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)

O OH

Ph1. TsCl, pyridine

2. DBU, benzeneO

Ph

O

O CH3COCl

AlCl3

Zn(Hg), HCl H3O+

BrSS

THF

Hg(OAc)2, H2O N2H4, KOH

HO OHheat

N

1. Hg(OAc)2, H2O

2. NaBH4, EtOHN

Br CN 1. PhLi, THF

2. H3O+

O

O

O

O

O

OHCO2H

CH2N2

Et2O

DIBAL

-78°C

PhO NaBH4, EtOH Ph

OTs

PhD

H2

P-2 nickel

H3PO4, H2O 1. DMSO, TFAA

2. Et3N