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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.
NaOH NaNR2
Na
N
O
O
H N
O
ONa
H
(pKa=9) (pKa=16) (pKa=25) (pKa=37)
Beauchamp Organic Reaction Review 2 Free radical substitution reactions at sp3 C-H to make R-Br from alkanes.
CH4Br2
h
Br2
hH3CBr
Br
Br2
h
Br2
h
Br Br
Br2
hBr2
h
Br
Br
Br2
h
Br2
h
Br
Br
Br2
h
2 equivalents
Br2
h
2 equivalentsBr
Br
Br Br
Br2
h
2 equivalents
Br2
h
2 equivalents Br BrBr Br
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
O
K
OBr
Br
K
O
K
OBrBr
K
O
K
O
BrBr
Beauchamp Organic Reaction Review 3
1. excess NaNR22. workup
Br
Br
Br Br1. excess NaNR22. workup
H
H H
1. excess NaNR22. workup
Br BrBr Br
1. excess NaNR22. workup
H
Free radical addition reactions of HBr to alkenes (makes anti-Markovnikov addition of HBr)
HBrROOR
h
HBrROOR
hBr Br
HBrROOR
h
HBrROOR
hBr
Br
BrHBr
ROORh
HBrROOR
h
Br
Free radical substitution at allylic or benzylic sp3 C-H, synthesis of allylic or benzylic RBr
Br2
h
Br
RBr + NaOH (= hydroxide) (SN2 at methyl and primary RBr, E2 > SN2 at secondary RBr and E2 at tertiary RBr, makes alcohols)
H3CBr NaOH NaOH
Br OH
H3COH
SN2 SN2 > E2alcohol alcohol
NaOH NaOH
OHBr
OHBr
minor
majorE2 > SN2 SN2 > E2alcohol
Beauchamp Organic Reaction Review 4
NaOH NaOH
BrBr
OH
SN2 > E2 only E2alcohol alkene
NaOHNaOH
E2 > SN2
BrBr
SN2 > E2(benzylic)
OH
alkene alcohol
NaOHNaOH
SN2 > E2(allylic)
Br OHBr
SN2 > E2
OH
alcoholalcohol
RBr + NaOR (= alkoxides) (SN2 at methyl and primary RBr, E2 > SN2 at secondary RBr and E2 at tertiary RBr, makes ethers)
H3CBr NaOR NaOR
Br OR
H3COR
SN2 SN2 > E2ether ether
NaOR NaOR
ORBr
ORBr
minor
majorE2 > SN2 SN2 > E2 ether
NaORNaOR
E2 > SN2
BrBr
SN2 > E2(benzylic)
OR
alkene ether
NaORNaOR
SN2 > E2(allylic)
Br ORBr
SN2 > E2
OR
etherether
Beauchamp Organic Reaction Review 5 RBr + NaO2CR (=carboxylates) (SN2 at methyl, primary and secondary RBr, SN2, makes esters and E2 at tertiary RBr)
H3CBr
Br
H3CO
SN2 SN2 > E2ester
O
O
Na O
O
NaO
O
O
ester
O
Br
O
Br
SN2 > E2
O
O
NaO
O
Na
SN2 > E2
OO
esterester
BrBr
SN2 > E2 only E2 alkene
O
O
Na O
O
Na
O
O
ester
E2 > SN2
BrBr
SN2 > E2(benzylic)
O
O
O
NaO
O
Na
ester
O
O
O
ester
SN2 > E2(allylic)
Br O Br
SN2 > E2
OO
O
Na O
O
Na
Oester
Oester
Hydrolysis of esters, R’O2CR to make alcohols (acyl substitution reaction)
Beauchamp Organic Reaction Review 6
RBr + NaOC(CH3)3 (t-butoxide) (SN2 at methyl and E2 at primary, secondary and tertiary RBr, makes alkenes)
Br
Br
alkene
O
K
E2
O
K
E2alkene
BrBr
O
K
E2
O
K
E2 alkenealkene
RBr + NaSH (monohydrogen sulfide) (SN2 at methyl, primary and secondary RBr, and E2 at tertiary RBr, makes thiols)
H3CBr
Br
H3CSH
SN2
SH
NaSH
thiolthiol
SN2
NaSH
Br Br SHSH
thiolthiolSN2
NaSH
SN2
NaSH
Br
BrSH
thiol alkene
SN2
NaSH
SN2
NaSH
Beauchamp Organic Reaction Review 7
BrBr
SHSH
thiol thiolSN2
NaSH
SN2
NaSH
Br BrSH SH
thiolthiolSN2
NaSH
SN2
NaSH
RBr + NaSR (= alkylthiolate) (SN2 at methyl, primary and secondary RBr, makes sulfides and E2 at tertiary RBr)
H3CBr
Br
H3CSR
SN2
SR
NaSR
sulfideSN2
NaSR
sulfide
Br Br SRSR
SN2
NaSR
SN2
NaSR
sulfidesulfide
BrBr
SRSR
SN2
NaSR
SN2
NaSR
sulfide sulfide
Br BrSR SR
SN2
NaSR
SN2
NaSR
sulfidesulfide
RBr + Na+ / imidate (1. SN2 at methyl, primary and secondary RBr, and E2 at tertiary RBr 2. NaOH (acyl substitution), makes 1o amine)
Beauchamp Organic Reaction Review 8
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)
H3CBr
Br
H3CNH2
NH2
1o amine
1. NaN3 (SN2)2. LiAlH4 (SN2)3. workup
1o amine
1. NaN3 (SN2)2. LiAlH4 (SN2)3. workup
Br Br NH2NH2
1o amine1o amine
1. NaN3 (SN2)2. LiAlH4 (SN2)3. workup
1. NaN3 (SN2)2. LiAlH4 (SN2)3. workup
Br
BrNH2
alkene1o amine
1. NaN3 (SN2)2. LiAlH4 (SN2)3. workup
1. NaN3 (E2)2. NA
BrBr
NH2
NH2
1o amine 1o amine
1. NaN3 (SN2)2. LiAlH4 (SN2)3. workup
1. NaN3 (SN2)2. LiAlH4 (SN2)3. workup
Br BrNH2 NH2
1o amine1o amine
1. NaN3 (SN2)2. LiAlH4 (SN2)3. workup
1. NaN3 (SN2)2. LiAlH4 (SN2)3. workup
RBr + NaCN (= cyanide) (SN2 at methyl, 1o and 2o RBr, and E2 at 3o RBr, makes nitriles)
Beauchamp Organic Reaction Review 9
RBr + NaCCR (terminal acetylide) (SN2 at methyl and 1o RBr and E2 at 2o RBr and 3o RBr makes larger alkynes)
Beauchamp Organic Reaction Review 10
RBr + Li+ / ketone enolate (SN2 at methyl, 1o and 2o RBr, and E2 at 3o RBr, makes larger ketones)
RBr + Li+ / ester enolate (SN2 at methyl, 1o and 2o RBr, and E2 at 3o RBr, makes larger esters)
Br BrO
OR
O
OR
O
OR
LiO
OR
Li
esterester
SN2SN2
newbond
Beauchamp Organic Reaction Review 11
BrBr
O
OR
OR
OO
OR
LiO
OR
Li
ester esterSN2SN2
newbond
RBr + Li+ / dithiane anion (SN2 at methyl, 1o and 2o RBr, and E2 at 3o RBr, makes aldehydes and ketones after hydrolysis with HgX2/H2O)
Beauchamp Organic Reaction Review 12 RBr + diphenylsulfide (SN2 at methyl, 1o and 2o RBr, and E2 at 3o RBr), makes sulfur salts that are used to make epoxides when reacted with 2. n-butyl lithium and 3. aldehydes and ketones
Br Br
Ph
S
Ph
Ph
S
PhPh
SPh
Ph = phenyl
PhS
Ph
Ph = phenyl sulfur salt for ylidsulfur salt for ylid
Br Br
SN2SN2
BrBr
S
SPh
Ph
Ph
Ph
SN2
PhS
Ph
Ph = phenylSN2
PhS
Ph
Ph = phenylsulfur salt for ylid sulfur salt for ylid
Br
Br
Br BrS
SPhPh
Ph
SN2
PhS
Ph
Ph = phenyl
SN2
PhS
Ph
Ph = phenyl Phsulfur salt for ylid sulfur salt for ylid
Br Br
RBr + triphenylphosphine (SN2 at methyl, 1o and 2o RBr, and E2 at 3o 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)
Beauchamp Organic Reaction Review 13
BrBr
P
PPh
Ph
Ph
PhBr
Br
SN2
PhP
Ph
Ph = phenyl
Ph
SN2
PhP
Ph
Ph = phenyl
Ph
Ph
Ph
phosphorous salt for ylid phosphorous salt for ylid
Br BrP
PPhPh
Ph
Ph
Br Br
SN2
PhP
Ph
Ph = phenyl
PhSN2
PhP
Ph
Ph = phenyl
PhPh
Ph
phosphorous salt for ylid phosphorous salt for ylid
RBr + lithium aluminum hydride (LiAlH4 = LAH) or deuteride (LiAlD4 = LAD) or sodium borohydride (NaBH4) or deuteride (NaBD4) (SN2 at methyl, 1o and 2o RBr, and E2 at 3o RBr?)
H3CBr
Br
SN2
LiAlD4
H3CDor
NaBD4
SN2
LiAlD4or
NaBD4
D
Br Br
SN2
LiAlD4or
NaBD4
SN2
LiAlD4or
NaBD4
D D
BrBr
SN2
LiAlD4or
NaBD4
SN2
LiAlD4or
NaBD4
DD
Br Br
SN2
LiAlD4or
NaBD4
SN2
LiAlD4or
NaBD4
D D
Beauchamp Organic Reaction Review 14 ROH + (HCl,HBr,HI or SOCl2, SOBr2 or PCl3, PBr3) (all are similar), SN2 at methyl, 1o ROH, and SN1 at 2o and 3o ROH , makes RX from alcohols
H3COH
OH
SN2 H3CBr
BrHXor
SOX2or
PX3X = Cl,Br
SN2
HXor
SOX2or
PX3X = Cl,Br
OH OHBr Br
SN1
HXor
SOX2or
PX3X = Cl,Br
SN2
HXor
SOX2or
PX3X = Cl,Br
OHOH
BrBr
SN2
HXor
SOX2or
PX3X = Cl,Br
SN1
HXor
SOX2or
PX3X = Cl,Br
OHOH
BrBr
SN1
HXor
SOX2or
PX3X = Cl,Br
SN1
HXor
SOX2or
PX3X = Cl,Br
OH OHBr Br
SN2
HXor
SOX2or
PX3X = Cl,Br
SN1
HXor
SOX2or
PX3X = 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
SN1
HXor
SOX2or
PX3X = Cl,Br
OH
SN1
HXor
SOX2or
PX3X = Cl,Br
Br
Br
rearranged product rearranged product
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.
Beauchamp Organic Reaction Review 15
OH OHH2SO4 /
(-H2O)H2SO4 /
(-H2O)
E1 E1
ROH + acid chloride (Cl = good leaving group), acyl substitution, makes esters
H3COH
OHO
Cl
O
OCH3
O
O
O
Cl
R3N (base) R3N (base)ester ester
OH OHO
O
O
O
O
Cl
O
Cl
R3N (base) R3N (base) ester
OHOHO
OO
O
O
Cl
O
Cl
R3N (base) R3N (base) esterester
OHOH
O
O
O
OO
Cl
O
Cl
R3N (base) R3N (base)ester ester
OHOHO
Cl
O
O
O
O
O
Cl
R3N (base) R3N (base) esterester
Beauchamp Organic Reaction Review 16 RNH2 + acid chloride (Cl = good leaving group), acyl substitution, makes 2o amides.
Oxidation with CrO3/pyridine = PCC (pyridinium chlorochromate) (methyl and 1o ROH aldehydes, 2o ROH ketones, 3o ROH don’t react), The oxidation step proceeds by an E2 mechanism
H3COH
OH
H
O
H
O
H(pyridine = base)
CrO3/pyridine(PCC)
(pyridine = base)
CrO3/pyridine(PCC)
aldehyde aldehyde
OH OH O
H
O
(pyridine = base)
CrO3/pyridine(PCC)
(pyridine = base)
CrO3/pyridine(PCC)
ketone aldehyde
OHOH
O
(pyridine = base)
CrO3/pyridine(PCC)
(pyridine = base)
CrO3/pyridine(PCC)
aldehyde
H
No reaction
OHOHO O
ketone ketone(pyridine = base)
CrO3/pyridine(PCC)
(pyridine = base)
CrO3/pyridine(PCC)
Beauchamp Organic Reaction Review 17
Oxidation with CrO3/H2O/H3O
+ = Jones (methyl and 1o ROH acids, 2o ROH ketones, 3o ROH don’t react), The oxidation step proceeds by an E2 mechanism
H3COH
OH
H
O
OH
O
OH(H2O = base)
CrO3/H2O/H3O+
(Jones)
acid (H2O = base)
CrO3/H2O/H3O+
(Jones)
acid
OH OH O
OH
O
ketone (H2O = base)
CrO3/H2O/H3O+
(Jones)(H2O = base)
CrO3/H2O/H3O+
(Jones)
acid
OH
OH
O
OH
No reaction(H2O = base)
CrO3/H2O/H3O+
(Jones)
(H2O = base)
CrO3/H2O/H3O+
(Jones)
acid
OHOHO O
ketone ketone(H2O = base)
CrO3/H2O/H3O+
(Jones)
(H2O = base)
CrO3/H2O/H3O+
(Jones)
RCO2H (carboxylic acids) + SOCl2 (thionyl chloride) acid chlorides
SOCl2R3N
acid chloride acid acid chloride
SOCl2R3N
O
OHacid
OH
O
Cl
O
Cl
O
Beauchamp Organic Reaction Review 18 RCO2H (carboxylic acids) + RCOCl (acid chloride) anhydrides
acid
O
OHacid
OH
O
O
OO
Cl
acid chloride
O
O O
anhydride
O
Cl
acid chloride
O
anhydride
Fischer Esterification (RCO2H + R’OH + TsOH (remove H2O)) esters, reverse reaction with H2SO4/H2O
H3COH
OHO
O
O
O(-H2O)
O
OHTsOH
CH3
ester (-H2O)
O
OHTsOH
ester
OH OH
(-H2O)
O
OHTsOH
(-H2O)
O
OHTsOHO
Oester
O
Oester
OH
OH
(-H2O)
O
OHTsOH
(-H2O)
O
OHTsOH
O
O
ester
O
Oester
OHOH
(-H2O)
O
OHTsOH
(-H2O)
O
OHTsOHO
Oester
O
O
OHOH O
Oester(-H2O)
O
OHTsOH
(-H2O)
O
OHTsOHO
O
ester
Hydrolysis of esters with H2SO4/H2O to form alcohol and carboxylic acid (reverse steps of Fischer esterification)
H3COH OH
O
O
O
O
H2SO4 / H2OCH3
ester ester
O
OH
O
OH
H2SO4 / H2O
Beauchamp Organic Reaction Review 19
OH OHO
Oester
O
Oester
O
OH
O
OH
H2SO4 / H2O H2SO4 / H2O
OH OHO
O
ester
O
Oester
H2SO4 / H2O H2SO4 / H2OO
OH
O
OH
(probably alkene)
OH OH
O
Oester
O
O
H2SO4 / H2O H2SO4 / H2OO
OH ester
O
OH
OH OH
O
Oester
O
O
ester
H2SO4 / H2OH2SO4 / H2OO
OH
O
OH
Protection of alcohols with dihydropyran (DHP) as tetrahydropyran ether (THP) using TsOH (cat.) and NO water.
H3COH
OH
O OCH3
THP ether
O
= DHP
TsOHO
= DHP
TsOH
O O
THP ether
OH OH
OO
= DHP
TsOHO
= DHP
TsOH
O O
THP ether THP ether
OHOH
O
= DHP
TsOHO
= DHP
TsOH
O O
THP ether
O
THP ether
OHOH
O OO
= DHP
TsOH
O
= DHP
TsOHO O
THP ether THP ether
OHOHO
OO
= DHP
TsOHO
= DHP
TsOH
O O
THP etherTHP ether
Beauchamp Organic Reaction Review 20 Making epoxides with sulfur ylid and aldehydes and ketones
Making epoxides with mCPBA
Beauchamp Organic Reaction Review 21
Making Grignard reagents (organomagnesium reagents = RMgBr)
Making organolithium reagents (RLi)
Beauchamp Organic Reaction Review 22
Making cuprate reagents (R2CuLi)
Organometallic reactions with RMgBr and/or RLi (aldehydes, ketones, esters, acid chlorides, nitriles, 3o amides, CuBr,…)
Beauchamp Organic Reaction Review 23
Reactions of cuprates (with acid chlorides, RBr and conjugated carbonyl compounds)
Beauchamp Organic Reaction Review 24
Beauchamp Organic Reaction Review 25
Beauchamp Organic Reaction Review 26
Beauchamp Organic Reaction Review 27
Beauchamp Organic Reaction Review 28
Beauchamp Organic Reaction Review 29
Beauchamp Organic Reaction Review 30
Na
C N
Na
O H
CH2
Li
Na H
N
H
N
O
O
H
Na
S H
O
OH
H2O
O
Na
HBr H2SO4
SCl
O
O
N
S
S
Pd / H2quinoline
(Lindlar's cat)Pd / H2
Na
N N N
OH
pyridine
H2O / H3O+
CO2carbon dioxide
NH3ammonia
NHR2
HCCl3
HCBr3
CH2I2Zn / Cu
potassium permanganateosmium tetroxide
3 ozonereactions
1. O3, -78oC2. CH3SCH3
1. O3, -78oC2. NaBH4
1. O3, -78oC2. H2O2, HO
1. Hg(OAc)2/H2O2. NaBH4
1. Hg(OAc)2/ROH2. NaBH4
O
O O
H
Cl
Na / NH3
= py
NO O
Na
Mn
O O
OO
Os
O O
OOK
OO O
Cr
O
OO
Cr
O
OO
B
H
H
H
H Al
H
H
H
HNa Li
B
H
H
H
B
R
R
H
P
Ph
Ph
Ph
Na Cl
Br
INa
Na
BrCu
1.
2. H2O2/HO 2. Br2/CH3O
1.
2. H2O2/HO
B
H
H
H1.
HgX2(mecuric salts)
HOOH H2N
NH2NH
OSHO
O
O
B
H
H
H
CNNa
Mg Li Na
Zn
SOCl2
PBr3
