ (-H2O)

H2SO4H2O

OH

H2SO4CH3OH

OH3C

H2SO4H2O

OH

H2SO4H2O

OH

H2SO4H2O

O

CN

H2SO4H2O

NH2

O

O

OH

OH

O

H2SO4H2O

(both ways)

R R

O H2SO4H2O

(both ways) R R

OHHO

HOOH

OTsH

H2SO4 / H2OR R

O

R R

OO(-H2O)

OH

OH

OTsH

(-H2O)

O O

O

OH

O

OTsH

O O

H2SO4 / H2O

(THP)

OH2SO4H2O

OH

OH

O

O

OH

OTsH

OH CH3

H3C

O

OTsH

OH CH3

O

OHH

CH3

OTsH

H2SO4 / H2OO

O(-H2O)

OH

O OH

R R

OH2N

pH≈ 5

OTsH(-H2O)

pH≈ 5

R R

N

imines

H2SO4 / H2O

H2SO4 / H2O

2


Examples of acyl substitution reactions, you should be able to write arrow-pushing mechanisms for.

O

Cl

O

O

Cl

O

H

O

Cl

O

OH

O

N

Li

Cu

(cuprates)

Al

H (DIBAH)1.

2. WK

HO

H

undesiredside rxn.

O

Cl O

O O

OH

O

O

Cl

SH

O

S

O

ClOH

O

Cl

NH

O

O

O

N

O

O OOH

O

O

O

O ONH

Rriedel-Craftsreactions

AlCl3

O

Cl

O

Rriedel-Craftsreactions

AlCl3

O

O

O O

O

OR

Al

H

H

H

HLi

OHR

HO

O

OR

B

H

H

H

HNa

very slow reaction

Al

H (DIBAH)1.

2. WK

O

OR

O

H

O

OR

NH

O

N

RLi1.

2. WK

O

OR

R

R

OH2 eqs.

(Grignard reagents too)

OH Na1.2. WK

OHR

HO

OO

OR

OH Na1.2. WK

OH

O

O

N HN

3


Reaction Mechanism Worksheet Guidelines 1. Factors to consider when looking at reactants, reaction intermediates and product(s).

a. Are there any resonance effects? b. Are there any inductive effects? c. Are there any steric effects? d. Are there any stereochemical considerations?

2. Where are the pairs of electrons that can be donated? (nucleophilic sites)

3. Which site(s) can accept a pair of electrons? (electrophilic sites)

4. Is the reaction in acid? (A Lewis or Bronsted acid = E+ = strong, the acidity drives the reaction) a. Usually use a strong acid to supply protons, often the strong acid is the protonated solvent. (ROH2

+), (nonproton Lewis acids can also be species with an empty valency such as BH3, BF3, AlCl3, FeBr3, TiCl4, SbF5, etc. which all complex very well with lone pairs.) b. There are no strong electron pair donors in strong acid (bases or nucleophiles are weak). Often the weak base or leaving group is the neutral solvent. (ROH)

5. Is the reaction in base? (The strong base/nucleophile drives the reaction.) a. Usually use a weak acid to supply protons, usually the neutral solvent, (ROH), or other neutral molecule of similar acidity. b. Usually an anion (often the conjugate base of the solvent) acts as the strong nucleophile, strong base or good leaving group (RO --)

6. Are free radicals or one electron transfers involved? Often a photon or neutral (or reduced) metallic compound is part of the reaction. Oxygen or a peroxide can also serve as a free radical initiator.

In mechanism problems of our course include the following.

1. Show all lone pairs of electrons 2. Show all formal charge, when present 3. When resonance is a factor in the stability of an intermediate, draw at least one additional resonance

structure, including the “best” resonance structure. 4. Show all curved arrows to show the flow of electrons (full headed arrow = 2 electron movement) 5. Any free radical centers if present (half headed/fish hook arrow = 1 electron movement)

4


Mechanism for “Fischer” synthesis of ester - Has catalytic toluene sulfonic acid with removal of water to shift equilibrium to right.

tosylsulfonic acid = TsO-H

OH

OH

OOTsH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

RO

H

OH

OH

O

RO

H

H

OH

OH

O

H

O

OH

HO

H

O

OH

O

OH R

O

H

O

O

OHTs

Mechanism for hydrolysis of ester in acid - Has catalytic sulfuric acid in large excess of water to shift equilibrium to the right.

H2SO4 : aqueous sulfuricacid (and lots of water)

OH

O

OSO3HH

OH

OH

OH

O

HO

H

O

OH

HO

H

HO

H

O

OH

HO

HO

H

H

O

OH

O

O

OH

OH

O

OH

OH

OH

O

O

OSO3H

O

OH

H

H

HO

H

carboxylic acid

alcohol

ester

5


Mechanism for hydrolysis of ester in base (also called saponification) – Aqueous sodium hydroxide (NaOH).

OH

O

O H

O

O

OO

O

OH

HO

H

carboxylic acid alcohol

esterO O

H

OH

O

O

2. workup

HO

H

H

Protecting Aldehydes and Ketones as acetals and ketals with ethylene glycol (…and deprotection) Possible mechanism for synthesis of ketal - Catalytic toluene sulfonic acid with removal of water to shift equilibrium to right.

OTsHO

H

HO

RO

H

OH

OH

OOHTs

ketoneOH

OH

HO

OH

O

HO

TsO HOH

O

HO

H

OH

O

HO

H

O

ethylene glycol

O O

RO

H

O O

ketal

remove H2O

OH H

hemiketal

6


Possible mechanism for hydrolysis of ketal or acetal = addition of water with catalytic amount of sulfuric acid.

OH

OH O

ketone

O

H

O OH

H

O

ethylene glycol

O O

HO

H

O O

ketal

OH

HOHH

O

OH

H2O

H2O

O

H

O OH

OHH

O

H

O OH

H

H2OO OH

H

(water added)

Imine Formation from Aldehyde or Ketone Reaction with Primary Amines R-NH2 derivatives (primary amines and hydrazine) 1. Follow by reduction with sodium cyanoborohydride (NaH3BCN) to form 1o, 2o and 3o amines, or

acid cat. = TsOH (remove water)

O N

H

H

primary aminecarbonyl group

imine

O

N

H

H

OTsHO

N

H

H

H

OTs

O

N

H

H

OTsH

OH

N N

H

OTs H2O (remove)

Step 1 - making an imine

O

H

R

B

H

H

H

CN

Na

sodium cyanoborohydride(reduces imines to amines)

Step 2 - reducing an imine to an amine with sodium cyanoborohydride

N

imine

N N

H

secondary amine

HH2BCN

7


Possible Hydrolysis Mechanism of an imine (if not reduced to an amine) = addition of water with catalytic amount of sulfuric acid.

O

N

H

H

primary amine

carbonyl group

N

imine

O

N

H

H

OH2H

O

N

H

H

NN

HH

H2OH

OH2H

H2O

O

N

H

HH

OH

OH

Possible Mechanism for reaction of hydrazine H2NNH2 with aldehydes and ketones in strong base leading to reduction to a methylene group (CH2) = Wolff Kishner Reduction.

RO

O N

H

H

NH2

primary aminecarbonyl group

O

N

H

H NH2

O

N

H N

HOH

N

N

O

N

H NH2

O

H

R

H

H

O

N

N

H

H

O

H

R

R O

HH

H

N

N

H

O

H

H

N

N

H

O

H

R

N

N

H

H

RO

N

N

HN

N

H

O

H

R

H

H

8


Possible Enamine Mechanism – Secondary amine plus carbonyl compound with removal of water (we’ll always use pyrrolidine).

acid cat. = TsOH (remove water)

O N

H

pyrrolidinecarbonyl group

O

N

H

OTsHO

N

H

H

OR

N

O

N

HH

HHO

N

O

H

H

(remove water)

enamine

Possible Mechanism of Enamine with an Electrophile, (allyl bromide used in this example), Followed by hydrolysis of imminium ion back to a carbonyl compound.

N

enamine

Br

N

H

N

H

ON

HHO

HH

H2O

ONH

H OH2

ONH

HOH

resonance

NHR2O

H NHR2

alkylated ketone

9


Wittig Reaction (pronounce “Vittig”)

1. Form Wittig salt with triphenylphosphine SN2 reaction on an RX compound. 2. Use a strong base to remove a proton from the carbon alpha to the phosphorous atom and 3. Add a carbonyl compound (aldehyde or ketone) which undergoes an addition / elimination reaction

to alkenes (we’ll assume usually Z stereochemistry).

Possible Mechanistic steps for preparation and reaction of a Wittig reagent.

1. Make the Wittig salt.

triphenylphosphine

P

Ph

Ph

Ph

Br P

Ph

Ph

Ph

Br

RX compound

SN2 reaction

Wittig salt

2. Make the ylid.

P

Ph

Ph

Ph

Br

C

CH3

Wittig salt

H

HCH2

Li

n-butyl lithium

acid/baseproton transfer

P

Ph

Ph

Ph

C

CH3

H

ylid and its resonance structure

P

Ph

Ph

Ph

C

CH3

H

3. React the ylid with a carbonyl compound.

P

Ph

Ph

Ph

C

CH3

H

O

H

P

Ph

Ph

Ph

O

Usually the Z alkene is the major product.

Aldehydes and ketones react.dipolar ylid

triphenylphosphine oxide

Ph3P

C C

O

HH3C H2C

H

intermediate "betaine"

CH3

Ph3P

C C

O

HH3C H2C

H

CH3

intermediate "oxaphosphatane"

CC

H

H3C

H

H2C CH3

10


Nucleophilic hydride reactions: with organic electrophiles such as: aldehydes, ketones, esters, epoxides, nitriles and RX compounds.

Common forms of nucleophilic hydride used in this course. (Remember NaH is always basic in our course.)

Lithium aluminium hydride, LiAlH4, (LAH, very reactive, reduces many functional groups in our course, including aldehydes, ketones, esters, epoxides, nitriles and RX compounds.)

Sodium borohydride, NaBH4 (somewhat reactive, reduces aldehydes, ketones, epoxides, and RX compounds)

Sodium cyanoborohydride, NaBH3CN (used to reduce imines to amines in a reaction similar to the reduction of aldehydes by sodium borohydride).

Diisobutylaluminiumhydride, DIBAH (or DIBAL), used to diliver a single hydride to esters, nitriles and acid chlorides which become aldehydes after the workup hydrolysis step. This hydride is different from the others in that it is neutral and only has a single hydride nucleophile.

AlH

H

H

H

BH

H

H

H

BH

H

C

H

N

Li NaA H

Na

Hydride nucleophiles (e- pair donors) + organic electrophiles (e- pair acceptors), WK = work up = acidic neutralization (electrophilic “hydrogen”). a. formaldehyde (methanal) = reduced to methanol

AlH

H

H

H

Li

C O

H

H

CH

H

O

H

Li

OH2H

2. workupCH

H

O

H

H

NaBH4 works too.

b. general aldehydes = reduced to primary alcohols (like an ester or carboxylic acid with LAH)

AlH

H

H

H

Li

C O

H

R

CH

H

O

R

Li

OH2H

2. workupCH

H

O

R

H

NaBH4 works too.primary alcohols

d. general ketones = reduced to secondary alcohols

BH

H

H

H

Li

C O

R

R

CH

R

O

R

Li

OH2H

2. workupCH

R

O

R

H

LiAlH4 works too. secondary alcohols

11


e. general esters = reduced to primary alcohols only with LAH (like the aldehyde or a carboxylic acid)

AlH

H

H

H

Li

C O

R

O

CH

R

O

O

OH2H2. workup

CH

R

O

R

H

primary alcohols

RR

Li

O

R

C O

R

HH3Al H

CH

R

O

H

Two equivalents of nucleophilic hydride add to the ester carbonyl carbon. One equivalent of electrophilic hydrogen (acid) adds at the oxygen atom. Only LAH will reduce esters at a practical rate under normal conditions.

f. general carboxylic acid = reduced to primary alcohol (like the aldehyde or ester)

AlH

H

H

H

LiC O

R

O

CH

R

O

HH2O H

2. workup

H

Li

C O

R

OAlH

H

H C O

R

OH3Al AlH

H

H

H

Li

C

R

OH3Al

O

HC

R

O

H

AlH

H

H

H

Li

CH

R

O

H

H

primary alcohols

g. ethylene oxide (epoxides) = reduced to ethanol

O

BH

H

H

H

Na

H2C

O

H2. workup

OH2H

H2C

O

H

HNa

f. imines (made from primary amine and ketone or aldehyde) reduced to amines with sodium cyanoborohydride

O

H

R

B

H

H

H

CN

Na


N

imine

N N

H

secondary amine

HH2BCN

12


B

H

H

H

CN

Na


N

iminium ion

N

tertiary amine

HH2BCN

g. nitriles reduced to 1o amines with 1. LiAlH4, 2. workup.

CR N

AlH

H

H

H

Li

primary amine

C N

R

H

Li

AlH H

H

C N

R

H AlH H

HAlH

H

H

H

C N

R

H AlX X

X

H

2. workup

OH H

H

C N

R

H AlX X

X

H

HOH H

H

C N

R

H AlX X

X

H

HH

C N

R

H

H

HH

OH H

H

C N

R

H

H

HH

H(neutralize)

nitrile

h. esters and nitriles = reduced to aldehydes with diisobutylaluminium hydride, DIBAL (text = DIBAH)

O

H

R C

H

O

H

R C

HH

N

R

R

Al

H

O

H

R C

H

HO H

H

N

R CR

R

Al

HO H

H

N

R CR

R

Al

H

H

O

H

HO H

H

N

R CR

R

Al

HH

O

H

H

N

R CR

R

Al

H

N

R CR

R

Al

R NC

H

H

H OH Al

HH

O

H

H

H O

nitrile

aldehyde

13


i. hydrolysis of nitriles in HCl/1 eq H2O to amides j. hydrolysis of nitriles in H2SO4/excess H2O to carboxylic acids k. hydrolysis of nitriles in NaOH/H2O to carboxylic acids

14


Possible Mechanism for some of the cuprate reactions– Supply all necessary mechanistic details, including lone pairs, formal charge and curved arrows to show electron movement. a. Formation of dialkyl lithium cuprate

Li

Cu

Cu

Li

dialkyllithium cuprate

Br

A transmetallation allows the more electronegative anion (Br) to pair up with the more electropositive cation (Li), producing a better salt. The less electronegative anion (C) then pairs up with the less electropositive cation (Cu) to produce a better covalent bond.

Cu

Li

BrLi

2 equivalentsorganolithium reagent

1 eq.CuBr

b. Conjugate addition to α,β-unsaturated carbonyl

O

H

HH

2. WK

O

Cu

Li

OOLi

Cu

c. Acyl substitution with an acid chloride

Cl

O

Cu

Li

Cu

LiO

ClO

The ketone is LESS reactive than the acid chloride and does not react further with a cuprate reagent. (It would react further with an organolithium reagent.)

Cl

Li

d. Coupling reaction with an RX compound

Cu

Li

Cu

This reaction can be viewed as an SN2 reaction, but free radicals are likely involved. Lithium andmagnesium reagents produce a lot of sidereactions that make this coupling poor for them.

LiBr Br

2 "R" groups are coupled together with both comingfrom RX compounds.

15


Possible Mechanism for Formation of Organometallics – Supply all necessary mechanistic details, including lone pairs, formal charge and curved arrows to show electron movement.

Mg

Li Li Li Li

Mg Mg

BrR

BrR

Mg

Li

Li

Li Li

BrR

BrR

Mg Mg Mg Mg

BrR

RBr

LiLi

Li Li

Grignard (Mg) reagents

Lithium reagents

Mg Mg

BrMg2RMg

Li Li Li

R

carbanionnucleophile

carbanionnucleophile

Possible Mechanism for Reaction of Organometallics with typical Organic Electrophiles – Supply all necessary mechanistic details, including lone pairs, formal charge and curved arrows to show electron movement.

BrMgR carbanionnucleophile

(MgBr) CH

HO

OH

H

H

OHH

C

H

R

H

O

2. Workup

C

H

R

H

OH

methanal 1o alcohol

+2

CH

R'OR (MgBr) Br OH

H

H

OHH

C

H

R

R'

O

2. Workup

C

H

R

R'

OH

2o alcoholaldehydes

Mg+2

CR'

R"OR (MgBr) Br OH

H

H

OHH

C

R'

R

R"

O

2. Workup

C

R'

R

R"

OH

3o alcoholketones

Mg+2

OR (MgBr) Br

OH

H

H

OHH

2. Workup

it dependsepoxides

RO R

OH

Mg+2

16


C

O

OR (MgBr) Br OH

H

H

OHH

CRO

O

2. Workup

carbon dioxide carboxylic acid

CRO

O HMg+2

CR'

OO

R"

R (MgBr) BrMgC

R'

R

O

O

R"esters

CR'

OR

OR"R (MgBr)

C

R'

R

R

O (MgBr)OH

H

H

OHH

2. Workup

C

R'

R

R

OH

Esters react twice with organomagnesium and lithiumreagents, since the initially formed intermediatecollapses back to a ketone, which is more reactivethan the initially attacked ester, and gets attacked asecond time.

+2

LiR carbanionnucleophile

CH

HO

OH

H

H

OHH

C

H

R

H

O

2. Workup

C

H

R

H

OH

methanal 1o alcohol

Li


CH

HO

OH

H

H

OHH

C

H

R

H

O

2. Workup

C

H

R

H

OH

methanal 1o alcohol

Li


CH

HO

OH

H

H

OHH

C

H

R

H

O

2. Workup

C

H

R

H

OH

methanal 1o alcohol

Li

CH

R'OR

OH

H

H

OHH

C

H

R

R'

O

2. Workup

C

H

R

R'

OH

2o alcoholaldehydes

Li Li

17


CR'

R"OR OH

H

H

OHH

C

R'

R

R"

O

2. Workup

C

R'

R

R"

OH

3o alcoholketones

Li Li

OR

OH

H

H

OHH

2. Workup

it dependsepoxides

RO R

OH

Li Li

C

O

OR OH

H

H

OHH

CRO

O

2. Workup

carbon dioxide carboxylic acid

CRO

O HLi Li

CR'

OO

R"

RC

R'

R

O

O

R"esters

CR'

OR

OR"

R

C

R'

R

R

OOH

H

H

OHH

2. Workup

C

R'

R

R

OH

Esters react twice with organomagnesium and lithiumreagents, since the initially formed intermediatecollapses back to a ketone, which is more reactivethan the initially attacked ester, and gets attacked asecond time.

Li Li

Li

Li

Li

R Li

carboxylic acid

CR'O

O H CR'O

OLi

HR

R Li

secondequivalent

CR'O

O

R

Li

LiOH

H

H

OHH

CR'O

O

R

H

Li

OH

H

H

CR'O

O

R

HH

OH

H

HCR'O

O

R

HHH

CR' O

R

HOH

H

CR' O

R

HOH

H

H

CR'R

O

This is the one difference between Mg (Grignard) and Li reagents in our course. The lithium organometallics are a bit more reactive and will add to even a carboxylate, which after workup hydrolyze to a ketone. This takes the addition of three protons.

18


Oxidation of alcohols with chromium reagents (PCC, Jones,there are others too…) Overall Reactions

HC

O

H HC

O

OH

OHO

H

O

OH

OH O

a. PCC reagent b. Jones reagent

OHH3C

methyl alcohol

primary alcohol

secondary alcohol

tertiary alcohol

CrO3 / N

CrO3 / N

CrO3 / N

OHCrO3 /

N

No Reaction

OH

OH O

OHH3C

methyl alcohol

primary alcohol

secondary alcohol

tertiary alcohol

CrO3 / N

CrO3 / N

CrO3 / N

OHCrO3 /

N

No Reaction

Possible Oxidation Mechanism – all viewed as CrO3 (either without water present or with water present). Supply all necessary mechanistic details, including lone pairs, formal charge and curved arrows to show electron movement.

a. PCC - without water present – no carbonyl hydrate forms

CR

HH

OH

primaryalcohol

CrO3 / N

PCC conditions (no water) CR

HH

OH

CrO

OO

NCr

OO

O

N H

CR

HH

OCr

OO

O

N

N H CRH

OCr

OO

Oaldehyde

Cr = +6

Cr = +4

19


CR

R'H

OH

secondary alcohol

CrO3 / N

PCC conditions (no water) CR

R'H

OH

CrO

OO

NCr

OO

O

N H

CR

R'H

OCr

OO

O

N

N H CRR'

OCr

OO

Oketone

Cr = +6

Cr = +4

PCC with water – Possible Hydration Mechanism, followed by oxidation of the carbonyl hydrate (Jones reaction).

CRH

O

aldehyde from firstCr oxidation

H OH

OHH

H

CRH

OH

H OH

CRH

OH

HO

H H O

CRH

OH

OHH

H

CrO

OO

Cr = +6

carbonylhydrate

H O

CRH

OH

CrOO

O

H OHOH

H

H

O

CRH

OH

CrOO

OCrOO

O

H

carboxylic acid Cr = +4

HO

H

CRO

H

O

That’s all I could do for now. Try some keto/enol mechanisms in acid and in base.

Documents

Acid Catalyzed Reactions Important