Bruice_SC_v4.

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6. Conjugated dienes form 1,2- and 1,4addition products. At low temperatures,

where the reaction is not reversible, the
kinetic product (the one that is formed
faster) is favored. At higher temperatures,
where the reaction is reversible, the
thermodynamic product (the more stable
product) is favored. The 1,2-product is
always the kinetic product; either the 1,2or 1,4-product can be the thermodynamic
product; it will depend on which is the
more substituted alkene (7.10, 7.11).
7. A conjugated diene reacts with a
dieneophile (an alkene with an e!
withdrawing group) to form a cyclohexene
via a concerted Diels-Alder reaction. The
diene adopts an s-cis conformation for this
[4 # 2] cycloaddition reaction where the
HOMO of one reactant interacts with the
LUMO of the other. The reaction is
stereospecific; e.g., a cis dienophile forms
cis products. Bridged, bicyclic products
favor the endo configuration when the
substituent has p e - (7.12).
electron-withdrawing group

nucleophile

3C
2C

CH2

CH

CCH3

H
30 C

CH2

CH2
1

electrophile

3C
2C

CH2
CH

O
CCH3

CH2

CH2
1

a 1,4-addition reaction to 1,3-butadiene

Chapter 8
Substitution Reactions of Alkyl
Halides

1. Substitution reactions involve

replacement of a leaving group with a
nucleophile. Alkyl halides have good
leaving groups 1I -, Br -, Cl -2 (8.1).

Nu +

d+

Nu + X

substitution
product

a nucleophile

2. The reaction of bromomethane with HO is a bimolecular nucleophilic

substitution reaction 1SN22, with a rate
law dependent on [RX] and [HO -] (a
second-order reaction). HO - attacks with
simultaneous departure of the leaving
group. Steric effects govern the relative
rates with 1 alkyl halides faster than 2,
and 3 very slow. The reaction occurs with
inversion of configuration because the
nucleophile (HOMO) interacts with the
s* (LUMO) on the backside of the carbon
attached to X (8.2).
the configuration of the
product is inverted relative
to the configuration of
the reactant

CH3
+ HO
C
H
CH3CH2 Br
(R)-2-bromobutane

CH3
H
HO

+ Br
CH2CH3

(S)-2-butanol

3. Leaving group tendencies for RX:

I - 7 Br - 7 Cl -. Strong bases are better
nucleophiles, except if there is a large
difference in size and they are in a protic
solvent, because of the greater
polarizability of the large nucleophile and
its weaker solvation (in which case I - is a
better nucleophile than F -). Aprotic polar
solvents (DMSO, DMF) are used in S N2
reactions of alkyl halides with negatively
charged nucleophiles because such
solvents solvate only cations (8.3, 8.4).
4. The reaction of a 3 alkyl halide with H 2O
is a unimolecular nucleophilic
substitution reaction 1SN12, with a rate
law dependent only on [RX] (a first-order
reaction). The leaving group leaves,
forming a carbocation that is attacked by
the nucleophile. Formation of the
carbocation is the rate-limiting step, so 3
alkyl halides are the most reactive;
carbocation rearrangements can occur.
Products with inverted and retained
configurations are obtained. Partial
racemization can occur because one face
of the carbocation can be partially
blocked by the leaving group (8.58.7).
5. Benzylic and allylic halides undergo both
S N1 and S N2 reactions. Vinyl and aryl
halides undergo neither S N1 nor S N2
reactions (8.8).
6. High concentration of a good nucleophile
favors S N2; a poor nucleophile favors
S N1. If a reactant is charged, increasing
the polarity of the solvent decreases the
rate of the reaction; if neither of the
reactants is charged, increasing the
polarity of the solvent increases the rate
of the reaction (8.9, 8.10).
7. Bifunctional molecules can undergo
intramolecular reactions to form cyclic
products. Five- and six-membered rings
are favored (8.11).
8. A common cellular methylating agent is
S-adenosylmethionine (SAM), a methyl
sulfonium ion (8.12).

Chapter 9
Elimination Reactions of Alkyl
Halides

1. An E2 reaction of an alkyl halide involves

the simultaneous removal of a proton
from a b-carbon and the halide ion from
the a-carbon (dehydrohalogenation) to
form an alkene (a B-elimination). An E1
reaction is a two-step reaction; the
leaving group departs (the rate-limiting
step), forming a carbocation, which loses
a proton from the b-carbon. Leaving
group order in both E2 and E1:
I - 7 Br - 7 Cl - 7 F - (9.1, 9.3).
2. E2 and E1 reactions are regioselective: the
more stable (more substituted) alkene is
the major product (the hydrogen is
removed from the b-carbon bonded to the
fewest hydrogens; Zaitsevs rule), because
the transition state is alkene-like.

3.

4.

5.

6.

7.

However, alkyl fluorides, with a poor

leaving group, preferentially form the less
substituted alkene, because the transition
state is carbanion-like. The relative
stabilities of carbanions are 1 7 2 7 3,
the reverse of carbocation stabilities (9.2).
E2 and E1 reactions are stereoselective:
the alkene with the bulkiest groups on
opposite sides of the double bond is
favored (9.5).
In E2 reactions of substituted
cyclohexanes, both groups that are
eliminated must be in axial positions
because of anti elimination (9.6).
Under S N1/E1 conditions: 1 alkyl
halides do not react because primary
carbocations are too unstable to be
formed; 2 and 3 alkyl halides undergo
both substitution and elimination. Under
SN2/E2 conditions: 1 alkyl halides favor
substitution; 2 undergo both
substitution and elimination; 3 undergo
only elimination (9.8).
Bulky, strong bases (tert-butoxide) favor
E2 over S N2 due to steric hindrance. High
temperatures favor E2 over S N2 due to a
greater S (9.8).
Ethers are formed from alkoxide ions and
1 alkyl halides (Williamson ether
synthesis). Na or NaH converts an
alcohol to an alkoxide ion. Geminal and
vicinal dihalides react with excess -NH 2
to form alkynes (9.9, 9.10).

Chapter 10
Reactions of Alcohols, Amines,
Ethers, Epoxides, and SulfurContaining Compounds

1. Alcohols and ethers have poor leaving

groups due to the strong basicity of HO and RO -. If protonated, they become
good leaving groups that can be replaced
by halide ions. These are S N1 reactions
(so carbocation rearrangements can
occur) except in the case of 1 alkyl
halides, which are S N2 reactions (10.1).
a weakly basic leaving group

CH3

O H + HBr
poor leaving
group

CH3

+H

OH

good leaving Br

CH3

Br + H2O

weak base

group

2. Alcohols react with PBr3, PCl3, or thionyl

chloride 1SOCl22 to form alkyl halides.
Alcohols react with sulfonyl chloride to
form sulfonate esters (10-2, 10-3).
3. Alcohols undergo dehydration when
heated with a strong acid 1H 2SO42 to
form alkenes. These are S N1 reactions,
except in the case of 1 alcohols, which are
S N2. POCl3 + pyridine dehydrates
alcohols without carbocation formation,
so there are no rearrangements (10.4).
4. 2 alcohols are oxidized to ketones; 1
alcohols are oxidized to carboxylic acids
with chromic acid 1H 2CrO42 and to
aldehydes with PCC (10.5).