http://pages.towson.edu/ryzhkov/handouts/sehand.

html
NUCLEOPHILIC SUBSTITUTION AND ELIMINATION

These comments summarize the two substitution mechanisms and the two
elimination mechanisms encountered for alkyl halides.
A. The S
N
2 Reaction.
Kinetics: Rate = k [RX] [Nu:-]. Both RX and Nu:- are involved in the rate-
determining step.
Nucleophile: Negatively-charged (strong nucleophile) work best; occasionally
neutral nucleophiles can be used. See examples at the end of Handout.
Reactivity of alkyl halides: CH
3
> 1 > 2 due to steric effects that hinder backside
attack. 3 halides do not react. Allyl (CH
2
=CH-CH
2
X) and benzyl (C
6
H
5
CH
2
X)
halides are unusually reactive (comparable to or more reactive than methyl).
Stereochemistry: Complete inversion of configuration via pentacoordinate carbon
Transition State.
Rearrangements: Do not occur
Solvents: Wide variety can be used, but polar, aprotic solvents (see end of Handout)
are favored and usually cause 2 halides to react by this mechanism.
Transition State:



Examples: The S
N
2 reaction is concerted, with all bonds being made and broken at
the same time.



B. The S
N
1 Reaction.
Kinetics: Rate = k [RX]. Only RX is involved in the rate-determining step.
Nucleophile: Neutral (weak nucleophile) work best; see examples at the end of
Handout.
Reactivity of alkyl halides: 3 > 2 due to the relative stabilities of carbocations
that form (electronic effects). Methyl and 1 halides do not
http://pages.towson.edu/ryzhkov/handouts/sehand.html
react. Allyl and benzyl halides are unusually reactive due to the exceptional stabilities
of the allyl and benzyl carbocations (resonance effects).
Stereochemistry: Partial racemization via intimate and solvent-separated ion pairs.
Rearrangements: Occur if a more stable carbocation can form.
Solvents: Wide variety can be used, but polar, protic solvents (see end of Handout)
are favored and usually cause 2 halides to react by this mechanism.
Transition State:



Examples: The S
N
1 reaction occurs in several steps, with formation of the
carbocation being involved in the first, rate-determining step (see Transition State
section above).


Carbocations are involved in this mechanism, with some features of carbocations
being:
Stability: 3 > 2. The more stable an intermediate is, the more easily it is
formed; hence the relative reactivities of and halides. Methyl and 1
carbocations are seldom formed. Allyl and benzyl carbocations form readily
because of resonance stabilization of the positive charge.
Rearrangements: If possible, a carbocation may rearrange to a more stable
one by an alkyl group shift or a hydride shift. The most common
rearrangement is from a 2 to 3 ion. Primary carbocations, if formed (and
they seldom are), could rearrange to either a 2 or 3 cation.
Example:

http://pages.towson.edu/ryzhkov/handouts/sehand.html


Comparison of S
N
1 and S
N
2 Reactions
From a practical standpoint, S
N
2 reactions are useful for introducing various
functional groups in place of halogen in 1 and 2 halides. Only one substitution
product is formed, and many different nucleophiles can be used.Optically active
halides cleanly invert their stereochemistry in a S
N
2 reaction.
S
N
1 reactions are considerably less useful for several reasons. Only a limited number
of nucleophiles may be used, possible carbocation rearrangement can lead to
multiple products and racemization of the optically active substrates.
C. The E2 Reaction.
Kinetics: Rate = k [RX] [B:-]. Both RX and B:- are involved in the slow, rate-
determining step.
The base: Strong bases, such as KOH/alcohol or NaOCH
2
CH
3
(NaOEt), are
required.
Reactivity of alkyl halides: 3 > 2 > 1. With a strong base, alkyl halides undergo
elimination by the E2 reaction.
Rearrangements: Do not occur
Solvents: Reaction can occur in a variety of solvents. The use of a strong base is the
driving force for elimination to occur.
Reactants:
1) Must have one or more hydrogens.
2) H and the leaving group must be anti to one another and must be in the
same plane as the two carbons to which they are attached.
Products: If two or more alkenes are produced, the one having the greater or greatest
number of carbon-containing substituents attached to the C=C bond is usually
the major product. The reason for this trend is based upon the stabilities of various
alkenes, with the more or most stable alkene being formed more easily and thus is
the major product.
http://pages.towson.edu/ryzhkov/handouts/sehand.html
Isotope Effects: Because breaking the C-H bond is involved in the rate-determining
step, the use of D in place of H results in different rates of reaction because it is more
difficult to break a C-D bond than a C-H bond. For example, CD
3
CH
2
Br undergoes
E2 elimination more slowly than CH
3
CH
2
Br.
Transition State:



Examples: The E2 reaction is a concerted reaction, with all bonds being made and
broken at the same time.



D. The E1 Reaction.
Kinetics: Rate = k [RX]. Only RX is involved in the slow, rate-determining step.
The base: Weakly basic substances, such as H
2
O, CH
3
OH, and CH
3
CH
2
OH can
cause elimination to occur by the E1 reaction.
Reactivity of alkyl halides: 3 > 2> 1 halides usually do not undergo E1
reaction. Note: If a strong base is present, E2 reaction occurs.
Rearrangements: If possible, a carbocation may rearrange to a more stable one by
an alkyl group shift or a hydride shift. The most common rearrangement is from a 2
to 3 ion. Primary carbocations, if formed (and they seldom are), could rearrange to
either a 2 or 3 cation.
Rearrangement occurs more rapidly than does the loss of a proton from a
carbocation, so rearrangement products usually predominate.
Solvents: Reaction is favored in polar, protic solvents.
http://pages.towson.edu/ryzhkov/handouts/sehand.html
Reactants:
1) Must have one or more hydrogens.
2) Unlike the E2 reaction, no special geometry is required.
Products: If two or more alkenes are produced, the one having the greater or greatest
number of carbon-containing substituents attached to the C=C bond is usually
the major product. The reason for this trend is based upon the stabilities of various
alkenes, with the more or most stable alkene being formed more easily and thus is
the major product.
Isotope Effects: None. The rate-determining step doesn't involve breaking a C-H or a
C-D bond. For example, (CH
3
)
3
CBr undergoes E1 elimination at the same rate as
(CD
3
)
3
CBr.
Transition State:



Examples: The E1 reaction occurs in several steps, with formation of the
carbocation being involved in the first, rate-determining step (see Transition State
section above).



Comparison of E1 and E2 Reactions
From a practical standpoint, E2 reactions are useful for converting alkyl halides into
alkenes, even when a mixture of alkenes is formed. E2 reactions can be carried out
on any class of alkyl halide.
http://pages.towson.edu/ryzhkov/handouts/sehand.html
E1 reactions are considerably less useful for converting alkyl halides into alkenes. In
addition to formation of the mixture of alkenes, more elimination products yet can be
formed if a carbocation rearrangement is possible.
E. Competition Between S
N
1 and E1 Reactions.
Unlike the S
N
2 and E2 reactions that occur by different mechanisms, the S
N
1 and E1
reactions have one thing in common: both involve the initial formation of
a carbocation intermediate resulting from the solvent assisted ionization of the C-X
bond. Once formed, the carbocation may undergo several type of reactions:
1. react with a nucleophile to give products
2. lose a proton from the -carbon(s) to give one or more alkenes
3. rearrange to a more stable carbocation that undergoes reactions 1) and 2)
E1 and S
N
1 reactions occur with 2 and 3 halides but not with 1 halides. They
occur with neutral, weakly basic nucleophiles such as H
2
O and ROH. Both
mechanisms compete to give substitution and elimination. With any 2
halide, always consider possible carbocation rearrangements.
In the examples that follow, pay particular attention to the class of alkyl halide and
the solvent if specified. These features indicate if both substitution and elimination
occur. You should be able to identify the type of mechanism (E1 or S
N
1) and identify
the major alkene formed in elimination.<



F. Competition Between SN2 and E2 Reactions.
S
N
2 and E2 reactions compete to give substitution and elimination. This competition
exists when alkyl halide is 1 or 2; with 3 halides, elimination is the only reaction
of importance. Primary halides generally undergo substitution much more readily
than elimination, unless the base is very strong and bulky.
Nucleophiles that are basic, such as OH-, result in competition. A limited number of
nucleophiles, such as , are weakly basic (soft bases) and hence cause only
substitution to occur without any elimination.
http://pages.towson.edu/ryzhkov/handouts/sehand.html
In the examples that follow, pay particular attention to the class of alkyl halide and
the nature of the nucleophile (weak or strong base), and the solvent if specified.
These features dictate the type of mechanism(s) and whether substitution and/or
elimination occurs. You should write mechanisms for each example. You should be
able to identify the type of mechanism (E2 or S
N
2) and identify the major alkene
formed in elimination.



G. How to Analyze Problems.
To properly determine the correct or most plausible mechanism(s) for substitution
and/or elimination, consider the following factors. This is precisely the analysis that
was done in the examples given above.
1. Classify halide (1, 2, 3) and identify the nucleophile. Is the latter negatively-
charged or neutral? Is it a soft or a hard base?
2. Examine starting materials and, if given, products.
a) If the nucleophile is on a different carbon than the leaving group or if the
carbon skeleton has changed, consider S
N
1 and carbocations for substitution,
and E1 for elimination.
b) If the nucleophile is on the same carbon as the leaving group and there is
no change in the structure of the carbon skeleton, consider S
N
2 and for
substitution, and E2 for elimination.
3. Regarding the nucleophile/base:
a) If it is negatively charged and a hard base, consider S
N
2 and for
substitution, and E2 for elimination.
b) If it is negatively charged and a soft base, consider S
N
2 (there will be no
substitution if halide is 3 and no elimination unless the solvent is polar,
protic). If it is neutral, consider S
N
1 and E1.
4. Identify the class of alkyl halide.
a) If primary, consider S
N
2 and/or E2.
http://pages.towson.edu/ryzhkov/handouts/sehand.html
b) If secondary, consider S
N
2 or E2 (in aprotic solvent) or S
N
1 or E1 (in
polar, protic solvent).
c) If tertiary, consider S
N
1 or E1 only.
5. 2 halides may react by some combination of S
N
2, S
N
1, E1 or E2. The
mechanism is often dictated by the solvent. Aprotic polar solvents favor S
N
2/E2 and
polar, protic - S
N
1/E1.
6. If a 2 carbocation is formed, always consider possible rearrangement to a
more stable 3 carbocation (see Carbocations Section above).

NUCLEOPHILES.
1. Weak, charged nucleophiles (soft bases) (Favor S
N
2).
OH
-
, CN
-
, I
-
, RS
-

2. Weak, neutral nucleophiles (soft bases) (Favor S
N
1 and E1)
ROH, H
2
O, RSH, R
3
P:
3. Strong nucleophiles (hard bases) (Favor S
N
2 and E2)
Cl
-
, RNH
2
, RCO
2
-
(mainly S
N
2)
F
-
, RO
-
, HO
-
/alcohol, NH
3
, CO
3
2-
(mainly E2)

SOLVENTS.
1. Polar, protic solvents (good H-bonding donors and acceptors) (Favor S
N
1
and E1).
ROH, H
2
O, RNH
2
, liq. NH
3
, CH
3
CO
2
H
2. Polar, aprotic solvents (no H-bonding, but good dipoles) (Favor S
N
2 and
E2).