Learning Group Problems 547

Summary and Review Tools

Some Synthetic Connections of Alkenes, Alkynes, Alcohols, Alkyl Halides, and Ethers

OH OH

C C

(1) OsO4
H2O, HA or HO–
(2) NaHSO3
(anti)
(syn)
H2, Ni2B (syn) O OH
or
RCO3H Nu:
C C C C C C C C
(1) Li, EtNH2 (under acidic or
(2) NH4! (a peroxy acid)
basic conditions) Nu
(anti)
Markovnikov
(1) Hg(OAc)2,
THF/H2O
(2) NaBH4
or
H2O, HA cat. C C OTBS
HA, Anti-Markovnikov F–
heat (1) BH3:THF
(2) H2O2, HO– TBSCl
imidazole
–
RO , E2 elim. O
(best if RX is
C C OH Oxidation/Reduction (Chapter 12) C C
2" or 3°, or
use bulky RO– ) Y
Y & H, R, or OH
NaH or Na", K" (also by alkene
oxidation, see
I. HX Chapter 8)
HX HO– TsCl or
(1" or 3") C C O%
(Markov.) (1" RX) MsCl, etc.
or if 1" or 2"
or pyr
II. PBr3
HBr, ROOR, H2O or
# (Anti- (3" RX) III. SOCl2 RX or ROTs
Markov.) C C OTs(or Ms or Tf) (if RX or ROTs is 1")

R'O– (if RX or ROTs is 1")

C C H C C X C C OR'
Br2, h$ or #
(best if RH is 3")

• Alkynes to alkenes
• Alkenes and alcohols
• Alcohols and alkyl halides
• Alkenes and alkyl halides
• Alcohols and ethers
• Alkenes, epoxides, and 1,2-diols
• Alkanes to alkyl halides
• Alcohol silyl protecting group
• Alcohols to carbonyl compounds

Figure 11.4 Some synthetic connections of alkynes, alkenes, alcohols, alkyl halides, and ethers.

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 Summary of Reactions 583

Summary of Reactions
Summaries of reactions discussed in this chapter are shown below. Detailed conditions for the
reactions that are summarized can be found in the chapter section where each is discussed.

Synthetic Connections of Alcohols and Carbonyl Compounds

Substrate Reducing agent

1. Carbonyl Reduction Reactions
NaBH4 LiAlH4 (LAH)
• Aldehydes to primary alcohols
• Ketones to secondary alcohols O OH OH
• Esters to alcohols [H]
• Carboxylic acids to primary alcohols Aldehydes
R H R H R H
H H

O OH OH
[H]
Ketones R R¿ R R¿ R R¿
H H

O OH
[H]
Esters ! R¿¬ OH
R OR¿ R H
H

O OH
Carboxylic [H]
acids R OH R H
H

(Hydrogen atoms in blue are added during the reaction workup by

water or aqueous acid.)

2. Alcohol Oxidation Reactions

• Primary alcohols to aldehydes

• Primary alcohols to carboxylic acids
• Secondary alcohols to ketones

Substrate Oxidizing agent [O]

PCC H2CrO4 KMnO4

O O O
[O]
Primary alcohols
R OH R H R OH R OH

OH O O O
[O]
Secondary alcohols
R R¿ R R¿ R R¿ R R¿

OH
[O]
Tertiary alcohols
R R¿
R–

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m_c12_548-584hr1.qxd 14-10-2009 15:46 Page 584

584 Chapter 12 Alcohols from Carbonyl Compounds

Synthetic Connections of Alcohols and Carbonyl Compounds

3. Carbon-Carbon Bond Forming Reactions

• Alkynide anion formation

• Grignard reagent formation
• Alkyllithium reagent formation
• Nucleophilic addition to aldehydes and ketones O OH
• Nucleophilic addition to esters
• Nucleophilic ring-opening of epoxides (1) R¿(H) R–(H) R¿(H) R–(H)
Nu
(2) H3O! (or NH4!)

NaNH2 "
R H R
(or other
strong base) O
OH
(1) R OR¿
Mg in ether R MgX Nu: R Nu ! R¿¬ OH
(2) H3O! (or NH4!) Nu
R X
2 Li

R Li ! LiX O
(1)
OH

(2) H3O! (or NH4!)

Nu
(a substituted or
unsubstituted oxirane

Nu # alkynyl group, or alkyl group

from Grignard or alkyllithium
reagent

See First Review Problem Set in WileyPLUS

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 SUMMARY OF MECHANISMS

Acetals, Imines, and Enamines: Common Mechanistic Themes in Their Acid-catalyzed Formation from Aldehydes and Ketones

Many steps are nearly the same in acid-catalyzed reactions of aldehydes and ketones with alcohols and amines. Compare the
mechanisms vertically to see the similarities and differences. Note differences in completion of the mechanism for each type of product.
I. Hemiacetal and acetal formation: reaction with alcohols
"
A "
H A
H A H
H A
O H H H
H !
R O
! ! R R
O O H O !O H O O H O O –HOH O R O !O R O O R
R R R R

R' R"(H) R' R"(H) R' R"(H) R' R"(H) R' R"(H) R' R"(H) R' R"(H) R' R"(H)

Hemiacetal Acetal
In acetal formation, the oxonium ion is
attacked by a second alcohol molecule.
II. Imine formation: reaction with primary amines
" "
H A A
H A
N H
H A H
H H
H R H
H ! !
! H ! R R
O O H O N H O N H O N "HOH N N
R R R

R' R"(H) R' R"(H) R' R"(H) R' R"(H) R' R"(H) R' R"(H) R' R"(H)
In imine formation, the proton on Imine
the initial iminium ion is removed,

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leading to the stable imine product.
III. Enamine formation: reaction with secondary amines
"
H A
H A
N R
H A R
H R R ! R
R R H R R
H ! ! N N
! R ! R
O O H O N H O N H O N "HOH N
R R R
Summary of Mechanisms

C R"(H) C R"(H)
R' R"(H) R' R"(H) R' R"(H) R' R"(H) R' R"(H) R' R"(H)
H
" Enamine
A
In enamine formation, a proton is removed from a carbon adjacent
to the iminium carbon (because no proton is available for removal
from the nitrogen).
775
 SUMMARY OF MECHANISMS
776

Nucleophilic Addition to Aldehydes and Ketones Under Basic Conditions

Generalized nucleophilic addition to an aldehyde or ketone:

A H ! Protonation during H
O workup O
O
(in most reactions)
" Nu! " A!
R' Nu or by protic solvents R' Nu
R' R"(H)
R"(H) R"(H)
Aldehyde or
ketone Nucleophile Tetrahedral intermediate Product

!
H
O O
Examples: ! H Alcohol (reduction)
Chapter 16

R' H R' H
Hydride [e.g., from R"(H) R"(H)
NaBH4 or LiAlH4 (LAH)]
!
H
Li" O O
Li R Alcohol (with C¬C bond formation)
R' R R' R
Alkyllithium R"(H) R"(H)

!
H
X!Mg2" O O

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XMg R

Orgánica  II,  DC  Angel  A.  Ramos  O.  

Aldehydes and Ketones

Alcohol (with C¬C bond formation)

R' R R' R
Grignard reagent R"(H) R"(H)
!
H
O O
! Alkynyl alcohol (C¬C bond formation)
C C R
R' C R' C
Alkynide anion R"(H) C R"(H) C
R R
!
H
O O
! C N Cyanohydrin
R' C R' C
Cyanide R"(H) N R"(H) N
 SUMMARY OF MECHANISMS

Nucleophilic Addition to Aldehydes and Ketones Under Basic Conditions

Generalized nucleophilic addition to an aldehyde or ketone:

A H ! Protonation during H
O workup O
O
(in most reactions)
" Nu! " A!
R' Nu or by protic solvents R' Nu
R' R"(H)
R"(H) R"(H)
Aldehyde or
ketone Nucleophile Tetrahedral Intermediate Product

" R' R2
P(C6H5)3 O P(C6H5)3
Examples ! Oxaphosphetane Wittig preparation of alkenes
R2 R' R2
(continued): intermediate (with loss of triphenylphosphine
R"(H) R1
R1 R"(H) R1 oxide [(C6H5)3PO])
(plus diastereomer)
Phosphorus ylide

b-Hydroxy and a,b-unsaturated

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! ! H carbonyl compounds
O O O O O O R' O
!
R3 R3 R4 R' R4 R'
R4 R4 (H)R" R4
R"(H) R"(H)
H R3 H R3 H
H ! A R3
Enolate (see Chapter 18)
Summary of Mechanisms
 Synthetic Connections
778

Some Synthetic Connections of Aldehydes, Ketones, and Other Functional Groups

Clockwise from center, O OH ROH, OR

bottom: cat. HA

I. Preparation of aldehydes R¿ Cl R¿ OR H2O, R¿ OR

and ketones: (1) ArH, AlCl3; ROH, R–(H) cat. HA R–(H)
R¿ R– (2) HOH cat. HA
• Nitrile, ester, acyl (leads to R–=Ar)
R¿ C N
halide reduction H2O, SR H 2, H
R– R¿ (1) R–MgBr cat. HA Raney Ni
• Alcohol oxidation (1) O3 or R–Li
• Ozonolysis (2) Me2S (2) H3O! R¿ SR R¿ H
• Friedel–Crafts (products depend RSH (2 equiv.), R–(H) R–(H)
acylation on R groups) cat. HA
• Grignard with nitrile
OH H2O, OH
• Acetal and hemiacetal O
Chapter 16

H2CrO4 or KMnO4 cat. HA

hydrolysis
R¿ R– R¿
R¿ R" C
(1) RC C" R–(H) C
R
NaBH4; or (1) LAH; (2) H2O (2) H3O!

R¿ OH PCC O OH

R¿ H (1) CN"
II. Reactions of aldehydes R¿
(2) H3O! C
and ketones: (1) LiAlH(O-t-Bu)3 R–(H) N

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Aldehydes and Ketones

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(2) H2O
• Hemiacetal and O
acetal formation 3 4
(1) CHR R Br, (C6H5)3P
• Thioacetal formation R¿ Cl (1) DIBAL-H (2) RLi (as strong base)
and reduction (2) H2O
• Alkynide anion addition R2NH,
RNH2, R¿ R3
• Nitrile addition SOCl2 (1) DIBAL-H cat. HA
O cat. HA
(cyanohydrin formation) (2) H2O
• Wittig synthesis of alkenes R R
O R N
• Enamine synthesis R¿ OR– R–(H) R4
• Imine synthesis R¿ C N N
R¿ OH (E ) and (Z )
• Reduction to alcohols R–(H)
(left, center) R¿ R–(H) (when R¿ bore a
hydrogen for removal)
Reactions of Carboxylic Acids

1. As acids (discussed in Sections 3.11 and 17.2C):

O

H
R O – Na! ! H 2O
O NaO

R OH NaH
O
CO
O – Na! ! H 2O ! CO2
3
R
2. Reduction (discussed in Section 12.3):
O (1) LiAlH4 H H
! +
R OH (2) H3O R OH

3. Conversion to acyl chlorides (discussed in Section 17.5):

O SOCl2 or PCl5
O

R OH R Cl
4. Conversion to esters (Fischer esterification) or lactones (discussed in Section 17.7A):
O HA O
! R# OH ! H2O
R OH R OR#
5. Conversion to amides (discussed in Section 17.8E):
O O heat O
! NH3 ! H 2O
R OH R O NH4
! "
R NH2
An amide

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6. Decarboxylation (discussed in Section 17.10):
O O O
heat
+ CO2 c
R OH R CH3

O O O

heat
+ CO2 c
HO OH OH

Reactions of Acyl Chlorides

1. Conversion (hydrolysis) to acids (discussed in Section 17.5B):

O O
! H2O ! HCl
R Cl R OH
2. Conversion to anhydrides (discussed in Section 17.6A):
O O O O
! ! Cl$
R Cl R! O$ R O R!
3. Conversion to esters (discussed in Section 17.7A):
O O
pyridine
! R!9 OH ! Cl$ ! pyr-H#
R Cl R OR!
4. Conversion to amides (discussed in Section 17.8B):
O O # $
! R!NHR" (excess) ! R!NH2R"Cl
R Cl R NR!R"
R! and/or R" may be H.

5. Conversion to ketones (Friedel–Crafts acylation, Section 15.7–15.9):

O
O
AlCl 3 R
!
R Cl

6. Conversion to aldehydes (discussed in Section 16.4C):

O O
(1) LiAlH(t-BuO)3
! +
R Cl (2) H3O R H

Reactions of Acid Anhydrides

1. Conversion (hydrolysis) to acids (discussed in Section 17.6B):

O O O
! H2O 2
R O R R OH
2. Conversion to esters (discussed in Sections 17.6B and 17.7A):
O O O O
! R!OH !
R O R de  Reacciones  Química   R OR! R OH
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3. Conversion to amides (discussed in Section 17.8C):

O O R! O O
H
! N R! !
R O R R N R OH
R"
R! and/or R" may be H.
R"

4. Conversion to aryl ketones (Friedel–Crafts acylation, Sections 15.7–15.9):

O R

O O O
AlCl3
! !
R O R R OH

Reactions of Esters

1. Hydrolysis (discussed in Section 17.7B):

O O
HA
! H2O ! R!OH
R OR! R OH

O O
! OH$ ! R!OH
H2O
R OR! R O$

2. Conversion to other esters: transesterification (discussed in Review Problem 17.10):

O HA
O
! R"OH ! R!OH
R OR! R OR"

3. Conversion to amides (discussed in Section 17.8D):

O R" O
! HN R" ! R!OH
R OR! R N
R#
R" and/or R# may be H. R#

4. Reaction with Grignard reagents (discussed in Section 12.8):

O OMgX OH
Et2O H3O!
! 2 R"MgX R99 R" ! R!OMgX R99 R"
R OR!
R" R"

5. Reduction (discussed in Section 12.3):

O
(1) LiAlH4
+ R9 CH2OH ! R!OH
R OR! (2) H3O
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 Key Terms and Concepts

Reactions of Amides

1. Hydrolysis (discussed in Section 17.8F):

O O H
$
R! ! H O$ ! H9 N9 R!
3 H2O
R N R OH
R#
R#

O O H R!
R! ! OH" ! N
R N H2O R O "

R#
R#
R, R!, and/or R# may be H.

2. Conversion to nitriles: dehydration (discussed in Section 17.8G):

O
P4O10
R9C#N
R NH2 heat
("H2O)

Reactions of Nitriles

1. Hydrolysis to a carboxylic acid or carboxylate anion (Section 17.8H):

O
H3O!
R9C#N heat
R OH

O
HO"
R9C#N
H2O, heat
R O"
2. Reduction to an aldehyde with (i-Bu)2AlH (DIBAL-H, Section 16.4C):

(1) (i-Bu)2 AlH

O
R9C#N
(2) H2O
R H
3. Conversion to a ketone by a Grignard or organolithium reagent (Section 16.5B):
O
(1) R!MgBr or R!Li
R9C#N !
(2) H3O! R R!

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 868

Summary of Mechanisms

Enolates: a-Substitution
–
General Reaction O O O
– d+ d–
A E A
a a + – A
R R R
H E + stereoisomer (if a carbon is, and/or if E contains, a stereogenic center)

Resumen  
Some groups that Typical bases (–:A) Possible electrophiles (E–A) Product(s)
increase a-hydrogen and solvents for
acidity enolate formation O
H A
O I. HO– in H2O or ROH; Deprotonation–protonation
R

SeedSpecial
or RO– in ROH; (may lead to racemization
Useful for reactions involving or epimerization) H
R
thermodynamically favored

e  Reacciones  
H enolates and equilibrium product O
X X
Carbonyl control Substitution of enolate
Halogenation a hydrogen by H, X, or R
R
N II. LDA (lithium diisopropylamide)
X

TopicQuímica  
in THF or DME;

Orgánica  II,  DC  Angel  A.  Ramos  O.  

C
Useful, in general, for forming O
enolates in aprotic solvents R´ X
H (especially kinetically favored Alkylation
Nitrile enolates and direct alkylation) R
(cyano group)
R´

C in WileyPLUS
(and in general, other
groups that can stabilize
an a-carbanion)
Chapter 18 Reactions at the a Carbon of Carbonyl Compounds
 19.9 Summary of Important Reactions 897

19.9 Summary of Important Reactions

1. Claisen Condensation (Section 19.2):

O O O
2R (1) NaOEt R
OEt OEt
(2) H3O !

R
2. Crossed Claisen Condensation (Section 19.2B):
O O

(1) C6H 5CO2Et/NaOEt OEt

(2) H3O!
R

O
O
(1) EtOCOEt/NaOEt
R
(2) H3O! OEt
O
R O OEt
OEt
O
(1) HCO 2Et/NaOEt
R
(2) H3O! OEt

O H

O
(1) EtO2CCO2Et/NaOEt
R
(2) H3O! OEt
O
O
OEt
3. Aldol Reaction (Section 19.4)
General Reaction
O OH O O
2 R OH
– R –H2O R
H H H
H2O
R R
Specific Example

O O OH O O
–
OH –H2O
±
H H 10°C H H

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Chapter 19 Condensation and Conjugate Addition Reactions of Carbonyl Compounds

4. Directed Aldol Reactions via Lithium Enolates (Section 19.5B)

General Reaction
O O
O O–Li + (1)
LDA R– R‡ R
R THF, –78°C R H(R¿)
H(R¿) H(R¿) (2) NH4Cl
(formation of
the kinetic enolate) R– OH
R‡

Specific Example

O LDA
O–Li + (1)
H OH O
THF, –78°C (2) NH4Cl

5. Conjugate Addition (Section 19.7)

General Example

R– O –
(1) Nu (or Nu¬H)
R– O
$

(2) H ¬ A
R¿ R R¿ R
Nu H
– –
Nu =CN ; an enolate (Michael addition); R‡MgBr
Nu¬H=1º or 2º amines; an enamine

Specific Example

O CN O
–
CN
C6H5 C6H5 EtOH, HOAc C6H5 C6H5
H

Specific Example (Michael Addition)

O
O
– O O
, HO
C6H5 C6H5
MeOH C6H5 C6H5

6. Mannich Reaction (Section 19.8):

O O R! O
! ! H N R!
R H H R N
R"
R"

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 materials online to complete this problem.
Me 20

17
C
H
13
D
9 H 14

10 8
A H H
3 B
HO
Cholesterol

Summary of Mechanisms

Enolate Reactions with Carbonyl Electrophiles

– –
O O O O O O

LG
R R¿ LG R R R´
R´
Acyl substitution (addition–elimination), e.g., Claisen condensation when LG=OR

H A
– –
O O O O O HO O R–

R– R–
R R¿ R– R R (elimination if R R¿
R¿ R¿
– a hydrogen (E ) and (Z )
A H present)
Aldol reactions (addition and condensation)

– –
O R– O O R– O O R– O
*
R R¿ R‡ R R‡ R * R‡
R¿ R¿ *
* may be chirality centers
Michael (conjugate) addition

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 910

Synthetic Connections
Some Synthetic Connections Involving Enolates

• Enolate formation Enolates provide many ways to functionalize the a-carbon of a • Claisen condensation
• Keto–enol tautomerism carbonyl compound. Most importantly, enolates provide ways to form • Aldol reactions
• Halogenation new carbon–carbon bonds. Some of these synthetic connections are • Addition of Grignard and RLi
• Alkylation shown here. Previously studied reactions of carbonyl, alcohol, and • Michael addition
• Acylation alkene functional groups (e.g., reduction, oxidation, addition, • Conjugate addition of HCN
substitution) lead to or from some of these pathways. • Conjugate addition of amines

Reactions of X as LG, etc. O O (1) RO– O

O O O (1) RO–
(2) R3X (2) R4X R4 ! CO2
R2
R1 R2 R1

Orgánica  
R1 R1 R2
O Then decarboxylation
R3 R3
(1) LDA if R2 = OR
X

See Special
(1) LDA O (3) HO–
R1 (2) R2X (2) (4) H3O+, heat
R2 LG
X2,

II,  DC  Topics

base
OH R3
OH O
(1) R4MgBr +1,4 addition
a H

Angel  AD.  Rand

– or R4Li R R2
R1 HA or weak A R R4

amos  
(2) H3O+

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(1) LDA (1) LDA, O
Strong base O O OH O R3 H O R3 O
(e.g., LDA) HA (2)
R4
R2 R3 R1 R3 R R2 (2) H3O+ R1 R4
– R2
O O R2
(3) H3O+

E Oin.   WileyPLUS
– HNR5R6 HCN
R1 R1
Enolate resonance contributors O R3
O R3

R1 CN
R1 NR5R6 R2
R2
Chapter 19 Condensation and Conjugate Addition Reactions of Carbonyl Compounds