315 SN E Syn & Chem Catalog

Nucleophilic Substitution & Elimination Chemistry Beauchamp 1
y:\files\classes\315\315 Handouts\315 Fall 2013\2 315 SN and E & chem catalog.doc

Four mechanisms to learn: S
N
2 vs E2 and S
N
1 vs E1

S = substitution = a leaving group (X) is lost from a carbon atom (R) and replaced by nucleophile (Nu:)
N = nucleophilic = nucleophiles {Nu:) donate two electrons in a manner similar to bases (B:)
E = elimination = two vicinal groups (adjacent) disappear from the skeleton and are replaced by a pi bond
1 = unimolecular kinetics = only one concentration term appears in the rate law expression, Rate = k[RX]
2 = bimolecular kinetics = two concentration terms appear in the rate law expression, Rate = k[RX] [Nu: or B:]
S
N
2 competes with E2
S
N
1 competes with E1

These electrons
always leave with X. S
N
2
E2
S
N
1
E1
X R B Nu
B H
Nu H
Competing
Reactions
Competing
Reactions
Carbon
Group
Leaving
Group
Nu: / B: = is an electron pair donor to carbon (= nucleophile) or
to hydrogen (= base). It can be strong (S
N
2/E2) or weak (S
N
1/E1).
(strong) (weak)
R = methyl, primary, secondary,
tertiary, allylic, benzylic
X = -Cl, -Br, -I, -OSO
2
R (possible leaving groups in neutral,
basic or acidic solutions)
X = -OH
2
(only possible in acidic solutions)

Important details to be determined in deciding the correct mechanisms of a reaction.

1. Is the nucleophile/base considered to be strong or weak? We simplistically view strong electron pair donation
as coming from anions of all types and neutral nitrogen, sulfur and phosphorous atoms. Weak electron pair
donors will typically be neutral solvent molecules, usually water (H
2
O), alcohols (ROH), mixtures of the two,
or simple, liquid carboxylic acids (RCO
2
H).

2. What is the substitution pattern of the R-X substrate at the C
o
carbon attached to the leaving group, X? Is it a
methyl, primary, secondary, tertiary, allylic, or benzylic carbon? What about any C
|
carbon atoms? How
many additional carbon atoms are attached at a C
|
position (none, one, two or three)?

Answers to these questions will determine S
N
2, E2, S
N
1 and E1 reactivities and alkene substitution patterns and
relative stabilities in E2 and E1 reactions.

R-Br examples C1 C7 (infinite possibilities exist)

Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br Br
Br
Br
Br
Br
Br Br Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
H
3
C
Br
1C 2C 3C
4C
5C
6C
6C
7C
6C
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br Br
Br
Br
Br Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
7C
7C
7C
7C
7C Extra patterns to know (allylic and benzylic RX are very fast S
N
2 patterns) (1
o
neopentyl, vinyl and phenyl RX patterns are unreactive).
Br Br
Br Br
Br
Br
Br Br
allylic
allylic
allylic
benzylic benzylic
1
o
neopentyl RBr vinyl X phenyl X
a b a
b
c d
a
b
c
d e f
g
h
i j
k
l m
n
o
p
a
b
c
d
e
f
g
h
a
b
c
d e f
g
h i j k l
m
n
o p q
q r
s t
u v w
x
y z aa
bb
cc
dd
ee
ff gg hh
kk ll mm
ii jj
a b
c a
b
* = chiral center
*
*
* *
*
*
*
*
*
* *
*
*
*
*
*
* * *
*
*
*
*
*
*
*
* *
* *
*
*
*
* *
*
* *
1
o
neopentyl
2
o
1
o
1
o
1
o
1
o
1
o
3
o
2
o
2
o
3
o
1
o
1
o
2
o
2
o 1
o
methyl
1
o
2
o
2
o
1
o
3
o 2
o
3
o
1
o
1
o
neopentyl 2
o
2
o
1
o
1
o
2
o
neopentyl
1
o
1
o
3
o
2
o
2
o
1
o
2
o
1
o
3
o
3
o
2
o
1
o
1
o
2
o
1
o
1
o
1
o
neopentyl 2
o
2
o
2
o
1
o
1
o
1
o
3
o
3
o
2
o
3
o
2
o
1
o
neopentyl 1
o
1
o
2
o
2
o
2
o
2
o
1
o
1
o
3
o
2
o
1
o
neopentyl
3
o
1
o


Strong electron pair donation in our course (S
N
2 / E2).

Na
O H
Na
S H
O R
Na K
O
Na
O
O
hydroxide
alkoxides
potassium t-butoxide
carboxylates
(make, acetate)
hydrogen sulfide
(thiolate)
(buy)
(make)
(make, strong base)
(buy)
Nu
B
=
S
N
2/E2 concerted reactions (one step) S
N
2 = always backside attack at C
o
(inversion of configuration)
E2 = anti C
|
-H / C
o
-X elimination
(forms pi bonds)
Na
S R
alkyl sulfide
(thiolate)
(make)

Na
C N
N
O
O
phthalimidate
(an imidate)
C C H
Na
CH
2
O
Li
ketone enolates
Li
Na
cyanide
acetylides
ester enolates
H
2
C
O
O
(make)
(make)
(make)
(buy)
(make)
Na
N
N
N
(buy)
azide

B H
H
H
H
Na
Al H
H
H
H
Li
sodium
borohydride
lithium
aluminium
hydride
S
S
H
Li
dithiane anion
(make)
B D
D
D
D
Na
sodium
borodeuteride
Al D
D
D
D
Li
lithium
aluminium
deuteride
CH
2
Li
n-butyl lithium
(very strong base
or nucleophile, use
anytime)
Na Cl
Br
I
Na
Na
good nucleophiles
with tosylates and
in strong acid
(buy)
(buy)
(buy) (buy) (buy)
(buy)
S
Ph
Ph
CH
2
sulfur
ylids

(MgBr)
Grignard reagents
(very strong bases
and nucleophiles)
R
Li
alkyl lithium
(very strong bases
and nucleophiles)
R
R
2
Cu
organocuprates
(good carbon
nucleophiles)
Li
Na
H
N
lithium
diisopropylamide
(very strong base)
sodium hydride
(very strong base)
Na
sodium amide
(very strong base)
S Cl
O
O
= Ts-Cl (tosyl chloride)
makes ROH into tosylates
N
pyridine =
proton sponge
K H
potassium hydride
(very strong base)
R = C or H
NR
2
= py
Br Cu
cuprous
bromide
Li
(buy) (buy)
(buy)
(make)
(make)
(make)
(make)
(buy)
(buy)
Important additions for us.
S
Ph Ph
Ph = phenyl
P
Ph Ph
diphenylsulfide,
used with C=O
to make epoxides
triphenylphosphine
used with C=O
to make alkenes
Ph
CrO
3
/ pyridine
pyridinium chlorochromate
PCC
oxidizing E2 reaction
CrO
3
/ H
2
O
Jones reagent
oxidizing E2 reaction
(buy)
(buy)


These two reactions look similar, but there are important differences.
Br
O
major
minor
H
O
H
O
H
H
Br
Br
H
O
H
O
major
minor
H
Br
H
O
H
Rate = k
SN2
[HO ]
1
[RBr]
1
Rate = k
E2
[HO ]
1
[RBr]
1
Rate = k
E1
[RBr]
1
Rate = k
SN1
[RBr]
1

S
N
2 versus E2 overview (essential features)

Example: 1
o
RX, requires strong nucleophile/base, S
N
2 > E2, exceptions: potassium t-butoxide or sodium amide.

C
|
H
CH
3
H
C
o
Br
H
H
1-bromopropane
Nu
C
|
H
CH
3
H
C
o
Br
H
H
1-bromopropane
O
C
|
C
o
Nu
H
H
H
CH
3
H
E2 > S
N
2
(when t-butoxide)
C
o
C
|
H
H
H
3
C
H
alkene
E2
Nu B =
strong = anything
with negative charge,
and neutral sulfur,
phosphorous or nitrogen
S
N
2 > E2
(unless t-butoxide)
C
H
3
C
H
3
C
H
3
C
(also R
2
N = E2)
S
N
2 always
backside attack
E2 always
anti C
|
-H C
o
-X

S
N
2 reactions are the most important reactions always backside attack at C
o
-X carbon
X H
3
C
H
2
C R X
H
C R X
R
C R X
R
R
C
H
H
2
C
H
2
C X
H
2
C X
methyl (Me) primary (1
o
) secondary (2
o
)
tertiary (3
o
)
allylic
(1
o
, 2
o
, 3
o
versions)
C
|
C
o
X
C-beta carbon
(0-3 of these)
C-alpha carbon
(only 1 of these)
benzylic
(1
o
, 2
o
, 3
o
versions)


Relative rates of S
N
2 reactions - steric hindrance at the C
o
carbon slows down the rate of S
N
2 reactions.

X C
o
H
H
H
k ~ 30
methyl (unique)
X C
o
H
H
3
C
H
k ~ 1
ethyl (primary)
reference compound
X C
o
CH
3
H
3
C
H
k ~ 0.025
isopropyl (secondary)
X C
o
CH
3
H
3
C
CH
3
k ~ 0
t-butyl (tertiary)
(very low) 1
40

C
o
H
H
H
X
methyl RX
Methyl has three easy paths of
approach by the nucleophile. It is
the least sterically hindered carbon
in S
N
2 reactions, but it is unique.
C
o
H
R
H
X
primary RX
Primary substitution allows two easy paths
of approach by the nucleophile. It is the
least sterically hindered "general" substitution
pattern for S
N
2 reactions.
C
o
R
R
H
X
secondary RX
Secondary substitution allows one easy path
of approach by the nucleophile. It reacts the
slowest of the possible S
N
2 substitution
reactions.

tertiary RX
C
o
R
R
R
X
=
C
o
C
|
X
C
|
H
H
H
H
H
H
C
|
H
H
H
Nu Nu
Tertiary substitution has no easy path of approach
by the nucleophile from the backside. We do not
propose any S
N
2 reaction at tertiary RX centers.
When the C
o
carbon is completely
substituted the nucleophile cannot
get close enough to make a bond
with the C
o
carbon. Even C
|
-H
sigma bonds block the nucleophiles
approach.

All of these are primary R-X structures at C
o
, but substituted differently at C
|
.

H
2
C C
|
H
H
H
k ~ 1
ethyl
reference compound
H
2
C C
|
H
H
3
C
H
k ~ 0.4
propyl
H
2
C C
|
CH
3
H
3
C
H
k ~ 0.03
2-methylpropyl
H
2
C C
|
CH
3
H
3
C
CH
3
k ~ 0.00001 ~ 0
2,2-dimethylpropyl
(1
o
neopentyl)
X
X
X
X
C
o
C
|
X
H
C
CH
3
CH
3
H
H
H
H
Nu
A completely substituted C
|

carbon atom also blocks the
Nu: approach to the backside
of the C-X bond. A large group
is always in the way at the
backside of the C
o
-X bond.
C
o
C
|
X
H
H
CH
3
CH
3
H
Nu
If even one bond at C
|
has a
hydrogen then approach by
Nu: to the backside
of the C
o
-X bond is possible
and an S
N
2 reaction is
possible.


sp
2
carbon transition state as carbon
inverts configuration forms a high PE
carbon with 10 electrons at carbon.
This is a concerted, one-step reaction.
"Transition State"
C
H
H
H
Br
O H
Br C
H
H H
HO
C
H
H
H
HO
Br
reactants
products
E
a
- this energy difference determines
how fast the reaction occurs: "kinetics".
E
a
AG
AG - this energy difference determines the
extent of the reaction; the ratio of products
versus reactants at equilibrium (when
kinetics allows the reaction to proceed.
Thermodynamics is determined mostly by the
strengths of the bonds and solvation energies of
the reactant and product speces: "thermodynamics".
POR = progress of reaction
PE
Rate = k
SN2
[RX][Nu] = bimolecular reaction
k
SN2
= 10
E
a
= -2.3RT log(k
SN2
)
-Ea
2.3RT
AG
o
= -2.3RT log(K
eq
)
K
eq
= 10
-AGo
2.3RT

Problem 1 - How can you tell whether the S
N
2 reaction occurs with front side attack, backside attack or front and
backside attack? Use the two molecules to explain you answer. Follow the curved arrow formalism to show
electron movement for how the reaction actually works.

H
H
3
C
H
Br
C Br
H
H
3
C
CH
3
CH
2
I
C H
3
C
O
O
a b

Problem 2 - Why might C
3
and C
4
rings react so slowly in S
N
2 reactions? (Hint-think about bond angles in the
transition state versus bond angles in the starting ring structure.)

k
relative

(S
N
2)
Br
Br
Br
Br
Br
Br
Br
1.0 0.00001 0.008
1.6
0.01
0.97
0.22

Problem 3 - Why might C
6
rings react slower in S
N
2 reactions? What are the possible conformations from which a
reaction is expected? Trace the path of approach for backside attack across the cyclohexane ring to see what positions
block this approach. Which chair conformation would have the leaving group in a more reactive position (axial or
equatorial)? Is this part of the difficulty (which conformation is preferred)?


H H
H
H H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
These two chair
conformations
interconvert in a
very fast equilibrium.
X
X

Problem 4 - In each of the following pairs of nucleophiles one is a much better nucleophile than its closely related
partner. Propose a possible explanation.

N N
O
O
C C
C
C
O
H
H
H
H
H
H
H
H
H
b. c. a. relative rates 250/1
O C
H
H
H
methoxide
t-butoxide

Problem 5 Write out the expected S
N
2 product for each possible combination (4x8=32 possibilities).

Al D
D
D
D
Li
Nu
X
Nu
Nu
Nu =
H
O
H
3
C
O
O
O
N
C
H
S
H
3
C
S
N
N
N
?
?
X = Cl , Br , I ...a good leaving group
1
3
4 6 7
X
X
X
?
?
Nu
A
B
C
D
2
5
8


Problem 6 Using R-Br compounds from page 2 and reagents from page 3 to propose starting materials to make each
of the following compounds. One example is provided. TM-1 is an E2 product (see page 15), all the others are S
N
2
products.

N
N
N
?
Br
problem
solution
NaN
3
N
3
2-azidopropane
TM = target molecule

N
O
O
O
TM-1 TM-2 TM-3
O
R
TM-4
TM-5 TM-6
O

S
Ph Ph
C
H
3
C
O
TM-7
TM-8 TM-9 TM-10 TM-11
P
Ph
Ph
Ph
Br
N
Br
O

SH
TM-12 TM-13
TM-14 TM-15
HO
O
O
S
R

D
TM-16
TM-17
S
S
H

Acid/base reactions important to our course (some reagents have to be made, often by acid/base reactions) and
subsequent reactions (mostly S
N
2)

Make alkoxides and use as nucleophiles only at Me-X and 1
o
RCH
2
-X in S
N
2 reactions.

alkoxides are good nucleophiles at methyl,
primary, allyl and benzyl RX, mostly E2 at
secondary and only E2 tertiary RX, they are
also used as moderately strong bases
O R
Na
alkoxides
O R H
alcohols
Na
H
Br
R
O
S
N
2
ethers
K
eq
=
K
a1
K
a2
10
-16
10
-37
= =
10
+21
H
H
acid/base


Make carboxylates and use as nucleophiles at Me-X, 1
o
RCH
2
-X and 2
o
R
2
CH-X in S
N
2 reactions.

O
O
Na
ethanoate
(acetate)
O H
Na
O
O
ethanoic acid
(acetic acid)
H
Br
O
O
esters
S
N
2
O
H H
K
eq
=
K
a1
K
a2
10
-5
10
-16
= =
10
+11
carboxylates are good nucleophiles at methyl,
primary, secondary, allyl and benzyl RX,
making esters, only E2 at tertiary RX
acid/base

S
N
2 with acetate produces esters, then acyl substitution with hydroxide produces the alcohol, if desired. A new type
of substitution reaction.
O
O
O H
Na
O
O
O H O
H
O
O
O
O
O
H
Me, 1
o
, 2
o
alcohols
S
N
2 > E2 Look at similarities to imide hydrolysis, just below.
Na
Na
2
acid/base

Problem 7 Show the acyl substitution mechanism for each functional group with hydroxide.

Na
O H
C
R
O
X
X = possible leaving group
C R
O
X
O
H
tetrahedral
intermediate
C
R
O
O
H
X
C
R
O
O
X H
C
R
O
Cl
Functional Groups to use
C
R
O
O
C
R
O
O
C
R
O
N C
O
R
R
R
R
acid chloride anhydride
ester
3
o
amide
acid/base


Make imidates and use as nucleophile at RX centers to convert to primary amines. 1. Make alkyl imides 2. Hydrolyze
in base to make primary amines (acyl substitution) 3. Workup) = Gabriel amine synthesis; duplicates azide amine
synthesis (1. S
N
2 with NaN
3
2. S
N
2 with LiAlH
4
at nitrogen 3. workup)
N
O
O
H
Na
O H
N
O
O
Na S
N
2
rxns
N
O
O imide
imidate
alkyl imide
K
eq
=
K
a1
K
a2
10
-8
10
-16
= =
10
+8
Na
O H
N
O
O
OH
N
O
O
O
H
N
O
O
O
H
acyl substitution #1
reaction leads to
a primary amine
O H
N
O
O
O
H
O
H
N
O
O
H
O
O
H
O
O
O
O
N
H
H
primary amine
(also made by
1. NaN
3
2. LiAlH
4
3. workup)
throw away
resonance stabilized makes
imidate less basic and a better
behaved nucleophile
1
acid/base
rxn
2
3
Look at similarities with ester hydrolysis, just above.
Br
acyl substitution #2
acid/base
rxn
acid/base

Alternative azide strategy to make primary amines (S
N
2 and acid/base reactions)

Al H
H
H
H Li
N
N
N
Br
N
N
N
resonance
N
N
N
alkyl azide
N
N
N
N
N
N
H
gas
O H H
H
2. workup
N
H
1
o
amine
H
step 1 - make alkyl azide
step 2 - make primary amine
S
N
2
S
N
2
acid/base


Make potassium t-butoxide and use as sterically large, strong base at 1
o
RCH
2
-X, 2
o
R
2
CH-X and 3
o
R
3
C-X in E2
reactions.
O
K
K
O
H
t-butyl
alcohol
potassium
t-butoxide
H
Br
H
R
E2
R
alkenes
H
H
K
eq
=
K
a1
K
a2
10
-19
10
-37
= =
10
+18
potassium t-butoxide, sterically bulky base
that mostly does E2 reactions with RX
compounds (except S
N
2 with CH
3
-X).
acid/base

Make thiols using NaSH as the nucleophile at Me-X, 1
o
RCH
2
-X and 2
o
R
2
CH-X in S
N
2 reactions.
S H
Na
hydrogen sulfide
Br
H
S
thiol
S
N
2

Make thiolates and use as nucleophiles at Me-X, 1
o
RCH
2
-X and 2
o
R
2
CH-X in S
N
2 reactions.
acid/base
S R
Na
alkylthiolates
Na
S R H
thiols
O H
Br
S
N
2
R
S
sulfides
K
eq
=
K
a1
K
a2
10
-9
10
-16
= =
10
+7

Synthesis of lithium dithiane anion (acid/base) 2. SN2 with RX 3. Hydrolyze to make aldehydes or ketones)
A good nucleophile that
can be made into aldehydes
and ketones
S
S
dithiane anion
Li
S
S
dithiane
aldehydes
and
ketones
(later)
Br
S
N
2
H
2
C
H
H
Li
S
S
H
K
eq
=
K
a1
K
a2
10
-50
10
-35
= =
10
+15
acid/base

Make terminal acetylides and use as nucleophiles only at Me-X and 1
o
RCH
2
-X in S
N
2 reactions.
C C R
Na
terminal
acetylides
C C R
terminal
alkynes
H
Na
NR
2
H
3
C
Br
S
N
2
R
CH
3
alkynes
K
eq
=
K
a1
K
a2
10
-25
10
-37
= =
10
+12
terminal acetylides are good nucleophiles
at methyl, primary, allyl and benzyl RX, but
mostly E2 at secondary and only E2 tertiary RX
acid/base


Zipper reaction moves triple bond to end of linear chain to form the most stable anionic charge, further chemistry
is possible. This reaction is almost identical to tautomers, without any heteroatoms.

Synthesis of lithium diisopropyl amide, LDA, sterically bulky, very strong base used to remove C
-H proton of
carbonyl groups. (acid / base reaction) to make carbonyl enolates (next).
K
eq
=
K
a1
K
a2
10
-37
10
-50
= =
10
+13
CH
2
Li
N
H
N
Li
Think - sterically bulky, very basic
that goes after weakly acidic protons.
LDA = lithium
diisopropyl amide
given
given
acid/base

React ketone enolate (nucleophile) with R-Br electrophile (Me, 1
o
and 2
o
RX compounds)

H
2
C
O
Li
ketone enolates
(resonance stabilized)
React ketone enolate with RX compounds (methyl, 1
o
and 2
o
RX)
Br
O
1
o
RX
key bond
R
S
Larger ketone made
from smaller ketone.
S
N
2
reactions
-78
o
C


React ester enolate (nucleophile) with R-Br electrophile (Me, 1
o
and 2
o
RX compounds)

H
2
C
O
O
Li
ester enolates
(resonance stabilized)
React ester enolate with RX compounds (methyl, 1
o
and 2
o
RX)
Br
O
O
1
o
RX
key bond
R
S
Larger ester made
from smaller ester.
R
R
S
N
2
reactions
-78
o
C

diphenylmethylsulf onium
bromide salt
S
Ph
Ph
CH
2
sulfur ylid
to make epoxides
S
Ph
Ph
CH
2
make epoxides
from aldehydes
and ketones
H
2
C
Li
K
eq
=
K
a1
K
a2
10
-50
10
-35
= =
10
+15
H
S
Ph
Ph
H
3
C
Br
diphenyl
sulfide
S
N
2
acid/base


Clarification of Hydride electron pair donors: In our course sodium hydride and potassium hydride are
always basic, and lithium aluminum hydride and sodium borohydride are always nucleophilic hydride.

Basic hydride

In our course, sodium hydride (NaH) and potassium hydride (KH) are always basic (= electron pair donation by
hydride to a proton), never a nucleophile. The conjugate acid of hydride is hydrogen gas (with a pK
a
= 37, H
2
can
hardly be considered an acid).

Sodium hydride and potassium hydride (KH)
Na
Aldrich, 2012
$39 / 100 grams
60% oil dispersion
MW = 24.0 g/mol
H
K H
Aldrich, 2012
$128 / 75 grams
30% oil dispersion
MW = 40.1 g/mol

Problem 8 Write an arrow pushing mechanism for each of the following reactions.

O
H
O
H
H
Na
K
H
pK
a
ROH 16-19
H-H 37
pK
a
= 17
pK
a
= 19

Nucleophilic hydride Formation of C-H bonds using nucleophilic lithium aluminum hydride and sodium
borohydride.

In our course, sodium borohydride (NaBH
4
) and lithium aluminum hydride (LiAlH
4
= LAH) are inorganic salts
containing nucleophilic hydride, very unusual nucleophiles. Both reagents supply nucleophilic hydride that can
displace X in S
N
2-like reactions with RX compounds. Sodium borohydride and lithium aluminum hydride are used
in many other reactions. They also react with carbonyl compounds (C=O) and epoxides (both to be discussed more
later). We will often use the deuterium version of borohydride and aluminum hydride so we can identify where a
reaction occurred. In reality, this is not very common because of the expense. But, for purposes of probing your
understanding of S
N
2 reactions, using them shows if you understand what is happening. The deuterium isotope of
hydrogen reacts similarly to the proton isotope, but there are experimental methods which allow us to observe
where a reaction took place (e.g. NMR).

Sodium borohydride and lithium aluminum hydride (LAH) - 4 equivalents of hydride per anion

B H
H
H
H Na
Li
Al H
H
H
H
B D
D
D
D Na
Aldrich, 2012
$312 / 100 grams
MW = 37.8 g/mol
Aldrich, 2012
$120 / 100 grams
MW = 38 g/mol
Aldrich, 2012
$254 / 5 grams
MW = 41.8 g/mol
Aldrich, 2012
$125 / 5 grams
MW = 42 g/mol
Li
Al D
D
D
D
The deuteride salts are
way more expensive.
The hydride salts are
way more common.

All these reagents will undergo S
N
2 reactions at RX centers. Because there is a greater difference in
electronegativity between aluminum and hydrogen than boron and hydrogen, LAH is more reactive than sodium
borohydride. This wont be important for us to know until we study carbonyl reactions.


Problem 9 Write an arrow pushing mechanism for the following reaction.

Li
Al D
D
D
D
C
Cl
CH
3
H
+
?
Na
B H
H
H
H
C
Cl
D
CH
3
+
?
a.
b.

Problem 10 It is hard to tell where the hydride was introduced since there are usually so many other hydrogens in
organic molecules. Where could have X have been in the reactant molecule? There are no obvious clues. Which
position(s) for X would likely be more reactive with the hydride reagent? Could we tell where X was if we used
LiAlD
4
?

LAH
Where was "X"?
H
2
C
C
H
2
H
2
C
CH
3

E2 Reactions Compete with S
N
2 Reactions

E2 reactions also occur at the backside relative to the leaving group, but at C
|
-H instead of C
-X. The C
|
-H
proton has to be anti to the C
-X to allow for parallel overlap of the 2p orbitals that form the new pi bond. This
allows elimination to occur in a concerted manner. The syn conformation also has parallel overlap of 2p orbitals,
but is present in less than 1% due to an eclipsed conformation (staggered conformations > 99%).

E2 Potential Energy vs. Progress of Reaction Diagram (= concerted, energy picture looks very similar to S
N
2)

transition state
reactants
products
PE
potential
energy
POR = progress of reaction - shows how PE changes as reaction proceeds
higher
(less
stable)
lower
(more
stable)
E
a
= -2.3RT log(k
E2
)
AG = -2.3RT log(K
eq
)
O H
C
C
R
1
R
2
Br
C
C
R
1 R
2
Transition state - requires parallel overlap
of the two 2p orbitals forming the pi bond.
This is easiest when C
|
-H is anti to C
o
-X.
Br
HO
R
3
R
4
H
R
3 R
4
H O
H
Br
C
C
R
1 R
2
R
3 R
4
If stereochemical priority is R
1
> R
2

and R
3
> R
4
then this would be Z
configuration, which is fixed by the
requirement for anti C
|
-H / C
o
-X
elimination.
E2 mechanism depends on
steric factors and basicity of
the electron pair donor. More
steric hindrance and more basic
favors E2 over S
N
2
= negative
(exergonic)

Keeping Track of the C
|
Hydrogens in E2 reactions


At least one C
|
position, with a hydrogen atom, is necessary for an E2 reaction to occur. In more complicated
systems there may be several different types of hydrogen atoms on different C
|
positions. In E2 reactions there can
be anywhere from one to three C
|
carbons, and each C
|
carbon can have zero to three hydrogen atoms.
C
o
H
H H
X
C
o
H
C
|
H
X
C
o
C
|
C
|
H
X
C
o
C
|
C
|
C
|
X
zero C
|
positions
unique methyl,
only S
N
2 possible
one C
|
position
1
o
RX, usually S
N
2 > E2
(except with t-butoxide)
two C
|
positions
(2
o
RX, S
N
2 / E2
both competitive)
three C
|
positions
(3
o
RX, only E2)
0-3 H at C
|
0-6 H at C
|
0-9 H at C
|

With proper rotations, each C
|
-H may potentially be able to assume an anti conformation necessary for an E2
reaction to occur. There are a lot of details to keep track of and you must be systematic in your approach to
consider all possibilities. Using one of these two perspectives may help your analysis of E2 reactions Lets
consider a moderately complicated example (next problem).

B
Either sketch will work for every
possibility above, IF you fill in
the blank positions correctly.
C
o
C
|
H
X
C
|
H
C
o
X
?
B
?
horizontal perspective
C
|
-H / C
o
-X
vertical perspective
C
|
-H / C
o
-X

Problem 11 - How many total hydrogen atoms are on C
|
carbons in the given RX compound? How many different
types of hydrogen atoms are on C
|
carbons (a little tricky)? How many different products are possible? Hint - Be
careful of the simple CH
2
. The two hydrogen atoms appear equivalent, but E/Z (cis/trans) possibilities are often
present. (See below for relative expected amounts of the E2 products.)

C
o
CH
2
CH
3
CH
3
X
CH
H
3
C
CH
2
H
3
C
Redraw structure to explicitely show all
of the C
|
hydrogen atoms. Notice the
base/nucleophile is strong, so S
N
2 or E2
reaction are considered. The RX pattern is
tertiary, so no S
N
2 is possible. There are
three C
|
carbon atoms and all of them
have hydrogen atoms on them. That leaves
E2 reaction as the only possible choice.
O R OH R
Na
C
o
C
|2
CH
3
C
|3
X
C
|1
H
3
C
CH
2
H
3
C
H H
H
H
H
H
There are two chiral centers, C
o
and
C
|1
, that make this structure more
complicated than we are treating it.
Possible stereoisomers are RR, RS,
SR and SS.
?

Stability of pi bonds

In elimination reactions, more substituted alkenes are normally formed in greater amounts. Greater substitution
of carbon groups in place of hydrogen atoms at alkene carbons (and alkyne carbon atoms too) translates into greater
stability (lower potential energy). Alkene substitution patterns are shown below. There are three types of
disubstituted alkenes and their relative stabilities are usually as follows: geminal ~ cis < trans.


C
H
H
C
H
H
C
R
H
C
H
H
C
R
H
C
R
H
C
R
R
C
H
H
C
R
H
C
H
R
C
R
R
C
R
H
C
R
R
C
R
R
<
The more substituted alkenes are usually more stable than less substitued alkenes. Substitution
here, means an R group for a hydrogen atom at one of the four bonding positions of the alkene.
1
2
3
4 5
6
7
Relative stabilities of substitued alkenes.
1 = unsubstituted alkene (ethene is unique)
2 = monosubstituted alkene
3 = cis disubstituted alkene
4 = geminal disubstituted alkene
5 = trans disubstituted alkene
6 = trisubstituted alkene
7 = tetrasubstituted alkene
Saytzeff's rule: More stable alkenes tend
to form faster (because of lower E
a
) in
dehydrohalogenation reactions (E2 and E1).
They tend to be the major alkene product,
though typically a little of every alkene
product possible is obtained.
"unsubstituted"
"mono" "di-cis"
"di-geminal"
"di-trans"
"tri"
"tetra"
~
<
< <
<

Possible explanations for greater stability with greater substitution of the pi bond

A fairly simple-minded explanation (the one we will use) for the relative alkene stabilities is provided by
considering the greater electronegativity of an sp
2
orbital over an sp
3
orbital. An alkyl group (R) inductively
donates electron density better than a simple hydrogen. From the point of view of a more electronegative sp
2

alkene carbon, it is better to be connected to an electron donating alkyl carbon group than a simple hydrogen atom.
The more R groups at the four sp
2
positions of a double bond, the better. However, be aware that other features,
such as steric effects or resonance effects, can reverse expected orders of stability.

C C
C C
H
R
...inductively donating "R" substituent
is more stable than unsubstituted "H"...

Problem 12 - Reconsider the elimination products expected in problem 1 and identify the ones that you now expect
to be the major and minor products. How would an absolute configuration of C
as R, compare to C
as S? What
about C
|1
as R versus S?

O R OH R
Na
C
o
C
|2
CH
3
C
|3
Br
C
|1
H
3
C
CH
2
H
3
C
H H
H
H
H
H
Compare
(3S,4R)-3-bromo-3,4-dimethylheptane
(3S,4S)-3-bromo-3,4-dimethylheptane
?
C
o
C
|2
H
Br
C
|3
H
H
3
C
H
C
|1
H
3
C
CH
2
CH
3
one of your possibilities
(which one?)
*
= chiral center
* *
H
H
H
(3R,4R)-3-bromo-3,4-dimethylheptane
(3R,4S)-3-bromo-3,4-dimethylheptane


Problem 13 -Provide an explanation for any unexpected deviations from our general rule for alkene stabilities
above. A more negative potential energy is more stable.

AH
o
f
= -18.7 kcal/mole
AH
o
f
= -22.7 kcal/mole
AH
o
f
= -19.97 kcal/mole

Problem 14 Order the stabilities of the alkynes below (1 = most stable). Provide a possible explanation.

H C C H
R C C H R C C R
"R" = a simple alkyl group

Problem 15 - Propose an explanation for the following table of data. Write out the expected products and state by
which mechanism they formed. Nu:
--
/B:
--
= CH
3
CO
2

--
(a weak base, but good nucleophile).

H
2
C H
3
C Br
H
C H
3
C Br
CH
3
H
C CH Br
CH
3
C H
3
C Br
CH
3
CH
3
H
3
C
H
3
C
percent
substitution
percent
elimination
100 %
100 %
11 %
0 %
0 %
0 %
89 %
100 %
O
O
O
O
O
O
O
O
our rules
S
N
2 > E2
S
N
2 > E2
S
N
2 > E2
(wrong
prediction)
only E2

Problem 16 One of the following reactions produces over 90% S
N
2 product and one of them produces about 85%
E2 product in contrast to our general rules (ambiguity is organic chemistrys middle name). Match these results
with the correct reaction and explain why they are different.
Cl
O
pK
a
= 16
Cl
O
pK
a
= 19 ...versus...


Problem 17 - A stronger base (as measured by a higher pK
a
of its conjugate acid) tends to produce more relative
amounts of E2 compared to S
N
2, relative to a second (weaker) base/nucleophile. Greater substitution at C
o
and C
|

also increases the proportion of E2 product, because the greater steric hindrance slows down the competing S
N
2
reaction. Use this information to make predictions about which set of conditions in each part would produce
relatively more elimination product. Briefly, explain your reasoning. Write out all expected elimination products.
Are there any examples below where one reaction (S
N
2 or E2) would completely dominate?
a.
I
Cl
...versus...
I
Cl

b.
Cl
...versus...
Cl
O
O
O
pK
a
(RCO
2
H) = 5
pK
a
(ROH) = 16

c.
Cl
...versus...
Cl

d.
N C
...versus...
N C
Cl
Cl

e.
O R
Br
...versus...
O R
Br

f.
Cl
...versus...
N C
Cl
pK
a
(RCCH) = 25 pK
a
(NCH) = 9


Problem 18 - (2R,3S)-2-bromo-3-deuteriobutane when reacted with potassium ethoxide produces
cis-2-butene having deuterium and trans-2-butene not having deuterium. The diastereomer
(2R,3R)-2-bromo-3-deuteriobutane under the same conditions produces cis-2-butene not having deuterium and
trans-2-butene having deuterium present. Explain these observations by drawing the correct 3D structures, rotating
to the proper conformation for elimination and showing an arrow pushing mechanism leading to the observed
products. (Protium = H and deuterium = D; H and D are isotopes. Their chemistries are similar, but we can tell
them apart.)

(2R,3S)
trans-2-butene
(no D present)
cis-2-butene
(D present)
cis-2-butene
(no D present)
trans-2-butene
(D present)
and
and
(2R,3R)
O O
K
K

H
H
C C
H
H
C C
H
H
C C

Problem 19 - Draw a Newman projection of the two possible conformations leading to E2 reaction. Show how the
orientation of the substituents about the newly formed alkene compares.

B
C C
R
3
R
4
R
2
R
1
H
X
anti E2
reaction
staggered
reactant conformation 1
rotate about
center bond
syn E2
reaction
eclipsed
C C
R
3
R
4
X
reactant conformation 2
alkene stereochemistry?
alkene stereochemistry?
Newman
projections
B
< 1% > 99%


Alkyne synthesis (via two E2 reactions with RBr
2
and NaNR
2
, two times)

Sample alkynes using double E2 reactions of 1. RBr
2
+ NaNR
2
2. Workup (neutralize mixture)

Possible steps in mechanism (E2 twice then 2. acid/base or 2. RX electrophile)
Br Br
H
N
R R
Na
Br
H
H
N
R R
H
N
R R
Na
Na
2. workup
H
H
2
C
R
X
H
2
C
R
H
O
H
H
2.
a
b
a
b
S
N
2
2 eqs. Br
2
hv
(314 reaction,
see page 58-60
this topic)

Make starting alkynes using two leaving groups and very basic R
2
N
--
starting from an alkane.

Na
sodium amide
(very strong base)
Br
Br
Br
Br
and
Br
2
hv
free radical
substitution
(2 equivalents)
(2 equivalents)
NR
2
E2 twice
1.
2. workup
Use steric bulk and/or extreme
basicity to drive E2 > S
N
2.

Br
2
hv
free radical
substitution
(2 equivalents)
Br Br
Na
sodium amide
(very strong base)
(2 equivalents)
NR
2
E2 twice
1.
2. workup

Br
2
hv
free radical
substitution
(2 equivalents)
Br Br
Na
sodium amide
(very strong base)
(2 equivalents)
NR
2
E2 twice
1.
2. workup


Sample alkynes using S
N
2 reactions of 1. Terminal alkyne + NaNR
2
2. S
N
2 only at methyl or primary R-X (can do
this twice starting with ethyne)

new
bond
new
bond
new
bond
new
bond
new
bond
new
bond
new
bond

(1 equivalent)
Na
sodium amide
(very strong base)
1.
2.
Br H
3
C
acid / base
S
N
2 > E2
NR
2
new
bond

(1 equivalent)
Na
sodium amide
(very strong base)
1.
2.
acid / base
S
N
2 > E2
Br
NR
2
Terminal acetylides are OK
nucleophiles at methyl and 1
o
RX,
but E2 > S
N
2 at 2
o
RX and only E2
at 3
o
RX.
new
bond

1. RNH Na
RNH
2
1 equivalent
Na
Br
2.
(4C = 2C + 2C)
terminal alkyne
S
N
2

Br
2.
Na
1. RNH Na
RNH
2
1 equivalent
(5C = 3C + 2C)
internal alkyne
S
N
2

1. RNH Na
RNH
2
1 equivalent
Na
Br
2.
(6C = 3C + 3C)
terminal alkyne
S
N
2

Br
2.
Na
1. RNH Na
RNH
2
1 equivalent
(5C = 3C + 2C)
internal alkyne
(zipper reaction)
1. excess NaNRH
2. workup (neutralize)
S
N
2
acid/base
like tautomers


1. RNH Na
RNH
2
1 equivalent
Na
2.
2.
Na
(6C = 4C + 2C)
terminal alkyne
1. RNH Na
RNH
2
1 equivalent
(6C = 3C + 3C)
internal alkyne
(zipper reaction)
1. excess NaNRH
2. workup (neutralize)
Br
Br
like tautomers
S
N
2
S
N
2
acid/base
acid/base

terminal acetylides (S
N
2 only at methyl RX and 1
o
RX) larger alkynes
Br H
3
C
C C H
3
C
Na S
N
2
C C H
3
C CH
3
nucleophile = ?
electrophile = ?
Na
Br

Br H
2
C
C C H
3
C
Na
S
N
2
C C H
3
C CH
2
H
3
C CH
3
nucleophile = ?
electrophile = ?
Na
Br

Br H
2
C
C C H
3
C
Na
S
N
2
C C H
3
C CH
2
CH
2
H
2
C
H
3
C
CH
3
nucleophile = ?
electrophile = ?
Na
Br


Problem 20 What are the possible products of the following reactions? What is the major product(s) and what is the
minor product(s)? There are 55 possible combinations.

Al D
D
D
D
B D
D
D
D
Li Na
Nu
X
X
Nu
Nu
Nu =
H
O
R
O
C
O
H
3
C
H
3
C
CH
3
O
O
N
C
C
C
H
H
S
R
S
N
N
N
?
?
?
X = Cl , Br , I ...a good leaving group
1 2
3 4 5
6
7
X
X
X
?
?
Nu
Nu
A
B
C
D
E
OR
OR
8
OR
9
O
enolates
S
S
10
S
Ph
Ph
CH
2
sulfur
ylids
11
N
O
O imidate


C
o
H
H
H
X
C
o
D
H
T
X
easier
harder
Reaction Templates - sideways and vertical perspectives (either one will work)
C
o
C
|
H
H
X
methyl (Me)
primary (1
o
)
secondary (2
o
)
tertiary (3
o
)
H
H
H
C
o
C
|
H
X
H
H
H
C
o
C
|
H
D
X
H
R
D
C
|
H
H
H
C
o
C
|
H
X
H
R
1
D
C
|
H
D
R
2
C
o
C
|
X
H
H
H
C
|
H
H
H
C
|
H
H
C
o
C
|
X
H
R
1
D
C
|
H
D
R
2
C
|
H
D
priority R
1
> R
2
> R
3
Nu:
B
iotopes of hydrogen
H = protium (proton)
D = deuterium
T = tritium
H-Nu: / H-B:
Nu: B
O
O
O
O
=
O H
H-Nu : H-B :
OH
OH
O
=
O H H
C
o
H
H
H
X
C
o
D
H
T
X
C
o
C
|
H
H
X
H
H
H
C
o
C
|
H
D
X
H
R
D
C
o
C
|
H
X
H
H
H
C
|
H
H
H
C
o
C
|
H
X
H
R
1
D
C
|
H
D
R
2
C
o
C
|
X
H
R
1
D
C
|
H
D
R
2
C
|
H
D
R
3
C
o
C
|
X
H
H
H
C
|
H
H
H
C
|
H
H
H
Strong (S
N
2 / E2)
Weak (S
N
1 / E1)
S
N
2/E2 (Nu: / B: ) always backside for S
N
2 and usually anti C
o
-H/C
|
-X attack for E2
S
N
1/E1 (H-Nu: / H-B:) - attack from either face of R
+
for both reactions (S
N
1 and E1)
side view
vertical view
conjugate
acid pK
a
= 16
conjugate
acid pK
a
= 16
conjugate
acid pK
a
= 5
conjugate
acid pK
a
= 18
strong
weak
Nu:
B
H-Nu: / H-B:
strong
weak
Nu:
B
H-Nu: / H-B:
strong
Nu:
B
H-Nu: / H-B:
strong
Nu:
B
H-Nu: / H-B:
strong
weak
weak
weak
Nu:
B
H-Nu: / H-B:
strong
weak
Nu:
B
H-Nu: / H-B:
strong
weak
Nu:
B
H-Nu: / H-B:
strong
weak
H R
3

Example: 3-bromo-2-methoxyhexane (R,R), (S,S), (R,S), (S,R)

1
2
3
4
5
6
C
o
C
|
H
Br
H
a
H
b
C
2
H
6
C
|
H
CH
3
C
o
C
|
H
Br
C
|
H
H
3
C
H
3
CO
H
a
C
2
H
6
H
b
template side view
vertical view
(2R,3R)
(2S,3R)
OCH
3


1
2
3
4
Examples - you can use the vertical views or side views presented above. (Never ending supply of problems.)
(R,R)
(S,S)
(R,S)
(S,R)
2-bromo-3-deuteriobutane
2-bromo-3-methylbutane
(R or S)

1
2
3
4
5
(R,R)
(S,S)
(R,S)
(S,R)
2-bromo-3-deuteriopentane 2-bromo-3-methylpentane
(R,R)
(S,S)
(R,S)
(S,R)
3-bromo-2-methylpentane
(R,R)
(S,S)
(R,S)
(S,R)
3-bromo-2-deuteriopentane
(R or S)

1
2
3
4
5
6
(R,R)
(S,S)
(R,S)
(S,R)
2-bromo-3-deuteriohexane
2-bromo-3-methylhexane
(R,R)
(S,S)
(R,S)
(S,R)
3-bromo-2-methylhexane
(R,R)
(S,S)
(R,S)
(S,R)
3-bromo-2-deuteriohexane
(R or S)

1
2
3
4
5
6
(R,R)
(S,S)
(R,S)
(S,R)
3-bromo-4-deuteriohexane 3-bromo-4-methylhexane
(R,R)
(S,S)
(R,S)
(S,R)

1
2
3
4
5
6
7
(R,R)
(S,S)
(R,S)
(S,R)
2-bromo-3-deuterioheptane
2-bromo-3-methylheptane
(R,R)
(S,S)
(R,S)
(S,R)
(R,R)
(S,S)
(R,S)
(S,R)
(R or S)

1
2
3
4
5
6
7
(R,R)
(S,S)
(R,S)
(S,R)
(R,R)
(S,S)
(R,S)
(S,R)
(R,R)
(S,S)
(R,S)
(S,R)
(R,R)
(S,S)
(R,S)
(S,R)

Na
O H
N
O
O
Na
S H
phthalimidate
(an imidate)
C C
Na
O R
Na
K
O
Na
O
O
Na
hydroxide
acetylides
alkoxides
potassium t-butoxide carboxylates
(acetate)
hydrogen sulfide
(thiolate)
(buy) (make)
(make)
(make)
(make)
(buy)
Nu
B
=
S
N
2 / E2
Na
N
N
N
(buy)
azide

B H
H
H
H
Na
Al H
H
H
H
Li
sodium
borohydride
lithium
aluminium
hydride
Na
C N
CH
2
O
Li
ketone enolates
Li
cyanide ester enolates
H
2
C
O
O
(make)
(buy)
S
S
H
Li
(make)
dithiane anion
(make)
S
N
2/E2 concerted reactions (one step)
S
N
2 = always backside attack
(inversion of configuration)
E2 = anti C
b
-H / C
a
-X elimination
(forms pi bonds)
BD
4
AlD
4

Nu
B
=
H
H
H
O
H
R
O
H
O
O
H
water alcohols
carboxylic acids
S
N
1/E1 form carbocation (R
+
) in first step,
R
+
has three common choices
1. rearrange to similar or more stable R
+
2. add nucleophile (top/bottom)
3. lose any beta proton (top/bottom)
(forms pi bonds)
S
N
1 / E1


Strong base/nucleophile conditions (negative charge in our course) leads to S
N
2 and/or E2 reactions. Simple
mechanisms.
T
C
o
Br
D
H
reaction
conditions
T
C
o
Nu
D
H
Nu
S
N
2
Br
C
|
H
D
CH
3
C
o
Br
D
H
reaction
conditions
C
|
C
o
Nu
D
H
H
D
CH
3
B
S
N
2
C
|
H
D
CH
3
C
o
Br
D
H
reaction
conditions
Nu
E2
Br
Br
C
|
C
o
D
H
CH
3
D
C
|
C
o
CH
3
H
H
D
b = anti D
a = Z
b = E
C
|
D
CH
3
H
C
o
Br
D
H
reaction
conditions
E2
methyl pattern
primary pattern (S
N
2 > E2, except t-butoxide and R
2
N )
There is no E2 at methyl RX
S
R
1S,2R 1R,2R
1S,2R
1S,2R
a = anti H
b
a
B
E2 > S
N
2 when t-butoxide and R
2
N

B
C
|
H
D
CH
3
C
o
Br
C
|
C
H
2
H
CH
3
CH
2
CH
3
H
C
|
H
D
CH
3
C
o
Br
C
|
H
H
H
H
reaction
conditions
C
|
C
o
Nu
C
|
H
H
D
CH
3
H
H
H
Nu
S
N
2
C
|
H
D
CH
3
C
o
Br
C
|
H
H
H
H
reaction
conditions
E2
Br
Br
C
|
C
o
D
H
CH
3
CH
3
C
|
C
o
CH
3
H
H
CH
3
C
o
C
|
H
H
CHD
H
CH
3
a = anti H
b = anti D
c
There is no S
N
2 at tertiary RX
reaction
conditions
E2
Br
C
o
C
|
H
3
C
H
3
C
CHDCH
3
CH
2
CH
3
a = anti H
b = anti D
c
secondary pattern
tertiary pattern
d
C
C
HC
CHDCH
3
H
H
C
2
CH
3
CH
3
C
C
D
H
3
C
CH
3
CH
CH
2
CH
3
CH
3
C
C
H
3
C
H
3
C
H
CH
CH
2
CH
3
CH
3
2S,3R
b = E
2R,3R
c = neither
a = Z
a = Z
b = E
c = neither
d = Z
2S,3R
2R,3R,4S
B
(S
N
2 > E2, except HO , RO , R
2
N and RCC )


Example Mechanisms shown below.
Br
H
D
1
2
3
4
5
6
3R-bromo-2S-deuteriohexane
Na
O H
H
secondary RX (2
o
)
C
o
C
|
H
Br
H
CH
3
D
C
|
H
a
H
b
CH
2
CH
3
O H
C
o
C
|
H
HO
C
|
H
CH
3
D
H
a
CH
2
CH
3
H
b
a
b
c
(2S,3S)
C
|
C
o
H
3
C
H
D
CH
2
CH
2
CH
3
C
o
C
|
H
H
3
CH
2
C
CHDCH
3
H
b
a, b, c
C
o
C
|
H
Br
D
H
CH
3
C
|
H
b
CH
2
CH
3
H
a
O H
d
e C
|
C
o
H
H
CH
3
CH
2
CH
2
CH
3
C
o
C
|
H
H
a
CHDCH
3
CH
2
CH
3
d, e
sigma bond rotations
One S
N
2 product and four E2 products.
b
a
c
d
e
only one S
N
2 product
four possible E2 products
(2S,3R)
(2E, with "D")
(3E, lost H
a
)
(3Z, lost H
b
)
(2Z, without "D")
1. strong Nu: /B:
2. 2
o
R-X


Important acid/base reactions are shown on pages 15-19. When necessary for a preliminary step of a reaction, you
should consult those pages. Some of the strong base/nucleophiles used in our course are listed below along with
the usual preferred reactions according to our simplistic rules. Cuprates will be discussed later. Missing are
enolates, imidates, magnesium and lithium organometallics and a few others.


cuprates
H
3
C
Br
R
H
2
C
Br R
CH
Br R
C
Br
R R
R
methyl RBr
primary RBr secondary RBr tertiary RBr
R
Cu
R
Li
only S
N
2
S
N
2 > E2
S
N
2 > E2
only E2
R-Br
compounds
strong
base/nucleophiles
too sterically hindered
no C
|
-H
O
CH
2
Na
enolates
only S
N
2 S
N
2 > E2 S
N
2 > E2
only E2
too sterically hindered no C
|
-H
S
Ph
Ph
make
sulfur
ylids
S
Ph
Ph
CH
2
sulfur ylids
P
Ph
Ph
make
phosphorous
ylids
Ph
P
Ph
phosphorous
ylids
Ph
react with
aldehydes
and ketones
N
O
O
imidate
only S
N
2
S
N
2 > E2
S
N
2 > E2
only E2
no C
|
-H
Grignard reagents
R
Li
(MgBr)
R
organolithium
reagents
only S
N
2
S
N
2 > E2
S
N
2 > E2
only E2
no C
|
-H
only S
N
2
S
N
2 > E2
S
N
2 > E2
only E2
no C
|
-H
react with
aldehydes
and ketones
react with
aldehydes
and ketones
react with
aldehydes
and ketones
react with
aldehydes
and ketones
react with
aldehydes
and ketones
react with
aldehydes
and ketones
react with
aldehydes
and ketones
react with
aldehydes
and ketones
react with
aldehydes
and ketones
react with
aldehydes
and ketones
react with
aldehydes
and ketones
react with
aldehydes
and ketones
react with
aldehydes
and ketones
react with
aldehydes
and ketones
react with
aldehydes
and ketones CH
2
(covered in later topic)
Ph


S
N
1 and E1 Competition Multistep Reactions Arising From Carbocation Chemistry

S
N
2/E2 and S
N
1/E1 reactions look very similar overall, but there are some key differences. In S
N
2/E2 reactions
the nucleophile/base is a strong electron pair donor (negative charge in our course), which is why they participate in
the slow step of the reaction and force a concerted, one-step reaction. In S
N
1/E1 reactions the nucleophile/base is a
weak electron pair donor (stable, neutral molecules: H
2
O, ROH and RCO
2
H for us) and thats why they dont
participate in the slow step of the reaction, which is ionization of the C
-X bond. This leads to differences in

reaction mechanisms, which show up in the rate law expression (kinetics is bimolecular = 2 or unimolecular = 1).
The rate of 1 reactions only depends on how fast RX forms a carbocation. The unimolecular reactions lead to
possible side reactions from carbocation rearrangements. You need to carefully look at the reaction conditions to
decide what mechanisms are possible. You cut you choices in half when you decide that the electron pair donor is
strong (negatively charged = S
N
2/E2) or weak (neutral = S
N
1/E1).
X
X = Cl, Br, I
+
H
3
C
O
H
H
3
C
O
weak
nucleophil/base
(neutral in our course)
S
N
1/E1
reactions
S
N
2/E2
reactions
strong
nucleophil/base
(negatively charged
in our course)
X
X = Cl, Br, I
O
S
N
1 product
(major)
S
N
2 product
(minor)
E1 product
(minor)
E2 product
(major)
Rate = k
SN2
[RX][CH
3
O: ] Rate = k
E2
[RX][CH
3
O: ]
Rate = k
SN1
[RX]
Rate = k
E1
[RX]
CH
3
O
CH
3

S
N
1 and E1 reactions begin the same way, with ionization of the C
-X bond to form a carbocation. Ion formation

is energetically expensive. Protic solvents help by being able to solvate both cations and anions. Carbocations also
need some help from inductive and/or resonance effects. If it can form, the initial carbocation intermediate typically
follows one of three common paths: 1. addition of a weak nucleophile at carbon and/or 2. loss of a beta hydrogen to
form a pi bond and/or 3. rearrangement to a similar or more stable carbocation. Rearrangement merely delays the
ultimate reaction products: addition of a nucleophile or loss of a beta hydrogen atom to forma pi bond.

S
N
1 and E1 reactions
begin exactly the same
way. The leaving group,
X, leaves on its own,
forming a carbocation.
C
o
C
|
X
R
2
R
1
H
R
3
R
4
The R-X bond
ionizes with help
from the polar, protic
solvent, which is also
usually the weak
nucleophile/base.
C
o
C
|
H
R
3
R
4
R
2
R
1
X
solvated
carbocation
has to be 2
o
or 3
o

in our course
(3 reaction choices)
addition of a weak
nucleophile (S
N
1
type reaction)
Loss of a beta hydrogen
atom, (C
b
-H in most E1
reactions that we study).
rearrangement to a new
carbocation of similar or
greater stability
add Nu: (S
N
1)
lose beta H (E1)
rearrange
B
weak
base
H Nu H
weak
nucleophile
=
Nu H
B H
?
next page
R
S
N
1 and E1 reactions are multistep reactions. (H-Nu: / H-B: = H
2
O, ROH, RCO
2
H in our course)


E1 approach comes
from parallel C
|
-H with
either lobe of 2p orbital,
anti or syn is possible
B
weak
base
E1 products
(pi bond forms)
E or Z is possible.
X
stable
leaving
group
Terms
S = substitution E = elimination H-Nu: = weak nucleophile H-B: = weak base X = leaving group
1 = unimolecular kinetics (first order reaction, the rate in the slow step depends only on RX)
R-X = R-Cl, R-Br, R-I, R-OTs, ROH
2
+
H
C
o
C
|
H
R
3
R
4
R
2
R
1
C
o
Nu
C
|
H
R
3
R
4
R
1
R
2
C
o
C
|
H
R
3
R
4 Nu
R
1
R
2
H
H
Nu H
Nu H
C
|
C
o
R
4
R
1
R
2
C
o
C
|
H
R
3
R
4 Nu
R
1
R
2
C
o
Nu
C
|
H
R
3
R
4
R
1
R
2
solvated
carbocation
S
N
1
R
3
Often a final
proton transfer
is necessary.
S
N
1 product (a nucleophile
substitutes for a leaving group)
B H Nu H = usually a polar, protic solvent (or mixture) of H
2
O, ROH or RCO
2
H =
redrawn
Nu H H
B H H
S
N
1 approach is from
either the top face or
the bottom face.
Racemization is possible
(if observable).
Nu H
weak
nucleophile
C
o
C
|
H
R
3
R
4
R
2
R
1
solvated carbocation
(from previous page)
S
N
1
E1
B
weak
base
E1 products
(pi bond forms)
E or Z is possible.
X
stable
leaving
group
H
C
o
C
R
2
R
1
C
|
C
o
R
3
R
1
R
2
R
4
B H H
E1
rotate 180
o
around C
o
-C
|
bond,
can lose any beta H, top or bottom
H
R
4
R
3
:B-H = :Nu-H = H
2
O or ROH or RCO
2
H
same C
|
-H
shown on
both faces
(top and
bottom)
C
|
-H bottom face
C
|
-H top face
"Z" if R
1
> R
2
and R
3
> R
4
"E" if R
1
> R
2
and R
3
> R
4
C
o
could
be R or S

reactants
E1 products
(PE)
Progress of reaction (POR)
(10)
-Ea (E)
2.3RT
Rate S
N
1 = k
SN1
[RBr]
1
Rate E1 = k
E1
[RBr]
1
=
(10)
-Ea (SN)
2.3RT
(10)
- Ea
2.3RT
Say E
a
(S
N
) = 13 kcal/mol and E
a
(E) = 14.6 kcal/mol
=
(10)
- Ea
2.3RT
= (10)
-(13 - 14.6)
1.3
= (10)
1.6
1.3
= = 10
1.2
=
Rate S
N
1
Rate E1
40
1
S
N
1 products
E
a
E1 rate (slower)
S
N
1 rate (faster)
E
a


R-X Substitution Pattern and rates of S
N
1 reactions

The order of stability at the electron deficient carbocation carbon is methyl << primary << secondary < tertiary.
This is consistent with our understanding of inductive electron donating ability of alkyl groups compared to
hydrogen. R groups (alkyl groups) are electron donating (an inductive effect). We observed, previously, that this
helps alkene stability and makes it harder to form an anionic conjugate base in acid/base chemistry. A carbocation
is extremely electron deficient (the opposite of a carbanion) and is very electronegative. Extra electron donation to
a carbocation center proves very helpful. This can occur through an inductive effect or a resonance effect.
Inductive effects are proposed to occur via polarizations of sigma bonds in the organic skeleton, helping (or
hurting) a center of reactivity. We can represent these in a carbocation center, simplistically, as shown below.
Hyperconjugation is an alternative explanation to rationalize how extra electron density can be donated to the
electron deficient carbocation carbon, but we will not use it in our course.
C
o
X
C
o
H
H
H
X
C
o
C
|
H
H
H
H
H
X
Sigma electrons are pulled toward the carbocation
carbon. Part of the o+ is distributed on to the
hydrogen atoms, but not typically shown with
formal charge.
C
o
H
H
H
o+
o+
o+
o+
Additional sigma bonds of alkyl substituent(s) allow
further polarizations of electrons from more bonds
(inductive donating effect), which spreads out o+
charge through sigma bond polarizations and helps
stabilize the electron deficient carbocation carbon.
C
o
C
|
H
H
H
H
H
o+
o+
o+
o+
o+
o+
o+

Resonance effects also make carbocations more stable. Allylic and benzylic RX compounds are very reactive
in S
N
1/E1 reactions (and S
N
2 reactions). With resonance, there is actually full pi electron donation from an
adjacent pi bond, instead of the inductive effect just mentioned above. An adjacent pi bond tends to produce
greater stabilization of a carbocation than a single alkyl substituent. Resonance donation from lone pairs of
heteroatoms can also be strongly stabilizing for carbocations. We will see such intermediates many times in later
chapters.


C C
C H
H H
H
H
C C
C H
H H
H
H
C C
C H
H H
H
H
C C
C H
H H
H
H
resonance from adjacent pi bond
2D
3D
O C
R
R H
resonance from adjacent lone pair
C O
H R
R
C O
H R
R
O C
R
R H
Resonance effects help stabilize carbocations.
2D
3D
C C
C H
H H
X
H
H
C O
R
R
A H
strong
acid
resonance
resonance
resonance
resonance

Gas phase Stabilities as Indicated by Hydride Affinities

Hydride affinity is the energy released when a hydride is added to a carbocation (gas phase reaction). The
energy of reaction, AH, is very negative because the two reactive species (carbocation and hydride) are very
unstable and the product formed is a stable molecule. How much do inductive and resonance effects help a
carbocation center? The following gas phase data below show the differences in carbocation stability are
enormous. In fact, differences are so large that we will almost never propose methyl or primary carbocation
possibilities as reaction pathways in our course. We will consider these two patterns (CH
3
-X and RCH
2
-X) as
unreactive in S
N
1 and E1 chemistry, and that should make your life a little bit easier.
Some of these values are
esitimated from different
sets of data.
We will not propose
these carbocations in
solution in this book.
CH
3
CH
2
CH
2
CH
2
CH
3
CH
2
methyl & primary
-277
-315
-270
-265
-267
tertiary "C" resonance "X" resonance
other / misc.
C
CH
3
H
3
C
CH
3
CH H
2
C CH
2
CH
2
H
C H C
C
H
H
C H
-232
-227
-227
-256
-239
-229
-220
-210
CH
2
H
2
N
O H CH
2 -248
-218
-230
-386
-287
ethynyl carbocation
(see problem below)
C
H
H
C H
phenyl carbocation
(see problem below)
-300
vinyl carbocation
(see problem below)
secondary
CH
H
3
C
H
3
C
-249
H -246
Inductive effects
Resonance effects
adjacent pi bond adjacent lone pair
C O CH
3
Hydride
Affinity
AH = energy released =
H R
R
H
Potential
Energy A larger hydride
affinity means a less
stable carbocation.
empty sp
orbital
empty 2p
orbital
empty sp
2
orbital
very unstable


Problem 21 - Explain the differences in stability among the following carbocations (hydride affinities).

CH
3
C
H
2
CH
2
C
H
CH
3
H
3
C
CH
3
C
H
3
C CH
3
H
2
C
H
C
CH
2
CH
2
HO
CH
2
H
2
N
CH
2
C
O
CH
3
315
H
3
C
270
reference
249
232
256 239 230 248
218
A = +45
A = -21
A = -38
A = -14
A = -31 A = -22 A = -52 A = -40
All relative energy values in kcal/mole versus a primary carbocation. A positive value is less stable and a negative value is more stable
relative to our reference primary carbocation.
Too unstable to propose
in our course.
2
o
R
+
3
o
R
+
1
o
allylic R
+
1
o
benzylic R
+
lone pair resonance stabilization of R
+
1
o
R
+
methyl R
+
pi bond resonance stabilization of R
+
A = 0
A more negative A is a more stable carbocation.
Inductive effect stabilization
of carbocations (3
o
> 2
o
R
+
)

Problem 22 - Why are vinyl carbocations so difficult to form? (Hint What is their hybridization?) How does an
empty sp
2
orbital (phenyl carbocation) or empty sp orbital (ethynyl carbocation) compare to a typical sp
2

carbocation carbon with an empty 2p orbital? (An empty 2p orbital is also present on the vinyl carbocation, but the
carbon hybridization is sp.)

Problem 23 The bond energy depends on charge effects in the anions too. Can you explain the differences in
bond energies below? (Hint: Where is the charge more delocalized?) We wont emphasize these differences.
C H
3
C
CH
3
CH
3
X
X = Gas Phase B.E.
Cl +157
Br +149
I +140

The activation energies for ionization in solvents are on the order of 20-30 kcal/mole (S
N
1 and E1
reactions) It is clear from the difference in the gas phase energies of ionization that the solvent is the most
stabilizing factor in ion formation. The magnitudes of these energies are compared in the potential energy diagram
below. Because solvent structure is so complex we ignore it, but we do so at our own peril.

Many small solvent/ion interactions make up for a single,
large covalent bond (heterolytic cleavage). A typical
hydrogen bond is about 5-7 kcal/mole and typical covalent
bonds are about 50-100 kcal/mole. In a sense the polar protic
solvent helps to pull the C
o
-X bond apart. The "polarized"
protons tug on the "X" end and the lone pairs of the solvent
molecules tug on the "C
o
" end. If the carbocation is stable
enough, the bond will be broken.
O R
H
R
O
H
O
R
H
O
R
H
C
H
3
C CH
3
CH
3
O R
H
R
O
H
O
R
H
O
H
R
X

gas phase reactions
polar solvent phase reactions
Carbocations are more stable and have smaller energy
differences in solution than the gas phase. (But methyl
and primary are still too unstable to form in solution
and we won't propose them in this book.)
Solvent / ion interactions
are the most significant
factor (about 130 kcal/mole
here).
C H
3
C
CH
3
CH
3
Cl
Cl C
H
3
C
H
3
C
CH
3
+160
+20-30
0
50
100
150
200
PE
C H
3
C
CH
3
CH
3
Cl
Cl C
H
3
C
H
3
C
CH
3


Weak Nucleophile/Bases are used in S
N
1/E1 Reactions

We emphasize the term weak here because if the Nu: were strong (negative charge), the reactions observed
would be S
N
2/E2. Weak, for us, is represented by a neutral solvent molecule with a pair of electrons. For us, this
will be a polar solvent molecule such as water (HOH), an alcohol (ROH) or a liquid carboxylic acid (RCO
2
H). All
of these are protic solvents, which are reasonably good at solvating both cations and anions. In every case, there is
an extra hydrogen atom on the oxygen atom of a solvent molecule that must be removed in a final acid/base
reaction to produce the neutral organic product. This protonated cationic intermediate results from the addition of
water (H
2
O, forms alcohols) or an alcohol (ROH, forms ethers) or a liquid carboxylic acid (RCO
2
H, forms esters).

X R
R
H Nu
Nu R H
Nu R Nu H H
H Nu
X
X
very reactive carbocation
strong Lewis acid = S
N
1
strong Bronsted acid = E1
weak nucleophile
(...or weak base)
(H
2
O, ROH or RCO
2
H)
cationic intermediate
requires proton transfer
to form neutral product
best base in
acidic medium
is usually anotehr
solvent molecule
substitution
product
protonated
solvent
H-Nu = H
2
O, forms alcohols
H-Nu = ROH, forms ethers
H-Nu = RCO
2
H, forms esters

Weak electron pair donation in our course.

We will view the attack on an sp
2
carbocation as equally accessible from either face (top or bottom). Because
carbocations are flat (in our simplistic view), attack is equally accessible from either face (top or bottom).
The carbocation carbon, itself, is not chiral since it is sp
2
hybridized and only has three atoms attached to
it. However, it is prochiral and can become chiral if the addition of a nucleophile brings in a fourth
different group. This would lead to enantiomers, if this was the only chiral center. We are assuming that
a 50/50 recemic mixture forms (in our course). It is also possible that there may be a stereogenic center
somewhere else in the carbocation structure. Top and bottom attack would then lead to the formation of
diastereomeric products.


C R
1
R
2
R
3
mirror
plane
achiral carbocation carbon
bottom face attack
top face attack
C R
1
R
2
R
3
achiral carbocation carbon with no
other chiral centers in R
1
, R
2
or R
3
H Nu
top
bottom
C R
1
Nu
R
2
R
3
C R
1
Nu
R
3
R
2
The new stereogenic center
forms a racemic mixture
of enantiomers (assuming
no other chiral centers
exist in the molecule)
(dl) (+/-)
If all three attached groups at a carbocation carbon are
different from one another and the attacking nucleophile,
then a racemic mixture of enantiomers will form.
bottom face attack
top face attack
C R
1
R
2
R
3
chiral branch in carbocation =
H Nu
top
bottom
C R
1
Nu
R
2
R
3
C R
1
Nu
R
3
R
2
The new stereogenic center
forms both R and S absolute
configurations. If another
chiral center is present that
does not change in the reaction,
then diastereomers will form,
(RR) vs (RS).
If one or more chiral centers were present in the carbocation,
the top and bottom attack at the carbocation center would
lead to diastereomers formed in unequal amounts.
R/S assumes priorities Nu > R1 > R2 > R3
S
R

Problem 24 Draw in all of the mechanistic steps in an S
N
1 reaction of 2R-bromobutane with a. water, b. methanol
and c. ethanoic acid. Add in necessary details (3D stereochemistry, curved arrows, lone pairs, formal charge).
What are the final products?

Br
a.
H
O
H
b.
H
3
C
O
H
c.
H
3
C
C
O
O
H
Donate the carbonyl (C=O)
electrons to the carbocation.

S
N
1 products will generally outcompete E1 products, in our course. The only exception for us (presented
later) will be when alcohols are mixed with concentrated sulfuric acid at high temperatures to form alkenes (the E1
product).

Keeping Track of the C
|
Hydrogens in E1 Reactions (more possibilities than E2 reactions)

E1 products arise from the same carbocation intermediate formed in S
N
1 reactions. Just as in E2 reactions, we
have to examine each type of C
|
-H. In more complicated R-X molecules there may be several different types of
hydrogen atoms on C
|
positions. After all, there can be either two or three C
|
carbons with zero to three hydrogen
atoms on each. We will only consider secondary and tertiary RX compounds below, since methyl and primary
carbocations do not form (in our course). That still leaves a lot of possibilities.

C
C
C
H
X
C
C
C
C
X
2
o
R-X has six C positions
3
o
R-X has nine C positions
C
C
C
H
C
C
C
C
X H
3
C
R
H
2
C
X
No Reaction
in our course.
Nu H
Nu H
Nu H
methyl primary
HNu: = H
2
O, ROH, RCO
2
H (weak, in our course)

E1 Mechanism (unimolecular kinetics) loss of proton from any adjacent C
-H position, top or bottom

The high reactivity (low stability) of carbocations forces some very quick choices to try and stabilize the
situation. The carbocation needs two electrons to complete its octet (in a hurry!). There are three ways it typically
does this. We have studied the two ultimate pathways, S
N
1 and E1 reactions.
The third possibility, rearrangements, is discussed next. Rearrangements are a temporary solution for an
unstable carbocation. Rearrangements transfer the unstable carbocation site to a new position having a similar
energy or, better yet, to a site where the positive charge is more stable. If such possibilities exist, this will very
likely be one of the observed reaction pathways. However, even with a rearrangement a carbocation will not gain
the two needed electrons. The electron deficiency is merely moved to a new position. This process can occur a
number of times before a carbocation encounters its ultimate fates, discussed above, S
N
1 and E1.


S
N
1 / E1 possibilities extra complications at C
positions, In this problem 2

o
RX, rearrangements are NOT considered
(H
2
O,ROH,RCO
2
H)


S
N
positions, 2
o
RX, rearrangements NOT considered, with deuterium
(makes it a little harder)
O R H
R
O
O
O H H
Examples of weak nucleophile/bases
a b
c
H
water alcohols
carboxylic acids

E1 products fromleft C carbon atom(4 possible alkenes f rom the lef t C carbon)
H
3
C
C
C
C
H
2
C
CH
3
D H
H
D
Br
H
H
3
C
C
C
C
H
2
C
CH
3
D H D H
H
Redrawn
(2S,3R,4S)
(2S,4S)
(2S,4S)
C C
H
C
D
H
H
3
C
H
C
H
2
D
CH
3
H
2
O
C C
H
C
H
C
H
2
D
CH
3
D
H
3
C
H
H
2
O
same f irst step
f or S
N
1/E1
add nuclephile (top/bottom) = S
N
1
lose -H (top/bottom) = E1
C C
H
C
H
H
D
H
3
C
C
H
2
D
CH
3
H
2
O
C C
H
C
H
C
H
2
D
CH
3
H
D
H
3
C
H
2
O
"D" parallel to
empty 2p orbital
on top
"D" parallel to
empty 2p orbital
on bottom
"H" parallel to
empty 2p orbital
on top
"H" parallel to
empty 2p orbital
on bottom
C C
H
3
C H
H C
HD
H
2
C
CH
3
C C
H H
H
3
C C
HD
H
2
C
CH
3
C C
D H
H
3
C C
HD
H
2
C
CH
3
C C
H
3
C H
D C
HD
H
2
C
CH
3
4S,2E-alkene
without "D"
4S,2Z-alkene
without "D"
4S,2Z-alkene
with "D"
4S,2E-alkene
with "D"
H
2
O
(2S,4S)
(2S,4S)
(2S,4S)
(2S,4S)
(4S)
(4S)
(4S)
(4S)
rearrangement to similar or
more stable carbocation (R
+
)
(start all over)
carbocation
choices
rotate bond
rotate bond
rotate bond


E1 products fromright C carbon atom(4 possible alkenes from the left C carbon)
Redrawn from above (2S,4S)
C C
H
C
D
H
H
3
C
H
C
H
2
D
CH
3
C C
H
C
D
H
3
C
H
"D" parallel to
empty 2p orbital
on top
"D" parallel to
empty 2p orbital
on bottom
"H" parallel to
empty 2p orbital
on top
"H" parallel to
empty 2p orbital
on bottom
2S,3E-alkene
without "D"
2S,3Z-alkene
without "D"
2S,3Z-alkene
with "D"
2S,3E-alkene
with "D"
OH
2
H
D
H
2
C
OH
2
C C
H
C
D
D
H
3
C
H
H
C
H
2
C C
H
C
D
H
3
C
H
OH
2
D
H
2
C
H
OH
2
H
3
C
H
3
C
CH
3
C
C
H
2
C
HDC
D
H
CH
3
H
3
C
C
C D
C
DH
H
2
C
H
H
3
C
C
C
H
2
C
HDC
H
H
CH
3
H
3
C
CH
3
C
C H
C
DH
H
2
C
H
H
3
C
CH
3
OH
2
C C
H
C
D
H
H
3
C
H
C
H
2
D
CH
3
OH
2
H
2
O
a
b
S
N
1 products (a. add fromtop and b. add frombottom)
C
C
DH
HDC
H
O
H H
H
3
C
H
2
C
CH
3
C
DH
C
H
DH
C
O
H H
H
3
C
C
H
2
CH
3
a
b
OH
2
OH
2
C
C
DH
HDC
H
O
H
H
3
C
H
2
C
CH
3
C
DH
C
H
DH
C
O
H
H
3
C
C
H
2
CH
3
(2S,4S)
(2S,3R,4S)
(2S,3S,4S)
diastereomers
acid/base
proton transf er
acid/base
proton transf er
(2S,4S)
(2S)
(2S)
(2S)
(2S,4S)
(2S,4S)
(2S,4S)
(2S)
rotate bond
rotate bond
rotate bond


Rearrangements of Carbocations

As we have seen, carbocations have very large potential energy differences. These differences provide a large
driving force to form more stable carbocations from less stable carbocations, in the range of ~15-20 kcal/mole in
the gas phase for 1
o
to 2
o
and 2
o
to 3
o
choices. Rearrangements are a competitive pathway in any reaction where a
carbocation is formed. A relatively simple example illustrates the necessity to be systematic in your approach to
determine all of the varied possibilities. Consider the migration of every group on a C
|
position, whether H or C.
To keep our choices simpler (than they really are) we will only consider rearrangements of 2
o
to 3
o
and 3
o
to 3
o

carbocations.

C
CH
2
H
3
C
H
H
C
X
CH
3
The RX compound must be
2
o
, 3
o
, allylic or benzylic to
f orm the initial carbocation.
S
N
1
E1
redrawn
All potentially migrating
bonds drawn with bold lines.
Consider all C -groups
(H and C).
S
N
1 and E1 are
possible here
2
o
carbocation
An adjacent C group migrates with its
electrons to the C carbocation position.
There are four possibilities in this problem.
C
CH
2
H
3
C
H
C
H
CH
3
C
CH
2
H
3
C
H
C
H
C
H
H H
d
a
b
d
d
a
H:
hydride
migrates
H
3
C:
methyl
migrates
c
b
C
CH
2
H
3
C C
H
CH
3 C
H
C
CH
3
CH
3
C
CH
2
H
3
C
H
C
H
CH
2
H
H
H
1
o
carbocation
looks very poor
2
o
carbocation
looks OK
3
o
carbocation
looks very good
We are not likely
to observe this
choice.
S
N
1 and E1 are
possible here
S
N
1 and E1 are
possible here
a
c
H
3
C H
3
C
c
d
d
H
3
C
b
H
3
CH
2
C:
ethyl
migrates
C H
3
C
H
C
X
CH
3
CH
2
2
o
carbocation
looks OK
S
N
1 and E1 are
possible here
X X
CH
2
H
3
C
H
3
C
H
3
C
H
3
C
possible
rearrangements
H:
hydride
migrates
H-Nu/H-B

Problem 25 What are the likely S
N
1 and E1 products of the initial carbocation and the rearranged carbocations
from a, b and c?

Problem 26 Write out your own mechanism for all reasonable products from the given R-X compound in water
(2-halo-3-methylbutane).

C
CH
3
H
3
C
H
H
C
X
CH
3
H
O
H
?

The most competitive rearrangement above will be to form the more stable tertiary carbocation from the
initially formed secondary carbocation. It is also likely that at least some of the initially formed carbocation will
react by the S
N
1 and E1 choices. However, those may be minor products when a much more stable carbocation can

form by rearrangement. In the end, S
N
1 and E1 possibilities are the ultimate fates of even the most stable
carbocation that can form. Our goal at this point is to understand how rearrangements occur and what S
N
1 and E1
products are possible.
All groups on any C
carbon can potentially migrate to the adjacent carbocation carbon (also called a 1,2
shifts), if a similar or more stable carbocation can form. If hydrogen with its two electrons is the group migrating,
the rearrangement is called a 1,2 hydride shift. If a carbon group migrates with its two electrons, the rearrangement
if called a 1,2 alkyl shift. Hydride and alkyl shifts can occur from further away than a C
|
position or even between
two positions in completely different molecules. However, these we will not emphasize such possibilities in our
course.

Transition state of a carbocation rearrangement

C
CH
2
H
3
C
H
H
C
X
CH
2
S
N
1
E1
rearrangement
2
o
carbocation
S
N
1 and E1 are
possible here
X
H
3
C
1,2-hydride shift
C C
H
CH
2
C
H
2
H
transition state
(no finite existance)
migrating group is positioned
between two vicinal carbon atoms
(vicinity = neighbors, Latin)
C C
H
CH
2
H
H
2
C
H
3
C
3
o
carbocation
C C
H
2
C
H
3
C
H
H
H
2
C
R-X
TS
1 TS
2
TS
3
E
a
AG
2
o
R
3
o
R
S
N
1 & E1
products
PE
Progress of Reaction (POR)
H: = hydride shift
R: = alkyl shift
The migrating gropu is always attached to
the carbon skeleton; it is never a free anion.
S
N
1 and E1 are
possible here
CH
3
CH
3
CH
3
CH
3
H
3
C
H
3
C
H
3
C
H
3
C

Two main rules will help guide you in evaluating possible rearrangements.

1. Rearrangements usually occur so that the migrating groups moves from a C
|
atom to the C
o
atom (the
carbocation center). These are the 1,2 hydride or 1,2 alkyl shifts mentioned above. The C
|
atom that gives up
the migrating group becomes the new electron deficient carbocation center, often because it is a more stable
carbocation site.

2. If a 1,2 shift of a hydrogen atom or an alkyl group can form a similar or more stable carbocation, then such a
rearrangement is likely to be competitive with other reaction choices (S
N
1 and E1). When interpreting a
reaction mechanism involving rearrangements, you may have to consider both equal (3
o
3
o
R
+
) and more
stable (2
o
3
o
R
+
) carbocation possibilities. However in this book when you are asked to predict what might
be possible, you usually only need to consider more stable carbocation possibilities (2
o
3
o
R
+
).


Problem 27 - Consider all possible rearrangements from ionization of the following RX reactants. Which
are reasonable? What are the possible S
N
1 and E1 products from the reasonable carbocation possibilities?

d. What would happen to the complexity of the above problems with a small change of an ethyl for a
methyl? Use the key of b and c as a guide. This problem is a lot more messy than those above,
(which is the point of asking it). There are too many possibilities to consider listing every answer.

There are other features that must also be considered in carbocation rearrangements in addition to
the relative stabilities of 1
o
, 2
o
and 3
o
carbocations. One such feature that modifies the relative potential
energies of the possible choices is strain energy. Consider the possible rearrangement choices available
to the following tertiary carbocation in a polar ionizing solvent.
Br
slow
step
R.D.S.
R
O
H
C
H
2
H
H
a
b
c
CH
2
H
H
CH
3
H
CH
3
H
H
CH
3
CH
3
a
b
c

a. A hydride migration makes a primary carbocation from a tertiary carbocation. This reaction
would increase the potential energy by about 35 kcal/mole and is not a realistic option.

b. At first this option (hydride shift) seems very reasonable (tertiary carbocation to tertiary
carbocation), but there would be much additional ring strain energy because of bond angle
changes in the small cyclobutane ring (109o = sp3 to 120o = sp2), while geometric shape in the
ring is trying to be 90o. This would, therefore, not be a favorable option.

c. At first this looks like a very poor reaction (tertiary carbocation to secondary carbocation vial
alkyl migration of a ring carbon) and would be uphill by about 15 kcal/mole based on carbocation
stabilities. However, the reduction in ring strain would be downhill by about 20 kcal/mole (26
kcal/mole 6 kcal/mole), resulting in an overall potential energy change of -5 kcal/mole.


What is actually observed? (Only E1 reactions are shown, S
N
1 possibilities are not included.)
Rearrangement c occurs, followed by another rearrangement from a secondary to tertiary carbocation.

H
CH
3
CH
3
H CH
3
CH
3
major
(85%)
minor
(14%)
H CH
3
CH
3
H
H
Path c leads to
ring expansion
rearrangement.
2
o
carbocation
3
o
carbocation
E1
H CH
3
CH
2
very
minor
(1%)
E1 products

Problem 28 Lanosterol is the first steroid skeletal structure on the way to cholesterol and other steroids in our
bodies. It is formed in a spectacular cyclization of protonated squalene oxide. The initially formed 3
o
carbocation
rearranges 4 times before it undergoes an E1 reaction to form lanosterol. Add in the arrows and formal charge to
show the rearrangements and the final E1 reaction.

R
CH
3
H
H
CH
3
CH
3
H
CH
3
HO
H
R
CH
3
H
CH
3
CH
3
CH
3
HO
H
H
lanosterol precursor
lanosterol
B H
R
O protonated
squalene
acid
catalysis
rearrangement
1
R
CH
3
H
CH
3
CH
3
H
CH
3
HO
H
H
rearrangement
2
R
CH
3
CH
3
H
CH
3
HO
H
H
H
rearrangement
4
CH
3
R
CH
3
H
CH
3
HO
H
H
H
CH
3
CH
3
R
CH
3
CH
3
CH
3
H
CH
3
HO
H
H
H
rearrangement
3
E1 reaction
19 more
steps
H
3
C
H
CH
3
CH
3
HO
H
H H
H
cholesterol
other
body
steroids
H
squalene
Requires 5
arrows to
show the
reaction.


Example S
N
1 / E1 Mechanisms with rearrangement

CH
3
H
H
1
2
3
4
5
6
2R-bromo-3R-methylhexane
H
3
C
O
H
Br
secondary RX (2
o
)
C
o
C
|
H
Br
H
H
H
C
|
H
CH
3
CH
2
CH
2
CH
3
C
o
C
|
H
O
C
|
H
CH
3
D
H
a
CH
2
CH
3
H
b
C
o
C
|
H
CH
3
C
|
H
3
CH
2
CH
2
CH
3
1. The first 2
o
R
+
forms two S
N
1 products and three E1 products
2. The rearranged 3
o
R
+
forms two S
N
1 products and five E1 products
C
o
C
|
H
H
H
H
C
|
CH
3
CH
2
CH
2
CH
3
H
a, b, c show attack on left face of carbocation,
attack also occurs from the right side of R
+
.
H
3
C
O
H
H
3
C
O
H
b
a
c
C
|
C
o
H
H
H
C
|
CH
3
H
CH
2
CH
2
CH
3
a
b c
E1 product after
loss of beta proton
from methyl (CH
3
)
E1 product after loss of beta proton
from methine (CH) from either face
C
o
C
|
H
O
C
|
H
CH
3
D
H
a
CH
2
CH
3
H
b
S
N
1 product from attack of left face
H
H
3
C
H
3
C
O
H
C
o
C
|
H
O
H
H
H
C
|
H
CH
3
CH
2
CH
2
CH
3
H
CH
3
H
3
C
O
H
C
o
C
|
H
O
H
H
H
C
|
H
CH
3
CH
2
CH
2
CH
3
CH
3
S
N
1 product from attack of right face
b, c
rearrangement
(next page)
d
d
C
o
C
|
H
CH
2
CH
2
CH
3
C
|
H
3
CH
3
c
H
3
C
d
a
1. weak H-Nu:/H-B:
2. 2
o
R-X
R
+
reactions
1. add H-Nu: (S
N
1)
2. lose C
|
-H (E1)
3. rearrange (start over)

C
o
C
|
H
H
H
H
C
|
CH
3
CH
2
CH
2
CH
3
H
carbocation continued with rearrangement)
C
o
CH
2
CH
2
O
H
3
C
H
CH
3
rearrangement
from 2
o
R
+
to 3
o
R
+
,
redrawn with new C
o
.
H
3
C
O
H
CH
3
O
H
C
o
C
|
H
3
CH
2
C CH
3
Same product forms from
loss of methyl proton from
either face (no E or Z).
H
3
C
O
H
CH
3
O
H
CH
2
CH
3
H
Two possible products from loss of proton
from left faceor right face on propyl branch.
C
|
C
o
CH
3
CH
2
CH
2
CH
3
CH
3
H
C
|
C
o
H
H
H
3
CH
2
C
CH
2
CH
2
CH
3
Two possible products from loss of proton
from left faceor right face on ethyl branch.
a
b
c
d e
a
b
c
c
a
H
3
C
O
H
d
e
CH
3
O
H
H
3
C
C
o
C
|
H
CH
2
CH
3
H
C
|
C
|
H
H H H
3
C
H
H
redraw R
+
to show
S
N
1 reaction
a, b, c = E1 products
(protons lost from
either face)
S
N
1 products
3E alkene
3Z alkene
2Z alkene
2E alkene
(3S)
(3R)
C
H
2
C
H
2
C
CH
3
H
3
C
CH
2
CH
3
C
o
H
2
C
H
2
C
O
CH
3
H
H
3
C
CH
3
CH
2
CH
3 C
o
H
2
C
H
2
C
O
CH
3
H
3
C
CH
3
CH
2
CH
3
H
3
CH
2
C
C
o
CH
2
CH
2
O
H
3
C
CH
3
H
3
C
H
3
CH
2
C
2
o
R
+
from previous page
C
|
C
o
CH
3
CH
2
CH
2
CH
3
H
H
3
C
C
o
C
|
H
3
CH
2
C CH
3
H H
3
CH
2
C


S
N
positions of 2
o
RX, rearrangement to more stable 3
o
R
+
considered


After rearrangement to 3
o
carbocation (R
+
) We will skip rearrangements in Chem 314

E1 products from left C
|
carbon atom (top and bottom, after rearrangement)
Redrawn (achiral)
H
2
O
C C
CH
3
H
2
C
H H
3
C
2E-alkene
2Z-alkene
3Z-alkene
3E-alkene
OH
2
C
C CH
2
H
2
C
H
3
C
H
CH
3
H
3
C
C
C
H
2
C
H
H
3
C
CH
2
OH
2
H
2
O
a
b
S
N
1 product (a. add from top and b. add from bottom), (after rearrangement)
C
O
H H
C
O
H H
a
b
OH
2
OH
2
(achiral)
acid/base
proton transfer
E1 product from right C
|
carbon atom (top and bottom, after rearrangement)
(3R)
diastereomers
C
H
2
C
H
C
H
H
3
C
C
H
2 H
3
C
CH
3
(4S)
initial 2
o
carbocation
rearranges via hydride
shift to a 3
o
carbocation
C
C
H
3
C
H
C
H
2
H
3
C
H
C
CH
3
4S stereochemistry is
lost in new carbocation
add nuclephile (top/bottom) = S
N
1
lose |-H (top/bottom) = E1
rearrangement to similar or
more stable carbocation (R
+
)
(none is possible here)
R
+
reaction possibilities start all
over again with new carbocation
H
H
C
C
H
3
C
H
C
H
2
H
3
C
H
C
CH
3
H
H
C
C
H
3
C
H
C
H
2
H
3
C
H
C
CH
3
H
H
"H" parallel to
empty 2p orbital
on top and bottom
of right C
|
position
C
H
2
H
3
C
C C
H
H
2
C
CH
3
H
3
C
C
H
2
H
3
C
diastereomers
C
C
H
3
C
H
C
H
2
H
3
C
H
C
CH
3
H
H
H
2
C
CH
3
CH
2
H
3
C
C
H
2
H
3
C
C
H
2
CH
3
C
H
2
H
3
C
H
2
C
H
3
C
acid/base
proton transfer
C
O
H
C
H
2
CH
3
C
H
2
H
3
C
H
2
C
H
3
C
C
O
H
H
2
C
CH
3
CH
2
H
3
C
C
H
2
H
3
C
(3S)
enantiomers
CH
3
H
3
C
C
H
2
C
CH
3
H
2
C
H
2
C
1-alkene
(does not have E/Z
stereochemistry)
OH
2
E1 product from methyl C
|
carbon atom (top and bottom, after rearrangement, only one product from the methyl)
C
C
H
2
C
H
C
H
2
H
3
C
H
CH
2
CH
3
C
H
2
H
3
C
H
(3R)
(3S)
"H" parallel to
empty 2p orbital
on top and bottom
of right C
|
position
"H" parallel to
empty 2p orbital
on top and bottom
of right C
|
position


Alcohols in strong acid = Protonated Alcohols - Water as a Good Leaving Group

We can make the hydroxyl group of an alcohol, OH, into a good leaving group in strong acid conditions (HCl,
HBr, HI and H
2
SO
4
). Strong protic acids are used to extensively protonate the alcohol OH. When the alcohol OH
is protonated, the leaving group is water, not hydroxide. Waters conjugate acid is H
3
O
+
, (pK
a
= -2), while
hydroxides conjugate acid is H
2
O, (pK
a
= 16). If substitution is the desired goal, then the strong halide acids are
normally used, HCl, HBr or HI. If elimination is the desired goal, then concentrated sulfuric acid (H
2
SO
4
) is used
at an elevated temperature ().
Using the hydrohalic acids (HCl, HBr or HI), very polar, strongly acidic conditions encourage S
N
1 reactions,
and these are assumed to be operating at all tertiary and secondary alcohol (ROH) centers. Rearrangements are
frequently observed under these conditions. The large energy expense of a methyl or primary carbocation prevents
the escape of water on its own. The H
2
O at methyl and primary ROH
2
+
is assumed to be pushed off by the halide
(S
N
2) of the strong acid to form a methyl or primary haloalkane without rearrangement.

a. 1
o
, 2
o
and 3
o
ROH reacted with HX acids (HCl, HBr, HI) - usually S
N
chemistry

i. methyl alcohols (S
N
2 emphasized, no rearrangement)

H
3
C
O H
Br H
methanol
H
3
C
O H
H
Br
H
3
C
O
H
H
Br
S
N
2
Br H
O
H
H H
bromomethane
Br
water is a good
leaving group
pK
a
= -9

ii. primary alcohols (S
N
2 emphasized, no rearrangement)

H
3
C CH
2
O H
Br H
primary alcohol
H
3
C CH
2
O H
H
Br
H
3
C CH
2
O
H
H
Br
S
N
2
Br H
O
H
H H
primary
bromoalkane
Br
pK
a
= -9
water is a good
leaving group

iii. secondary alcohols (S
N
1 emphasized, rearrangements possible)
water is a good
leaving group
Cl H
secondary alcohol (trans OH)
H
2
C H
3
C H
S
N
1
Cl
H
3
C
H
Cl
H
3
C
Cl
H
trans Cl
cis Cl
top and bottom
attack
H
3
C
H
O
H
H
O
H
H
secondary
chloroalkane
pK
a
= -7
O
H
H
O
H
H H
Cl H Cl


iv. tertiary alcohols (S
N
1 emphasized, rearrangements possible)
I H
tertiary alcohol (trans OH)
H
3
C H
3
C CH
3
O
H
H
S
N
1
I
O
H
H H
I
I
trans I
cis I
top and bottom
attack
H
3
C
CH
3
O
H
CH
3
O
H
H
I H
pK
a
= -10

Problem 29 - Propose a synthesis of monodeuterated cyclohexane from cyclohexanol.

O
H
H
H
D

b. 1
o
, 2
o
and 3
o
ROH reacted with H
2
SO
4
and high temperature = E1 chemistry

Using strongly acidic sulfuric acid, H
2
SO
4
, at elevated temperatures favors E1 reactions because lower boiling
alkenes distill out and continually shift the equilibrium to make more alkene, which continues to distill out, until
there is no more alcohol left in the reaction pot. We will assume that an E1 mechanism is operating in all of the
reactions below (even the primary alcohol, an exception to our rule about no primary carbocations the conditions
are very harsh). Rearrangements are possible and observed.

i. primary alcohols (with high temperature E1-? - emphasized, rearrangements possible)
water is a good
leaving group
primary alcohol
O
H
H
O
H
H H
O
H
O H SO
3
H
A
(heat)
O
H
H
C
H
H
H H
rearrangement
H
H
O SO
3
H
E1
bp = -47
o
C
distills out
bp = +82
o
C
very difficult
(high temperature)
O H SO
3
H
O SO
3
H
alcohol alkene
AT
bp
= 129
o
C
pK
a
= -10

ii. secondary alcohols (E1 emphasized, rearrangements possible)
secondary alcohol
O
H
H
O
H
H H
O
H
O H SO
3
H
A
(heat)
O
H
H
O SO
3
H
E1
bp = +83
o
C
distills out
bp = +161
o
C
O H SO
3
H
O SO
3
H
H
H
H
alcohol alkene
AT
bp
= 78
o
C
pK
a
= -10
water is a good
leaving group


iii. tertiary alcohols (E1 emphasized, rearrangements possible)
tertiary alcohol
O
H
H
O
H
H H
O H SO
3
H
A
(heat)
O SO
3
H
bp = +33
o
C
distills out
bp = +102
o
C
O H SO
3
H
O SO
3
H
O
H
O
H
H
H
H H
E1
bp = +39
o
C
distills out
90% < alkene
(more substituted)
minor alkene
(less substituted)
b
a
a
b
alcohol alkene
AT
bp
~ 63
o
C
pK
a
= -10
water is a good
leaving group

We have some, limited control to direct the alcohol functionality toward S
N
or E choices. The conditions to
effect these different pathways are important, so you must be aware of the details mentioned above (halide acids =
S
N
reactions and H
2
SO
4
/A = E1 reactions). Heat is a crucial aspect of the E1 reaction, since it allows the lower
boiling alkene to escape from the reaction mixture by distillation, while the higher boiling alcohol or inorganic
esters remains, in the reaction pot to reestablish equilibrium by forming more alkene, which distills......etc. The
alkene boils much lower than the alcohol it comes from because it does not have an OH to form hydrogen bonds.

Examples of Boiling Point Differences Between Alcohols and Possible Alkene Products
boiling points
of alcohols (
o
C)
boiling point
of alkenes (
o
C)
OH
H
2
C CH
2
OH
OH
OH
(79
o
C)
(82
o
C)
(-104
o
C)
(-47
o
C)
(97
o
C)
(100
o
C)
OH
(161
o
C)
(-47
o
C)
(-6
o
C)
(1
o
C)
(4
o
C)
(83
o
C)
DT
bp
(183
o
C)
(129
o
C)
(144
o
C)
(106
o
C)
(99
o
C)
(96
o
C)
(78
o
C)

There are important other ways to change OH into Br. The OH group can be an alcohol or a carboxylic acid.
Some possibilities are shown below.

1. Formation of tosylates from ROH + TsCl (toluenesulfonyl chloride = tosyl chloride), S
N
/E chemistry is possible
without rearrangements.

O R
O R
H
S
Cl
H
S Cl
O
O
O
O
N
O
S
Cl
O
O
N H
O
S
O
O
Br
Na
separate
step
Br
HBr
rearrangement
and
R,S (racemic)
S
1. TsCl/pyridine
2. NaCl
(prevents R
+
formation
and any rearrangement)
alkyl tosylate = RX compound
compare - a different result
R
R
R
R
R
R
R
Br
Br
S
N
1
toluene sulfonylchloride
(tosyl chloride)
S
N
2

Problem 30 We can now make the following molecules. Propose a synthesis for each. (Tosylates formed from
alcohols and tosyl chloride/pyridine via acyl substitution reaction, convert OH from poor leaving group into a very
good leaving group, similar to iodide)

2. Other acyl-like transformations include thionyl chloride (SOCl
2
) or thionyl bromide (SOBr
2
) with alcohols (makes
R-Cl and R-Br) or carboxylic acids (makes acid chlorides, RCOCl). Acid chlorides formed can make esters, amides
and anhydrides.

Thionyl chloride with methyl, 1
o
ROH = acyl-like substitution at SOCl
2
, then S
N
2 at methyl and primary RX.

R O
H S
Cl
O
Cl
H
2
C
R O
S
O
Cl
Cl
O
S
O
H
H
2
C
R O
S
Cl
O
CH
2
R
synthesis of an alkyl chloride from an alcohol + thionyl chloride (SOCl
2
) [can also make RBr from SOBr
2
]
S
N
2 at methyl and
primary alcohols
No rearrangement because no R
+
.
H
Cl H
Cl
O
S
Cl
O
H
product
O
S
O
H
acyl-like
substitution
Cl
Cl


Thionyl chloride with 2
o
and 3
o
ROH = acyl substitution, then S
N
1 (there are various ways you can write this
mechanism)

O
H
O
S
O
Br
Br
O
S
O
H
O
S
Br
O
H
H
Br
S
N
1 at secondary and
tertiary alcohols
synthesis of an alkyl chloride from an alcohol + thionyl chloride (SOCl
2
) [can also make RBr from SOBr
2
]
O
S
Br
O
H
Br H
R
R
R
R
R/S
acyl-like
substitution
S
Br
O
Br
Br
Br

Synthesis of acid chlorides from acids + thionyl chloride (SOCl
2
), use the carbonyl oxygen instead of the OH.
C
R
O
O
H
C
R
O
O
H
S
O
Cl
Cl
resonance
C
R
O
O
H
S
O
Cl
Cl
C
R
O
O
H
S
O
Cl
Cl
Base
C
R
O
O
S
O
Cl
Cl
Base H
C
R
O
O
S
Cl
O
C R O
C R O
resonance
C
R
Cl
O
acylium ion
S
Cl
O
Cl
O
S
O
Cl
Cl
resonance

Formation of esters from ROH + acid chlorides, amides from RNH
2
or R
2
NH + acid chlorides and anhydrides from
RCO
2
H + acid chlorides

O
R
O
R
H
Cl
O
Cl O
H
O
Cl
H
O
O
O
R
R
There are many variations of ROH and
RCO
2
H joined together by oxygen.
ester synthesis from acid chloride and alcohols
R
O
H
R
O
H
H



O
O
Cl
O
Cl O
Cl
There are many variations of R
1
CO
2
H and
R
2
CO
2
Hjoined together by oxygen.
anhydride synthesis f rom acid chloride and carboxylic acids
O
O
H
H
O
O
H
O
O
O
O
Cl H

Phosphorous trichloride (PCl
3
) = S
N
2 of alcohol at phosphorous, then S
N
2 (at methyl and primary R(OH)PCl
2
)

O
H
O
P
H
Cl
Cl
Cl
Cl
O
P
H
Cl
Cl
reacts
twice
more
P
Cl
Cl
Cl
S
N
2
S
N
2

Phosphorous tribromide (PBr
3
) = S
N
2 of ROH at phosphorous, then S
N
1 (at secondary, tertiary, allylic and benzylic
R(OH)PBr
2
)
O
H
S
Br
H
R,S
O
H
R
P
Br
Br
Br
S
N
2
O
P
H
Br
Br
Br
S
N
2
Br
O
P
H
Br
Br
reacts
twice
more
P
Br
Br
Br
O
P
H
Br
Br
Br
O
P
H
Br
Br
reacts
twice
more
Br
S
N
2
S
N
1


Chart of S
N
and E Chemistry (note exceptions)
typical strong base
nucleophiles are:
(f or our course)
H
O
R
O
R
O
O
H
O
R
O
O
O H H
H
N
C
C
C
R
H
S
R
S
N
N
N
H
3
C
X
C
H
2
X R
H
C
X R
R
C
X R
R
R
methyl
primary
secondary
tertiary
only S
N
2
only S
N
2 only S
N
2
only S
N
2 only S
N
2
only S
N
2 only S
N
2 only S
N
2
S
N
2 > E2 S
N
2 > E2
S
N
2 > E2 S
N
2 > E2 S
N
2 > E2
S
N
2 > E2
S
N
2 > E2 S
N
2 > E2
E2 > S
N
2
E2 > S
N
2
E2 > S
N
2 S
N
2 > E2
S
N
2 > E2 S
N
2 > E2
S
N
2 > E2
S
N
2 > E2
only E2
only E2
only E2
only E2
only E2
only E2 only E2 only E2
exception
(too basic)
O
t-butoxide
only S
N
2
E2 > S
N
2
exception
(bulky &basic)
E2 >> S
N
2
only E2
typical weak base
nucleophiles are:
(f or our course)
H
3
C
X
C
H
2
X R
H
C
X R
R
C
X R
R
R
methyl
primary
secondary
no
reaction
no
reaction
no
reaction
no
reaction
no
reaction
no
reaction
S
N
1 > E1
S
N
1 > E1
S
N
1 > E1
S
N
1 > E1
S
N
1 > E1
S
N
1 > E1
B H
H
H
H
only S
N
2
S
N
2 > E2
S
N
2 > E2
NA
exception
(bulky &basic)
exception
(too basic)
exception
(too basic)
tertiary
Al D
D
D
D
alcohol reactions in
strong acid:
(f or our course)
H
3
C
OH
C
H
2
OH R
H
C
OH R
R
C
OH R
R
R
methyl
primary
secondary
tertiary
H
X
(X = Cl, Br or I)
S
N
1
S
N
1
E1
not
discussed
H
2
SO
4
E1
E1
S
N
2
S
N
2
S
N
1
S
N
1
S
N
2
S
N
2
SOCl
2
SOBr
2
PCl
3
PBr
3
1. TsCl/py
2. NaBr
NA
S
N
2
S
N
2
S
N
2


Problem 31 Look back at the table of R-Br structures on page 2. Include stereoisomers together. Be able to list
any relevant structures under each criteria below.

1. Isomers that can react fastest in S
N
2 reactions
2. Isomers that give E2 reaction but not S
N
2 with sodium methoxide
3. Isomers that react fastest in S
N
1 reactions
4. Isomers that can react by all four mechanisms, S
N
2, E2, S
N
1 and E1 (What are the necessary
conditions?)
5. Isomers that might rearrange to more stable carbocation in reactions with methanol.
6. Isomers that are completely unreactive with methoxide/methanol
7. Isomers that are completely unreactive with methanol, alone.

The number of each type of product (S
N
1, E1, S
N
2, E2) is listed after a reaction arrow for each starting structure
(assuming I analyzed the possibilities accurately in my head, while sitting at the computer). Do you agree with
these numbers? Can you draw a valid mechanism for each one?

Br H
H
3
C H
OH
O
OH
H
O
H
S
N
1
E1 S
N
2 E2
O
O
O
H
O
2
4
1 3
1 3
1 3
a.
2
5
b.
2
4
a.
2 5
b.
2 4
a.
2
5
b.
b. after rearrangement
a. initial carbocation
Br H
H
3
C H

Br H
H
3
C H
OH
O
OH
S
N
1
E1 S
N
2 E2
O
O
O
H
O
2 6
1 3
1 3
1
3
a.
2 5
b.
2
6
a.
2 5
b.
2
6
a.
2
5
b.
b. after rearrangement
a. initial carbocation
Br H
H
3
C H
H
O
H
D H
D H


Similar patterns in cyclohexane RX structures. The leaving group has to be axial in S
N
2 and E2 reactions.

C
o
C
|1
C
Br
C
|2
H
H
b
H
a
H
H
H
H
H
C
o
C
|1
H
a
Br
C
|2
H
H
3
C
H
b
H
H
Rotation of C
o
-C
|1
brings H
a
or H
b
anti to C-Br, which allows S
N
2 and
two different E2 possibilities: H
a
(Z) and H
b
(E). Since C
|2
is a simple
methyl, there is no C
|2
substituent to inhibit either of these reactions.
C
o
C
|1
H
b
Br
C
|2
H
H
a
H
3
C H
H
When methyl on C
|
1 is anti
to C-Br, no S
N
2 is possible and
no E2 is possible from C
|
1.
S
N
2 possible
E2 from C
|1
(2Z- butene)
E2 from C
|2
(1-butene)
S
N
2 possible
E2 from C
|1
(2E- butene)
E2 from C
|2
(1-butene)
No S
N
2 possible and no
E2 from C
|1
, but E2 from
C
|2
(1-butene) is possible.
E2 possible here
Use these ideas to understand cyclohexane reactivity.
H H
H
H
H H
Br
H
H
H
H
H
H
H
H
H
H
H
Br
H
H
H
H
H
No S
N
2 is possible (1,3 diaxial
positions block approach of
nucleophile), and no E2 is
possible because ring carbons
are anti.
No S
N
2 or E2 when "X"
is in equatorial position.
S
N
2 possible if C
o
is
not tertiary and there
is no anti C
|
"R" group.
E2 possible
with anti C
|
-H.
Both S
N
2 and E2 are possible
in this conformation with leaving
group in axial position.
H H
H
H
H H
Br
H
C
H
H
H
H
H
H
H
H
H
Br
H
H
H
3
C
H
H
No S
N
2 or E2 when "X"
is in equatorial position.
No S
N
2 possible if there
is an anti C
|
"R" group.
E2 possible
with anti C
|
-H.
Only E2 is possible in this
conformation. Leaving group
is in axial position.
H
H
H
full rotation at
C
o
-C
|
is possible
in chain
only partial
rotation is
possible in ring
only partial
rotation is
possible in ring
H
H H
equatorial leaving group
axial
leaving
group
No S
N
2 is possible (1,3 diaxial
positions block approach of
nucleophile), and no E2 is
possible because ring carbons
are anti.
No E2 possible,
no anti C
|
-H.
full rotation at
C
o
-C
|
is possible
in chain
alkene stabilities tetrasubstituted > trisubstituted > trans-disubstituted > gem-disubstituted ~ cis-disubstituted > monosubstituted


Problem 32 Predict possible products of a. water and b. ethanoate (acetate) with structures 2, 10 and 13. Only
consider rearrangements to more stable carbocations where appropriate.

C
H
3
C
H
3
C
H
3
C
H
H
C
CH
3
CH
3
H
3
C
H
H
severe steric
repulsion
1
9,999
K
eq
t-butyl substituent locks
in chair conformation
with equatorial t-butyl
X
X
X
X
12
13
Cyclohexane structures
have two chair conformations
possible.
1. Which conformation is reactive?
2. Is S
N
2 possible? Requires an open approach
at C and C .
3. Is E2 possible? Requires anti C -H.
4. How many possible products are there?
5. What is the relationship among the starting
structures?
6. What is the relationship among the products?
7. Are any of the starting structures chiral?
8. Are any of the product structures chiral?
Cyclohexane Examples
1
X
X
X
X
X
X
X
X
X
X
X
2
3
4
5
6
7
8
9
10
11
chair 1 chair 2
X = Cl
Br
I
OTs
14 15
Mechanism predictions with:
O R H
R
O
OH
O H H
Some examples
O H Na O R Na R
O
O
Na
O
K
weak
nucleophiles
strong nucleophile/bases + other anions shown above


The number of each type of product (S
N
1, E1, S
N
2, E2) is listed after a reaction arrow for each starting structure
(assuming I analyzed the possibilities accurately in my head, while sitting at the computer). Only consider
rearrangements in part 9. Do you agree with these numbers? Can you draw a valid mechanism for each one?

H
O
H
2
3
chair 1
chair 2
S
N
1
X
X
X
a.
b.
S
N
2 E2
1 1
E1
1 1
1
S
N
1 S
N
2
E2
1 2
E1
2 2
S
N
1 S
N
2 E2
0 1
E1
5
6
S
N
1
X
X
X
S
N
2 E2
1 2
E1
2 2
4
S
N
1 S
N
2 E2
1 2
E1
2 2
S
N
1 S
N
2
E2
1 2
E1
2 2
8
9
S
N
1
X
X
S
N
2 E2
1 2
E1
2 2
7
S
N
1 S
N
2 E2
0 3
E1
2 3
S
N
1 S
N
2 E2
0 1
E1
2 1
1 2
Only consider carbocation
rearrangements that
immediately go to a more
stable carbocation (not
equally stable carbocations
= too many possibilities)
a.
b.
2 2
1 2
X
a.
b.
c.
d.
consider any 3
o
R
+
possibility
and consider stereoisomers
4 5
1 2
1 2
H
O
Na
condition 1
condition 2

Available chemicals from the catalog

Sources of carbon - you can invoke these whenever needed:
CH
4
Br

Br
2
Cl
2
Na
C N
Na
O H
CH
2
Li
n-butyl lithium
(very strong base
or nucleophile, use
anytime)
Na
H
N
H
diisopropylamine
N
O
O
H
Na
S H
O
OH
H
2
O
O
sodium hydride
(very strong base)
ketone
(a carbonyl)
pre alds / kets
phthalimide
(an imide)
ethanoic acid
a carboxylic acid)
pre alds / kets
Na
sodium amide
(very strong base)
HCl
HBr HI H
2
SO
4
Commercially available chemicals and reagents - you can invoke these whenever you need them.
N
O O
Br
NBS = N-bromosuccinimide
(supplies free radical bromine
for allylic & benzylic substitution)
S Cl
O
O
= Ts-Cl (tosyl chloride)
makes ROH into tosylates
N
pyridine =
proton sponge
lithium aluminumhydride = LAH
(very strong nucleophilic hydride)
(LiAlD
4
too)
sodium borohydride
(nucleophylic hydride)
S
S
dithiane
~ Br
2
Pd / H
2
quinoline
(Lindlar's cat)
Pd / H
2
H
3
C Li
methyl lithium
(very strong base)
C
Li
phenyl lithium
(very strong base)
Na
N N N
sodium azide
(excellent nucleophile)
H
3
PO
4
HNO
3
H
2
O
2
K H
OH
palladium &
hydrogen
phosphoric
acid
nitric acid
sodium nitrite
hydrogen
peroxide
diborane
use w/ alkenes
dialkylborane
use w/ alkynes
t-butyl alcohol
(use to make
t-butoxide)
pyridine
H
2
O / H
3
O
+
CO
2
carbon dioxide
bromine chlorine
hydrogen
chloride
hydrogen
bromide
hydrogen
iodide
sulfuric
acid
water
sodium
hydroxide
sodium
hydrogen
sulfide
sodium
cyanide
NH
3
ammonia
potassium hydride
(very strong base)
R = C or H
NHR
2
HCCl
3
HCBr
3
CH
2
I
2
Zn / Cu
chloroform
bromoform
Simmons
Smith
reagent
potassium permanganate
osmium tetroxide
Na
sodium
metal
3 ozone
reactions
1. O
3
, -78
o
C
2. CH
3
SCH
3
1. O
3
, -78
o
C
2. NaBH
4
1. O
3
, -78
o
C
2. H
2
O
2
, HO
1. Hg(OAc)
2
/H
2
O
2. NaBH
4
1. Hg(OAc)
2
/ROH
2. NaBH
4
O
O O
H
Cl
meta chloroperbenzoic acid
(mCPBA)
Na / NH
3
in ammonia
(Birch reagent)
= py
(PCC)
(Jones)
N
O
O
Na
Mn
O O
O O
Os
O O
O O
K
O
O
O
Cr
O
O O
Cr
O
O O
B
H
H
H
H
Al
H
H
H
H
Na
Li
B
H
H
H
B
R
R
H
pre aldehydes/ketones
P
Ph
Ph
Ph
triphenylphosphine
(to make Wittig salts)
Na Cl
Br
I
Na
Na
Br Cu
Salts / ionic substances
1.
2. H
2
O
2
/HO
2. Br
2
/CH
3
O
1.
2. H
2
O
2
/HO
diborane
use w/ alkenes
B
H
H
H
1.
Mg
magnesium
metal
Li
lithium
metal
Zn
zinc
metal
Lewis acids
AlBr
3
FeBr
3
BF
3
SOCl
2
PBr
3
SO
3
etc.
Various metals
HgX
2
(mecuric salts)
HO
OH
H
2
N
NH
2
NH
ethylene
glycol
(protect C=O)
hydrazine
(Wolff-Kishner)
pyrrolidine
(enamines)
O
THP
(protect O-H)
S HO
O
O
toluene sulfonic acid = TsOH
(very strong organic acid)
sodium cyanoborohydride
(nucleophylic hydride)
(NaBD
4
too)
B
H
H
H
CN
Na
cuprous
bromide

For now, the structures below represent your hydrocarbon starting points to synthesize target molecules (TM) that are
specified. We will only study two free radical reactions in our course, but they are very important reactions because
they make versatile functionalized starting molecules for synthesis of all the other functional groups studied in this
course.


Allowed starting structures our main sources of carbon 1. Free radical substitution of sp
3
C-H bonds to form sp
3

C-Br bonds at the weakest C-H position and 2. Anti-Markovnikov addition to alkenes makes 1
o
R-Br. From these two
reactions we can make 13 R-Br molecules below.

CH
4
Br
Br
Br
We need to make these 1
o
RBr
from anti-Markovnikov free
radical addition of H-Br (ROOR)
to alkenes.
Br
2
/ hv
Br
2
/ hv
Br
2
/ hv
Br
2
/ hv
Br
2
/ hv Br
2
/ hv
Br
2
/ hv
H
3
C
Br
Br
Br
Br
Br
Br
Br
HBr
H
2
O
2
/ hv
HBr
H
2
O
2
/ hv
HBr
H
2
O
2
/ hv
E2 reaction
O
K
E2 reaction
O
K
E2 reaction
O
K
E2 reaction
O
K
E2 reaction
O
K
Br
2
/ hv
Br
2
/ hv
Br
2
/ hv
Br
Br
Br
Examples of allylic RBr
compounds: This is just
free radical substitution
at allylic sp
3
C-H position
of an alkene.
Br
benzylic RBr,
f rom above
Br
Ph
Br
2
/ hv
2 eqs.
Ph
Br
Br
Br Br Br Br
E2 reaction
(twice)
Na R
2
N
1. 3 eqs.
2. workup
Ph
a
b c
a
a
b
b
c
c
Br
bromobenzene
is given until
aromatic chemistry
is covered in 316

You will need to propose a step-by-step synthesis for each target molecule from these given structures. Every step
needs to show a reaction arrow with the appropriate reagent(s) above each arrow and the major product of each step.
This is often accomplished by using retrosynthetic thinking. You start at the target molecule (the end) and work your

way backwards (towards the beginning), one step at a time until you reach an allowed starting material. The starting
material of each step becomes the target molecule for the next step until you reach the beginning.

1. Mechanism for free radical substitution of alkane sp
3
C-H bonds to form sp
3
C-Br bonds at weakest C-H
position
H
3
C
H
2
C
CH
3
H
3
C
CH
CH
3
Br
Br Br
overall reaction
hv
Br H

1. initiation
Br Br
hv
Br Br AH = 46 kcal/mole
weakest bond ruptures first

2b propagation
H
3
C
C
CH
3
H
Br Br
H
3
C
C
CH
3
H Br
Br
AH = -22 kcal/mole
(overall)
BE = +46 kcal/mole
BE = -68 kcal/mole
2a propagation
H
3
C
C
CH
3
H H
Br
Br H
H
3
C
C
CH
3
H
AH = +7 kcal/mole
(overall)
BE = +95 kcal/mole
BE = -88 kcal/mole
AH = -15
both steps

3. termination = combination of two free radicals - relatively rare because free radicals are at low concentrations
Br
H
3
C
C
CH
3
H
H
3
C
C
CH
3
H Br
H
3
C
C
CH
3
H
CH
3
C
H
3
C
H
CH
CH
3
H
3
C CH
CH
3
CH
3
AH = -68 kcal/mole
AH = -80 kcal/mole
very minor product

2. Free radical addition mechanism of H-Br alkene pi bonds (alkenes can be made from E2 or E1 reactions at this
point in course) (anti-Markovnikov addition to alkenes)

H
3
C
H
2
C
C
H
2
Br
H
3
C
H
C
CH
2
HBr
R
2
O
2
(cat.)
hv
overall reaction

1. initiation (two steps)
R
O
O
R
hv
R
O
O
R
Br H
R
O
R
O
H Br
AH = 40 kcal/mole
AH = -23 kcal/mole
BE = +88 kcal/mole
BE = -111 kcal/mole
(cat.)
reagent


2a propagation
H
3
C
H
C
CH
2
Br
H
3
C
C
C
H
2
Br
H
AH = -5 kcal/mole
BE = +63 kcal/mole
BE = -68 kcal/mole

AH = -15
both steps
(2a + 2b)
2b propagation
H
3
C
C
C
H
2
Br
H
Br H
H
3
C
H
2
C
C
H
2
Br
Br
AH = -10 kcal/mole
BE = +88 kcal/mole
BE = -98 kcal/mole

Miscellaneous E2 mechanism not included above; An E2 reaction that makes carbonyl compounds (C=O)

1. PCC = pyridinium chlorochromate, (CrO
3
/pyridine), CrO
3
oxidations of alcohols (methyl, 1
o
and 2
o
ROH)
without water. Steps are: 1. Cr=O addition, 2. acid/base and 3. E2 to form C=O (aldehydes and ketones).
H
3
C
C
H
2
C
H
O
H
H
Cr
O
O O
H
3
C
C
H
2
C
H
O
H
H
Cr
O
O
O
H
3
C
C
H
2
C
H
O
H
Cr
O
O
O
N
N H
N
H
3
C
C
H
2
C
H
O
Cr
O
O
O N H
PCC = pyridinium chlorochromate oxidation
of primary alcohol to an aldehyde (no water to
hydrate the carbonyl group)
primary alcohols
aldehydes
E2

CrO
3
o
and 2
o
ROH) without water = PCC, Cr=O addition, acid/base and E2 to
form C=O (aldehydes and ketones)
H
3
C
C
H
2
C
CH
3
O
H
H
Cr
O
O O
H
3
C
C
H
2
C
CH
3
O
H
H
Cr
O
O
O
H
3
C
C
H
2
C
CH
3
O
H
Cr
O
O
O
N N H
N
H
3
C
C
H
2
C
CH
3
O
Cr
O
O
O
N H
PCC = pyridinium chlorochromate oxidation
of primary alcohol to an aldehyde (no water to
hydrate the carbonyl group)
primary alcohols
E2
ketones


2. Jones reagent = CrO
3
/water/acid, CrO
3
o
and 2
o
ROH) with water. Steps are:
1. Cr=O addition, 2. acid/base and 3. E2 to form C=O (aldehydes and ketones) 4. hydration of C=O and repeat
reactions when the starting alcohol is a 1
o
alcohol (forms carboxylic acids from primary alcohols and ketones
from secondary alcohols).

H
3
C
C
H
2
C
H
O
H
H
H
3
C
C
H
2
C
H
O
Jones = CrO
3
/ H
2
O / acid
primary alcohols oxidize to carboxylic acids
(water hydrates the carbonyl group,
which oxidizes a second time )
primary alcohols
aldehydes (cont. in water)
H
O
H
H
O
H
H
H
3
C
C
H
2
C
H
O
H
H
3
C
C
H
2
C
H
O
H
H
O
H
H
3
C
C
H
2
C
O
H
O
H
H
H
H
O
H
H
3
C
C
H
2
C
O
O
H
H
H
H
O
H
H
O
H
H
3
C
C
H
2
C
O
O
H
hydration of
the aldehyde
second oxidation of the carbonyl hydrate
H
O
H
resonance
carboxylic acids
Cr
O
O O
H
3
C
C
H
2
C
H
O
H
H
Cr
O
O
O
H
3
C
C
H
2
C
H
O
H
Cr
O
O
O
Cr
O
O
O
H
O
H
H
H
O
H
H
Cr
O
O O
H
3
C
C
H
2
C
O
O
H
Cr
O
O
O
H
H
H
3
C
C
H
2
C
O
O
H
Cr
O
O
O
H
H
O
H
H
Cr
O
O
O
H
O
H
H


Problem 33 We can now make the following molecules. Propose a synthesis for each from our starting materials.

C
O
H H
C
O
H
3
C H
C
O
H
3
C CH
3
C
O
C
H
2
H
C
O
CH
3
H
3
C
O
C
O
H
C H
H
3
C
CH
3
C
O
H
C
O
C
H
2
H
C
O
H OH
C
O
H O
CH
3
C
O
H
3
C OH
C
O
C
H
2
OH
H
3
C
C
O
H
C OH
H
3
C
CH
3
C
O
OH
C
O
C
H
2
OH
C
O
H
3
C O
C
O
C
H
2
O
H
3
C
C
O
H
C O
H
3
C
CH
3
CH
3
CH
3 CH
3
C
O
O
C
O
C
H
2
O
CH
3
CH
3
aldehydes, carboxylic acids and esters
ketones
C
O
C
H
H
H
2
C C
O
C
H
OH
H
2
C C
O
C
H
O
H
2
C CH
3
O
C
O
C H
H
2
C
CH
3
C
O
C OH
H
2
C
CH
3
C
O
C O
H
2
C
CH
3
CH
3
conjugated aldehydes, carboxylic acids and esters

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Nucleophilic Substitution & Elimination Chemistry Beauchamp 1

y:\files\classes\315\315 Handouts\315 Fall 2013\2 315 SN and E & chem catalog.doc

-X bond. This leads to differences in

-X bond to form a carbocation. Ion formation

-H position, top or bottom

positions, In this problem 2

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Nucleophilic Substitution & Elimination Chemistry Beauchamp 1

y:\files\classes\315\315 Handouts\315 Fall 2013\2 315 SN and E & chem catalog.doc

-X bond. This leads to differences in

-X bond to form a carbocation. Ion formation

-H position, top or bottom

positions, In this problem 2

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315 SN E Syn & Chem Catalog

315 SN E Syn & Chem Catalog