Beauchamp Organic Reaction Review 1

Many of the reactions below have competing reactions. We mostly focus on the dominant reaction in a synthesis. That is what is shown in the small space available below. In a mechanism problem a more complete analysis is expected. You should be able to show the details of a mechanism when that is asked. In real reactions, specific recipes (solvent, temperature, concentration, etc.) are used. In these pages we only show typical results.

Acid/Base reactions to make important reactants. – The pKa’s of the starting materials and the conjugate acids of the reagents are shown in parentheses. These reactions make essential strong base/nucleohiles.

O O H NaOH NaNR2 N H N Na (pKa=9) (pKa=16) O (pKa=25) (pKa=37) Na O

Beauchamp Organic Reaction Review 2

Free radical substitution reactions at sp3 C-H to make R-Br from alkanes. Br Br2 Br Br2 CH4 h H3C h

Br Br

Br2 Br2 h h

Br

Br Br2 Br2 h h

Br

Br2 Br Br2 h h

Br 2 equivalents 2 equivalents Br Br

Br2 Br2 Br h h

Br Br 2 equivalents 2 equivalents Br Br

Br2 Br2 h h

E2 reactions to make alkenes (use one eq. potassium t-butoxide with RBr) and alkynes (use 3 eqs. sodium amide with RBr2, first two = E2, third equivalent = acid/base reaction)

K Br K O O Br

K K O O Br Br

Br Br K K O O

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Br Br Br 1. excess NaNR2 H H 2. workup 1. excess NaNR2 2. workup Br H

Br Br Br Br 1. excess NaNR2 H 2. workup 1. excess NaNR2 2. workup

Free radical addition reactions of HBr to alkenes (makes anti-Markovnikov addition of HBr)

HBr HBr ROOR Br ROOR Br h h

HBr HBr ROOR Br ROOR Br h h

Br Br HBr HBr ROOR ROOR h h

Free radical substitution at allylic or benzylic sp3 C-H, synthesis of allylic or benzylic RBr

Br

Br2 h

RBr + NaOH (= hydroxide) (SN2 at methyl and primary RBr, E2 > SN2 at secondary RBr and E2 at tertiary RBr, makes alcohols)

OH Br Br NaOH OH NaOH H3C H3C S 2 S 2 > E2 N alcohol N alcohol

OH OH Br Br NaOH minor NaOH

E2 > S 2 major SN2 > E2 N alcohol

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Br OH Br

NaOH NaOH

SN2 > E2 alcohol only E2 alkene

Br OH Br NaOH NaOH

SN2 > E2 E2 > SN2 alkene (benzylic) alcohol

Br Br OH NaOH OH NaOH

SN2 > E2 alcohol SN2 > E2 (allylic) alcohol

RBr + NaOR (= alkoxides) (SN2 at methyl and primary RBr, E2 > SN2 at secondary RBr and E2 at tertiary RBr, makes ethers)

Br OR Br NaOR OR NaOR H3C H3C SN2 ether SN2 > E2 ether

OR OR Br Br NaOR minor NaOR

S 2 > E2 E2 > SN2 major N ether

Br OR Br NaOR NaOR

SN2 > E2 E2 > SN2 alkene (benzylic) ether

Br Br OR NaOR OR NaOR

SN2 > E2 SN2 > E2 ether (allylic) ether

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RBr + NaO2CR (=carboxylates) (SN2 at methyl, primary and secondary RBr, SN2, makes esters and E2 at tertiary RBr)

O O Na O Na Br O Br O H3C O H3C O O SN2 ester SN2 > E2 ester

O Br O Na Br O Na O O O O O ester SN2 > E2 SN2 > E2 ester

Br O Na O Br O Na O O O

SN2 > E2 ester only E2 alkene

O Br O Na Br O Na O O O O O S 2 > E2 E2 > S 2 N N ester (benzylic) ester

O Na O Na Br O Br O O O O S 2 > E2 O S 2 > E2 ester N N (allylic) ester

Hydrolysis of esters, R’O2CR to make alcohols (acyl substitution reaction)

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RBr + NaOC(CH3)3 (t-butoxide) (SN2 at methyl and E2 at primary, secondary and tertiary RBr, makes alkenes)

Br Br K K

O O E2 alkene E2 alkene

Br Br K K

O O E2 alkene E2 alkene

RBr + NaSH (monohydrogen sulfide) (SN2 at methyl, primary and secondary RBr, and E2 at tertiary RBr, makes thiols)

Br SH Br SH NaSH NaSH H3C H3C SN2 S 2 thiol N thiol

SH Br Br SH NaSH NaSH S 2 SN2 N thiol thiol

Br SH Br NaSH NaSH

SN2 SN2 thiol alkene

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Br SH Br SH NaSH NaSH

SN2 SN2 thiol thiol

Br SH Br SH NaSH NaSH

S 2 N SN2 thiol thiol

RBr + NaSR (= alkylthiolate) (SN2 at methyl, primary and secondary RBr, makes sulfides and E2 at tertiary RBr)

Br SR Br SR NaSR NaSR H3C H3C SN2 SN2 sulfide sulfide

SR Br Br SR NaSR NaSR S 2 SN2 N sulfide sulfide

Br SR Br SR NaSR NaSR

SN2 SN2 sulfide sulfide

Br SR Br SR NaSR NaSR

S 2 N sulfide SN2 sulfide

+ RBr + Na / imidate (1. SN2 at methyl, primary and secondary RBr, and E2 at tertiary RBr 2. NaOH (acyl substitution), makes 1o amine)

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RBr + 1. NaN3 (= azide = SN2 at carbon) 2. LiAlH4 (hydride = SN2 at nitrogen) 3. Workup (acid/base) (1. SN2 at methyl, 1o and 2o RBr, and E2 at 3o RBr, makes 1o amines)

Br 1. NaN (S 2) 1. NaN3 (SN2) NH2 Br 3 N NH2 2. LiAlH (S 2) 2. LiAlH4 (SN2) H C 4 N H C 3 3. workup 3 3. workup o 1 amine 1o amine

Br NH2 Br 1. NaN (S 2) NH2 3 N 1. NaN3 (SN2) 2. LiAlH (S 2) 4 N 2. LiAlH4 (SN2) 3. workup 3. workup 1o amine 1o amine

Br NH2 Br 1. NaN3 (SN2) 1. NaN3 (E2) 2. LiAlH4 (SN2) 2. NA 3. workup 1o amine alkene

Br NH2 Br NH 1. NaN3 (SN2) 2 1. NaN3 (SN2) 2. LiAlH4 (SN2) 2. LiAlH4 (SN2) 3. workup 3. workup 1o amine 1o amine

Br NH2 Br 1. NaN (S 2) NH2 1. NaN3 (SN2) 3 N 2. LiAlH (S 2) 2. LiAlH4 (SN2) 4 N 3. workup 3. workup o 1 amine 1o amine

o o o RBr + NaCN (= cyanide) (SN2 at methyl, 1 and 2 RBr, and E2 at 3 RBr, makes nitriles)

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o o o RBr + NaCCR (terminal acetylide) (SN2 at methyl and 1 RBr and E2 at 2 RBr and 3 RBr makes larger alkynes)

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+ o o o RBr + Li / ketone enolate (SN2 at methyl, 1 and 2 RBr, and E2 at 3 RBr, makes larger ketones)

+ o o o RBr + Li / ester enolate (SN2 at methyl, 1 and 2 RBr, and E2 at 3 RBr, makes larger esters)

new O Br O Li bond O Br O Li

OR OR OR OR S 2 S 2 ester N ester N

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new Br O O Li bond Br O O Li OR OR OR OR

SN2 ester S 2 ester N

+ o o o RBr + Li / dithiane anion (SN2 at methyl, 1 and 2 RBr, and E2 at 3 RBr, makes aldehydes and ketones after hydrolysis with HgX2/H2O)

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o o o RBr + diphenylsulfide (SN2 at methyl, 1 and 2 RBr, and E2 at 3 RBr), makes sulfur salts that are used to make epoxides when reacted with 2. n-butyl lithium and 3. aldehydes and ketones

S Br S Br Br Ph Br Ph Ph Ph Ph Ph S S S 2 S 2 N Ph N Ph Ph = phenyl Ph = phenyl sulfur salt for ylid sulfur salt for ylid

Br S Br Ph Ph Br Ph Ph S S Ph Ph Ph Br SN2 S SN2 Ph = phenyl Ph sulfur salt for ylid Ph = phenyl sulfur salt for ylid

S Br Ph S Br Br Br Ph Ph S Ph Ph Ph Ph S SN2 SN2 Ph = phenyl Ph = phenyl Ph sulfur salt for ylid sulfur salt for ylid

o o o RBr + triphenylphosphine (SN2 at methyl, 1 and 2 RBr, and E2 at 3 RBr), make the phosphorous salts that are used to make the Z-alkenes when reacted with aldehydes and ketones. 2. n-butyl lithium and 3. aldehydes and ketones)

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Br P Br P Ph Br Ph Ph Ph Ph Ph Ph P Ph Ph Ph Br P SN2 Ph S 2 Ph N Ph = phenyl phosphorous salt for ylid Ph = phenyl phosphorous salt for ylid

P Br Ph P Br Ph Br Br Ph Ph P Ph Ph Ph Ph Ph Ph P S 2 SN2 Ph N Ph Ph = phenyl phosphorous salt for ylid Ph = phenyl phosphorous salt for ylid

RBr + lithium aluminum hydride (LiAlH4 = LAH) or deuteride (LiAlD4 = LAD) or sodium borohydride (NaBH4) or o o o deuteride (NaBD4) (SN2 at methyl, 1 and 2 RBr, and E2 at 3 RBr?)

D LiAlD4 Br LiAlD4 Br or D or H C NaBD NaBD 3 4 H3C 4

SN2 SN2

Br LiAlD4 D Br LiAlD4 D or or NaBD4 NaBD4

SN2 SN2

Br D LiAlD4 D Br LiAlD4 or or NaBD4 NaBD4 SN2 SN2

Br LiAlD4 D Br LiAlD4 D or or NaBD4 NaBD4

SN2 SN2

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o o o ROH + (HCl,HBr,HI or SOCl2, SOBr2 or PCl3, PBr3) (all are similar), SN2 at methyl, 1 ROH, and SN1 at 2 and 3 ROH , makes RX from alcohols HX HX or OH or Br OH Br SOX2 SOX2 H C 3 SN2 or H3C SN2 or PX3 PX3 X = Cl,Br X = Cl,Br

HX HX OH or Br OH or Br SOX2 SOX2 SN1 or SN2 or PX3 X = Cl,Br PX3 X = Cl,Br OH HX Br OH HX Br or or SOX2 SOX S 2 2 N or SN1 or PX 3 PX3 X = Cl,Br X = Cl,Br

HX OH HX Br Br OH or or SOX2 SOX2 SN1 or SN1 or PX PX3 3 X = Cl,Br X = Cl,Br HX HX OH or Br OH or Br SOX 2 SOX2 S 2 N or SN1 or PX 3 PX3 X = Cl,Br X = Cl,Br

ROH + TsCl (makes tosylates = sulfur esters = good leaving group), Can follow this with 2. NaBr to get a SN2 reaction and avoid rearrangements from the alcohol (ROH  RBr) OH HX Br HX or OH or Br SOX2 SOX S 1 2 N or SN1 or PX3 PX X = Cl,Br rearranged product 3 rearranged product X = Cl,Br

Dehydration of alcohols with H2SO4/ to form alkenes (E1 reaction), possible rearrangements. Alkenes distill away from the reaction mixture and shift the equilibrium towards alkene formation.

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OH OH H2SO4 / H2SO4 / (-H2O) (-H2O)

E1 E1

ROH + acid chloride (Cl = good leaving group), acyl substitution, makes esters

O O OH O OH O CH H3C Cl 3 Cl O O R3N (base) ester R3N (base) ester

OH O OH O O O Cl Cl O O R3N (base) R N (base) ester 3 OH O OH O O O O Cl Cl O R N (base)ester R N (base) ester 3 3 OH O OH O O O O Cl Cl O R N (base) 3 esterR3N (base) ester

O O O OH OH O Cl Cl O R N (base) O R3N (base) ester 3 ester

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o RNH2 + acid chloride (Cl = good leaving group), acyl substitution, makes 2 amides.

o o Oxidation with CrO3/pyridine = PCC (pyridinium chlorochromate) (methyl and 1 ROH  aldehydes, 2 ROH  ketones, 3o ROH don’t react), The oxidation step proceeds by an E2 mechanism

CrO3/pyridine O OH O OH (PCC) CrO3/pyridine (PCC) H3C (pyridine = base) H H H (pyridine = base) aldehyde aldehyde

O OH OH O CrO3/pyridine CrO3/pyridine (PCC) (PCC) H (pyridine = base) (pyridine = base) ketone aldehyde

OH H OH CrO3/pyridine CrO3/pyridine (PCC) (PCC) O No reaction (pyridine = base) (pyridine = base) aldehyde

OH O O OH CrO3/pyridine CrO3/pyridine (PCC) (PCC) (pyridine = base) (pyridine = base) ketone ketone

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+ o o o Oxidation with CrO3/H2O/H3O = Jones (methyl and 1 ROH  acids, 2 ROH  ketones, 3 ROH don’t react), The oxidation step proceeds by an E2 mechanism

+ O OH + O OH CrO3/H2O/H3O CrO3/H2O/H3O (Jones) (Jones) H3C H OH OH (H O = base) (H O = base) 2 acid 2 acid

O OH + CrO3/H2O/H3O OH + O CrO3/H2O/H3O (Jones) (Jones) (H2O = base) OH ketone (H2O = base) acid

OH OH OH CrO /H O/H O+ + 3 2 3 CrO3/H2O/H3O (Jones) O (Jones) No reaction (H O = base) 2 (H2O = base) acid

OH O O OH + + CrO3/H2O/H3O CrO3/H2O/H3O (Jones) (Jones)

(H2O = base) (H2O = base) ketone ketone

RCO2H (carboxylic acids) + SOCl2 (thionyl chloride)  acid chlorides

O O O O SOCl 2 SOCl2 R N OH Cl 3 R3N OH Cl acid acid chloride acid acid chloride

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RCO2H (carboxylic acids) + RCOCl (acid chloride)  anhydrides

O O O O O O O O O OH O Cl Cl OH acid acid chloride anhydride acid acid chloride anhydride

Fischer Esterification (RCO2H + R’OH + TsOH (remove H2O))  esters, reverse reaction with H2SO4/H2O O O TsOH O OH TsOH O OH OH OH H C CH3 3 O O (-H2O) ester (-H2O) ester

O OH O O TsOH OH TsOH O OH OH O O (-H O) (-H2O) ester 2 ester

OH O O OH O O TsOH TsOH OH O OH O (-H O) 2 ester (-H2O) ester

OH O O O OH TsOH O TsOH O OH OH O ester (-H2O) (-H2O)

O O O OH OH TsOH TsOH O OH OH O O ester ester (-H2O) (-H2O)

Hydrolysis of esters with H2SO4/H2O to form alcohol and carboxylic acid (reverse steps of Fischer esterification) OH OH O O H3C H2SO4 / H2O O H SO / H O CH3 2 4 2 O O O ester OH ester OH

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OH OH O O

H2SO4 / H2O O H2SO4 / H2O O O O ester OH ester OH

OH O OH (probably O alkene) H SO / H O O O 2 4 2 H2SO4 / H2O O O ester ester OH OH

O OH OH O O H SO / H O H2SO4 / H2O O 2 4 2 O O ester OH ester OH

OH OH O H SO / H O O H SO / H O 2 4 2 O 2 4 2 O O O ester ester OH OH

Protection of alcohols with dihydropyran (DHP) as tetrahydropyran ether (THP) using TsOH (cat.) and NO water.

= DHP OH OH = DHP O CH3 H3C O O O O O TsOH THP ether TsOH THP ether

OH OH = DHP = DHP O O O O O TsOH THP ether TsOH THP ether

OH OH = DHP = DHP O O O O O TsOH THP ether TsOH THP ether

OH OH = DHP = DHP O O O O O O TsOH TsOH THP ether THP ether

O OH OH = DHP = DHP O O O O O TsOH THP ether TsOH THP ether

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Making epoxides with sulfur ylid and aldehydes and ketones

Making epoxides with mCPBA

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Making Grignard reagents (organomagnesium reagents = RMgBr)

Making organolithium reagents (RLi)

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Making cuprate reagents (R2CuLi)

Organometallic reactions with RMgBr and/or RLi (aldehydes, ketones, esters, acid chlorides, nitriles, 3o amides, CuBr,…)

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Reactions of cuprates (with acid chlorides, RBr and conjugated carbonyl compounds)

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HBr H2SO4 H2O CO2 NH3 OH ammonia carbon dioxide

Na Cl Na Na Na Na Na O O OH Na NHR2 SH H N Na Br CN NNN Na Na I

H H Cu Br CH2 H B H H Al H S Li Na Li H H H N O H B CN Na O H S H O O N H Cl S HgX2 OH (mecuric salts) Cl O O O SOCl2 H N = py O PBr O O O 3 Ph O O 3 ozone Ph P reactions Cr 1. Hg(OAc) /H O O O O O 2 2 1. Hg(OAc)2/ROH O O 2. NaBH Ph o pyridine 4 2. NaBH4 1. O3, -78 C Mn Os 2. CH SCH 3 3 O O O O O HCCl3 CH I K 2 2 1. O , -78oC potassium permanganate Zn / Cu H H 3 2. NaBH Cr osmium tetroxide HCBr3 1. 1. 4 B H B H O O + H H H2O / H3O 1. O , -78oC 2. H2O2/HO 2. Br /CH O 3 2 3 2. H O , HO Mg Li 2 2 Na R 1. B H Na / NH O 3 Zn OH NH2 R HO S HO H N 2. H O /HO 2 NH 2 2 O O Pd / H2 quinoline (Lindlar's cat) Pd / H2