Post on 13-Mar-2022
Essentials of Chapter 7
A. Carboxylic Acids1. Oxidation of alkenes
(Videos: Nucleophilic Acyl Substitution, reactions of Aldehydes and Ketones (parts 1-3), Alcohol Reactions (parts 1-2), β-elimination)
RR' 1. O3
2. H2O2 (or KMnO4)
oxidative workup
R OH
O
R' OH
O
+
2. Oxidation of 1° alcohols
R OH
KMnO4, HO-
or
Na2Cr2O7, H2O, H2SO4(Jones reagent)
R OH
O
3. Degrative oxidation of benzylic substituentsR
KMnO4
CO2H"R" must contain at least one benzylic hydrogenfor the reaction to be successful
4. Degrative oxidation of a benzene ring
R RuO4
5. Hydrolysis of esters and nitriles
R OR'
OLiOH, THF/H2O
R OH
O
(+ R'OH)
NRNaOH, H2O, heat
orH2SO4, H2O, heat
orNaOH, H2O2, H2O
* protecting group applications
* protecting group applications
R OH
O
R OH
O
H C
H
H
H
H C
H
OH
HH
CH
O
HC
OH
O
O C O[O]
[R]
[O]
[R]
[O]
[R]
[O]
[R]carbon fully
reducedcarbon fully
oxidized• reductions are characterized by addition of hydrogen and/or loss of oxygen• oxidations are characterized by addition of oxygen and/or loss of hydrogen
6. BOC group removal
R O
OCF3CO2H
CH2Cl2 R OH
O* protecting group applications
7. Organometallic reagent addition to CO2
R MgBr
R Lior
1. CO2
2. H3O+ R OH
O
B. Acid Chlorides
R OH
O SOCl2
PCl3 (or PCl5)
(COCl)2
or
or
R Cl
O
*acid bromides possible but much less common
C. Esters
R OH
O
R OR'
OR'OH
H+ H+ = H2SO4, pTsOH(excess)
• best for reactions in which R'OH is easy to remove from products• intramolecular reactions possible
1. Fisher esterification
2. From Acid Chlorides
R Cl
OR'OH
Et3N or pyridineCH2Cl2
R OR'
O
3. Special methods for methyl esters
R OH
OCH2N2 diazomethane
R OCH3
O
R OH
OK2CO3
CH3I, THF R OCH3
O
SN2 reaction
*anhydrides can be used instead of acid chlorides
R O
O
R
O
D. Amides
1. From acid chlorides
R Cl
OR'NH2 or R'2NH
2 equivalents R NR2'
O
(+ R'2NH2Cl)
2. Using carbodiimides
R OH
O1. DCC
2. R2'NH R NR2'
ODCC = N C N
E. Aldehydes
1. Reduction of acid derivatives
R Cl
OH2
Pd/BaSO4 R H
O*Rosenmund reduction
R Cl
OLiAlH(OtBu)3
R H
O
R OR'
ODIBAL
R H
O
DIBAL = (iBuAlH)2
R N1. DIBAL
R H
O
2. H3O+
2. Oxidation of 1° alcohols
R OHPCC, CH2Cl2
R H
O
PCC = CrO3NH Cl
or
1. DMSO/ (COCl)2 or TFAA2. Et3N
(swern oxidation)TFAA = (CF3CO)2O
3. Hydroboration (anti-Markovnikov) of terminal alkynes
R1. (Sia)2BH
2. H2O2, KOH ROH R
O BH
(Sia)2BH
4. Ozonolysis of alkenes
RR' 1. O3
2. (CH3)2S
reductive workupR H
O
R' H
O+
5. Hydrolysis of acetals (ketals)
R H
O
R'
O
R'
H3O+
R H
O
+ 2 HOR'
R H
O OH3O+
R H
O+ HO
OH
* protecting group applications
F. Ketones
1. Ozonolysis of alkenes
RR'' 1. O3
2. (CH3)2S
reductive workupR R'
O
R'' R'''
O+
R'
R'''
2. Fridel Crafts Acylation
R Cl
O
AlCl3
R
O
*electrophilic aromatic substitution via
R
O
3. Oxidation of 2° alcohols
R R'
OH
R R'
ONa2Cr2O7, H2SO4, H2O
orNaOCl, CH3CO2H
4. Alkyne hydration
*PCC ok too
RR
H2O, H2SO4
Hg(OAc)2
OH
R CH3
O *terminal and symmetrical alkynes
5. Organocuprate addition to acid chlorides
R Cl
O R'2CuLi
–78 °C R R'
O
6. Organolithium addition to acids/nitriles
R OH
O
R R'
O1. R'Li, -78 °C
2. H3O+
R R'
O1. R'Li, -78 °C
2. H3O+NR
7. From dithianes
SSnBuLiTHF SS
R-X SS
R
H2O, Hg(OAc)21. nBuLi
2. R'XSS
R R'R R'
O
G. Imines and related C=N type compounds
R R'
O H2N-G
(H+) R R'
NG
*G = NH2, OH, R, etc.
H. Alcohols1. Reduction of aldehydes and ketones
R R'
OR H
O
NaBH4/CH3OHor
LiAlH4/THF
R R'
OH
R OH
2. Reduction of carboxylic acids and esters
R OH
OLiAlH4/THF
or1. BH3•THF2. H3O+
R OH
R OR'
O LiAlH4/THFR OH (+HOR')
3. Hydration of alkenes
i. Acid-Catalyzed "Markovnikov" addition
RH3PO4, H2O
Rrearrangements
possible!R
OH
ii. Oxymercuration/demercuration "Markovnikov" addition
RHg(OAc)2
H2O R
OH
HgOAcNaBH4
R
OH
iii. Hydroboration "anti-Markovnikov" addition
R
1. BH3•THF2. H2O2 HO-
ROH
OAcHg
Rintermediate
RB
3intermediate
I. Amines1. From azides
R XLiN3
R N3
LiAlH4
orH2/Pd°
R NH2 *1° amines only
2. Gabriel synthesis
R X
N
O
O N
O
O
RH2NNH2
EtOHR NH2 NH
NH
O
O
+
*1° amines only
3. Reduction of nitrobenzenes
NO2
H2/Pd°
orSn° or Fe°/HCl
NH2
4. Reductive amination
R R'(H)
O R"-NH2
NaCNBH3EtOH, Δ R R'(H)
NHR"via
R R'(H)
NR"
•NH3 or 2° amines are OK too, i.e., (R")2NH
5. Reduction of amides
R NR'R"
OLiAlH4
THF R NR'R"
6. Reduction of nitriles
NRLiAlH4
THF R NH2 *1° amines only
J. Alkenes
1. E2 eliminationLG
Baseand/or *generally the more stable (more
highly substituted) alkene product is formed (Zaitsev's rule). However, this can be overriden by the use of sterically bulky bases (Hofmann elimination).
LG= I, Br, Cl, OSO2RBase = HO-, RO-, DBU [Zaitsev]Base = tBuO-, LDA or LG = N(Me)3
+ [Hofmann]
2. Dehydration of alcohols (E1 reaction)
OH Acidand/or
*generally the more stable (more highly substituted) alkene product is formed (Zaitsev's rule).
3. Hydrogenation of alkynes
R R'H2
Pd/BaSO4(Lindlar catalyst)
orP-2 nickel
R R'Li°, NH3(l)
*selective for formation of Z-alkenes
*selective for formation of E-alkenes
4. Thermal elimination reactions
i. Selenoxides
R
O1. LDA
2. (PhSe)23. H2O2
R
O
R
H2C
O
SePh O
Hvia
ii. Wittig reaction
R R'
O(Ph)3P=CR"2
R R'
R" R"
*cis alkenes generally result where applicable
K. Alkanes
1. Hydrogenation of alkenes and alkynes
RR' R R'or
H2
Pd° or Pt° or Ni° RR'
2. Reduction of tosylates
R R'(H)
OTsLAH, THF
R R'(H)
3. Wolff-Kishner reduction of aldehydes and ketones
R R'(H)
O 1. N2H4
2. KOH, ΔHO OH
R R'(H)
4. Clemmensen reduction
R'(H)
OZn(Hg), HCl R'(H)
5. Reduction of alkyl halides
R XZn°, HOAc
orLi°, EtOH
R H
6. Organocuprate coupling
R2CuLi R' X R R'+ *typical SN2 restrictions
CO2CH3LiOH, THF, H2O
OCH3
OHCO2H
OCH3
PhRuO4
CH3CN, H2O
OEtO2C
O OH
Br1. Li°, Et2O2. CO23. H3O+
O
HO2C
Ph
O
1. O3
2. H2O2
O
PhO
MeHN
O
CN
O
CO2H
OO
OHCH2N2
Et2OCO2H
NH
O
ONH
HO2C
Li CO2H
CO2ClNH2
HO2C CO2H
KMnO4
CO2CH3
OMe
CO2H
K2CO3, MeI
O
KMnO4OHO2C
NO2
CO2Cl
NO2
O OCH3
O
O
OH
O
CO2H
O
CO2Cl
–78°C
OH
OCH3
LiAlH(OtBu)3
H2CrO4, H2SO4
acetone
SOCl2 EtOH, pyridine
CO2H CH3OH, H+ CHO
1. O3
2. (CH3)2S
K2Cr2O7, H2SO4
H2O
CH2N2, Et2O
NC
OH
1. Jones reagent
2. (COCl)2
NC
O
Li
Hg(OAc)2, H2O
OH
1. (COCl)2, DMSO2. E3N
1. O3
2. H2O2
SS1. nBuLi
2.NC Br
Hg(OAc)2, H2O
1. MeLi (3 quiv)
2. H3O+
1. EtLi
2. H3O+
O
O
OH
1. DMSO, (COCl)2
O
O
NH2CH3
N2H4
NH2OH
2. Et3N
MeNOMe
OMe
H3O+ H2N
NaCNBH3, EtOH, Δ
PhPh
Ph CO2HLiAlH4, THF
Br N3
H2, Rh°/C
HO
1. Jones reagent
2. N2H4, KOH, Δ
Br
O
ONH2
O
O NH
O
O
LiAlH4, THF PCC (2 equiv)
KMnO4 1. BH3•THF
2. H3O+
CO2H 1. DCC
2. MeNH2NH
1. BH3•THF
2. H2O2, KOH
H2CrO4, H2SO4
acetonenBuLi (2 equiv)