1 Acid catalyzed reactions you should be able to write arrow-pushing mechanisms for. O H O H2SO4 HO OH O H O S OH H2O O R R (both ways) R R

∆ (-H2O) H OTs O O OH H3C HO H O S OH O (-H2O) O O O R R R R ∆ (-H2O) H2SO4 / H2O H OTs H O OH O O O H O S OH O OH (-H2O) O ∆ (-H2O) H OTs H (THP) O O O H2SO4 OH H2O O

H3C H2SO4 / H2O O H SO OH 2 4 H2SO4 CH OH 3 O H2O

H2SO4 OH OH H2O OH O O H CH3

H OTs O H C H2SO4 OH 3 H2O H O OH H CH3 O CH3 O H OTs O H2SO4 H2O H OTs O O O (-H O) H 2 O H2SO4 O H2O OH H2SO4 / H2O C N NH2 O pH≈ 5 N H2N H OTs H2SO4 (-H O) imines O OH 2 H2O R R R R O OH (both ways) H2SO4 / H2O O pH≈ 5 H OTs N N (-H2O) R H ketones & R aldehydes H2SO4 / H2O pyrrolidine enamines R = C or H

Z:\classes\316\Organic mechanisms overview\316 arrow pushing practice.doc 2 Examples of acyl substitution reactions, you should be able to write arrow-pushing mechanisms for.

O O O O O O O N H OH N Cl O O

O O O SH O O Cl S

O O O AlCl3 Rriedel-Crafts OH reactions Cl O H O O O H Al H Li R N R H OH HO H N O Cl H O H B H O Na Li O R H very slow reaction Cu O Cl (cuprates) O Al O O O R 1. H (DIBAH) Al O 2. WK H 1. H (DIBAH) Cl H 2. WK O O O O N O R H N H H H O Cl undesired O side rxn. O 2 eqs. OH O 1. Li R R O 2. WK O R (Grignard reagents too) R Cl AlCl3 O H O Rriedel-Crafts 1. Na O reactions R 2. WK R O O O O OH HO OH O H O O O 1. Na O N 2. WK HN OH

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

Z:\classes\316\Organic mechanisms overview\316 arrow pushing practice.doc 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 H OHTs H OTs H H O O O O O H H H H H O O O O

H H H O O H O H H H H R H O O O H O H H O O O H O O O O H H R H O O O O O R H H O O O

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

H2SO4 : aqueous sulfuric acid (and lots of water) OSO H H H 3 H O H OSO H O O ester O 3

O O O O

H O H alcohol H H O O H H H H O O H H O O H O O

O O O O H H O H H H H O O O O O H H H H H H O O H O carboxylic acid

Z:\classes\316\Organic mechanisms overview\316 arrow pushing practice.doc 5 Mechanism for hydrolysis of ester in base (also called saponification) – Aqueous sodium hydroxide (NaOH).

H ester OH H O O O O

O O O O

2. workup

O H O H O O H H O H H H O carboxylic acid alcohol O

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.

ethylene glycol OHTs H H H OH H O H OTs ketone O O O O

O H H H H H remove H2O H O O TsO H O O R H HO

O O O

hemiketal

HO HO HO

OH H O O O O O

O ketal R H

Z:\classes\316\Organic mechanisms overview\316 arrow pushing practice.doc 6 Possible mechanism for hydrolysis of ketal or acetal = addition of water with catalytic amount of sulfuric acid.

H OH H O O OH OH O O O O

O ketal (water added) H2O H H

H OH

H2O H H O O OH O O OH O O OH H H H

H H H O O H2O O O OH

ketone ethylene glycol

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

Step 1 - making an imine acid cat. = TsOH H (remove water) H OTs H O O O N OTs H H H N N carbonyl group primary amine H H

OTs H2O (remove) H H H O O N H OTs N N

imine H

Step 2 - reducing an imine to an amine with sodium cyanoborohydride H Na H2BCN H H H O R N H B CN N N

H imine sodium cyanoborohydride secondary amine (reduces imines to amines)

Z:\classes\316\Organic mechanisms overview\316 arrow pushing practice.doc 7 Possible Hydrolysis Mechanism of an imine (if not reduced to an amine) = addition of water with catalytic amount of sulfuric acid. H H H N H OH2 N N N O imine H O H 2 H primary amine H H O O H O H2O

N H H

H N N H H OH2

O O carbonyl group H H

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.

H H O R O O O R O N NH 2 H

H N N carbonyl group primary amine NH H 2 H NH2

H H H O H O O O R N

N N N H H H N H N H RO H H

H H O H H O R N N N

N N N O R

H H H

H H N H

N N H H N O R

Z:\classes\316\Organic mechanisms overview\316 arrow pushing practice.doc 8 Possible Enamine Mechanism – Secondary amine plus carbonyl compound with removal of water (we’ll always use pyrrolidine).

H acid cat. = TsOH H OTs H (remove water) O O O N OR H H N N carbonyl group pyrrolidine

H (remove water) H H O H O O H H

N N N

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.

H2O O H H

N O N N N H H H H

Br

enamine

HNHR H HOH 2 H 2 O O NHR2 N O N O H H

resonance alkylated ketone

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

Ph P Br Ph P SN2 reaction Ph Ph triphenylphosphine RX compound Wittig salt

2. Make the ylid.

Ph H Br Li Ph Ph H Ph P C H H Ph P C Ph P C CH2 acid/base Ph CH3 Ph CH proton transfer 3 Ph CH3 Wittig salt n-butyl lithium ylid and its resonance structure

3. React the ylid with a carbonyl compound.

O Ph3P O Ph Ph3P O H C C Ph P C C C H H H H H Ph CH H3C H2C 3 H3C H2C CH3 CH3 Aldehydes and intermediate dipolar ylid intermediate "oxaphosphatane" ketones react. "betaine"

Ph H H

Ph P O C C

Ph H3C H2C CH3 triphenylphosphine oxide Usually the Z alkene is the major product.

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

A H H H H Li Na Na

H Al H H B H H B C N

H H H Diisobutylaluminiumhydride, Lithium aluminium hydride, LiAlH , Sodium borohydride, NaBH (somewhat Sodium cyanoborohydride, NaBH3CN 4 4 DIBAH (or DIBAL), used to (LAH, very reactive, reduces many reactive, reduces aldehydes, ketones, (used to reduce imines to amines in a reaction similar to the reduction of diliver a single hydride to esters, functional groups in our course, including epoxides, and RX compounds) nitriles and acid chlorides which aldehydes, ketones, esters, epoxides, aldehydes by sodium borohydride). become aldehydes after the workup nitriles and RX compounds.) hydrolysis step. This hydride is different from the others in that it is neutral and only has a single hydride nucleophile.

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

H Li Li H H H 2. workup H Al H CO H C O H C O H

H H H OH2 H H NaBH4 works too. b. general aldehydes = reduced to primary alcohols (like an ester or carboxylic acid with LAH)

H Li Li H H H 2. workup H Al H CO H C O H C O H

H R H OH2 R R NaBH4 works too. primary alcohols d. general ketones = reduced to secondary alcohols

H Li Li R R R 2. workup H B H CO H C O H C O H

H R H OH2 R R LiAlH works too. 4 secondary alcohols

Z:\classes\316\Organic mechanisms overview\316 arrow pushing practice.doc 11 e. general esters = reduced to primary alcohols only with LAH (like the aldehyde or a carboxylic acid)

H R R Li Li R R

H Al H CO H C O CO H C O O H O H H R H3Al H R O 2. workup H OH R 2

R

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

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

H R R Li H R CO H Al H CO H Li H Al H CO O O H H3Al H Al H O H H

R R 2. workup R Li H Li R O C H C O H H C O H Al H C O H Al H 3 O H H2OH H H H primary alcohols g. ethylene oxide (epoxides) = reduced to ethanol

H Na O O Na H OH2 H O

H C H C H B H 2 2 2. workup H H H f. imines (made from primary amine and ketone or aldehyde) reduced to amines with sodium cyanoborohydride

H Na H2BCN H H H O R N H B CN N N

H imine sodium cyanoborohydride secondary amine (reduces imines to amines)

Z:\classes\316\Organic mechanisms overview\316 arrow pushing practice.doc 12 H BCN H Na 2 H

N N H B CN

H iminium ion tertiary amine sodium cyanoborohydride (reduces imines to amines)

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

R R R Li R C N CN CN H CN nitrile H Li H H H Al H H X Al X H Al H H H Al H H X H H Al H H H H 2. workup

H O H H H H R R H H R H R H H H CN H O H H CN H CN H CN H H H X Al X H H H X Al X (neutralize) primary amine X H O H X

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

nitrile RNC H H R H R R N Al N Al N Al HOH HAl RC RC RC R R R H H O H H O H H H

O H H H R H N Al H H H R H H H R H R N RC Al N RC Al RC HOH RC O R RC H O R O H O H H H O aldehyde O H H

H

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

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

2 equivalents organolithium reagent Li 1 eq. Br CuBr Li Li Cu Cu Cu Br Li A transmetallation allows the more electronegative anion (Br) to pair up with the more dialkyllithium electropositive cation (Li), producing a better salt. The less electronegative anion (C) cuprate then pairs up with the less electropositive cation (Cu) to produce a better covalent bond. b. Conjugate addition to α,β-unsaturated carbonyl

Li O Li Cu O O H H O H Cu 2. WK

c. Acyl substitution with an acid chloride

Li O Li Cl O O Cl Li Cu Cu Cl

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.) d. Coupling reaction with an RX compound Li

Br Li Br This reaction can be viewed as an SN2 reaction, but free radicals are likely involved. Lithium and Cu magnesium reagents produce a lot of side Cu reactions that make this coupling poor for them.

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

Z:\classes\316\Organic mechanisms overview\316 arrow pushing practice.doc 15 Possible Mechanism for Formation of Organometallics – Supply all necessary mechanistic details, including lone pairs, formal charge and curved arrows to show electron movement. Grignard (Mg) reagents carbanion nucleophile R Br R Br R Br 2 Mg R Mg Br Mg

Mg Mg Mg Mg Mg Mg Mg Mg Mg

carbanion Lithium reagents nucleophile Br Li Li Li R Br R Br R R

Li Li Li Li Li Li Li Li Li Li Li Li

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.

2. Workup H H H H +2 H O H H R (MgBr) C O R C O Mg Br R C O O carbanion H H H H nucleophile H o methanal 1 alcohol

2. Workup H H H +2 H H R (MgBr) C O R C O Mg Br H O H R C O R' R' R' aldehydes o H O 2 alcohol H

2. Workup R' R' R' H H C O +2 R (MgBr) R C O Mg Br R C O R" H O H R" R" ketones o H O 3 alcohol H

2. Workup O O O +2 Br H R H R (MgBr) R Mg H O H it depends epoxides H O H

Z:\classes\316\Organic mechanisms overview\316 arrow pushing practice.doc 16

O 2. Workup O O H +2 R C R C Mg (MgBr) R C Br H O H OH O O carboxylic acid carbon dioxide H O H

R' R' R' +2 O R C O Mg Br C O R (MgBr) C O R (MgBr) R" O O R R" R" esters 2. Workup Esters react twice with organomagnesium and lithium H R' reagents, since the initially formed intermediate H H O H R' collapses back to a ketone, which is more reactive R C O R C O (MgBr) than the initially attacked ester, and gets attacked a O second time. R H R H

2. Workup H H H H H O H H R Li C O R C O Li R C O O carbanion H H H H nucleophile H o methanal 1 alcohol

2. Workup H H H H H O H H R Li C O R C O Li R C O O carbanion H H H H nucleophile H o methanal 1 alcohol

2. Workup H H H H H O H H R Li C O R C O Li R C O O carbanion H H H H nucleophile H o methanal 1 alcohol

2. Workup H H H H H R Li C O Li R C O H O H R C O R' R' R' o aldehydes H O 2 alcohol H

Z:\classes\316\Organic mechanisms overview\316 arrow pushing practice.doc 17 2. Workup R' R' R' H H C O R Li R C O Li R C O R" H O H R" R" ketones o H O 3 alcohol H

2. Workup O O O R H R H R Li Li H O H epoxides it depends H O H

O 2. Workup O O H C R C R Li R C Li H O H OH O O carboxylic acid carbon dioxide H O H

R' R' R' O C O R C O Li C O Li R Li R" O O R R" R" esters R Li Esters react twice with organomagnesium and lithium 2. Workup reagents, since the initially formed intermediate H collapses back to a ketone, which is more reactive R' H R' than the initially attacked ester, and gets attacked a H O H second time. R C O R C O Li O R H R H

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.

R H Li H H O second O O R' C equivalent H O H O R Li R' C O Li OH Li R' C R' C O Li O carboxylic acid R Li R H O R H H H O H H H H H H O H O H H O H H H O H O H H O H R' C R' C O O R' C O R' C R' C O R R R R R

Z:\classes\316\Organic mechanisms overview\316 arrow pushing practice.doc 18 Oxidation of alcohols with chromium reagents (PCC, Jones,there are others too…)

Overall Reactions

a. PCC reagent b. Jones reagent methyl alcohol methyl alcohol O N O N H C OH CrO3 / CrO / 3 C H3C OH 3 C H H H OH primary alcohol primary alcohol O N O N OH CrO3 / OH CrO3 / H OH

secondary alcohol secondary alcohol OH N O OH N O CrO3 / CrO3 /

tertiary alcohol tertiary alcohol

N N CrO3 / CrO3 / OH No Reaction OH 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

H NH O O N O CrO3 / N H Cr O O R C Cr O O H O PCC conditions O Cr O H (no water) R C O primary H O Cr = +6 H R C alcohol H H N

O O Cr O R C NH H O aldehyde Cr = +4

Z:\classes\316\Organic mechanisms overview\316 arrow pushing practice.doc 19 H O O N O NH O CrO3 / N H Cr O R C Cr O O Cr O H PCC conditions O O O O R' (no water) R C R C secondary H H Cr = +6 R' alcohol R'

N

O O NH Cr O R C R' O ketone Cr = +4

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

H H O H O H H H O O R C O H H R C R C R C H O aldehyde H H H H HO HO from first HO H O Cr oxidation H H O carbonyl Cr O H hydrate O Cr = +6

H H H O O O H H O H R C R C H H O R C O HO O Cr O O Cr O Cr H O HO O carboxylic O O O Cr = +4 H O H acid H

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

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