SUBSTITUTION REACTIONS

One group takes the place of another.

Y + R X R Y + X

NUCLEOPHILIC SUBSTITUTION Y takes the place of X ( Substitution )

Y “displaces” X
THE GENERAL REACTION AND TERMINOLOGY

NUCLEOPHILIC SUBSTITUTION
NUCLEOPHILIC DISPLACEMENT IMPORTANT:
This is a reaction at sp3 (tetrahedral) carbon atoms.
substrate leaving
group
sp3 sp2 sp

Nu:- + R X R Nu + :X- C
X
C C C C X
X X

nucleophile product yes no

Compounds that have sp2 or sp carbons generally

The nucleophile “displaces” the leaving group. do not give nucleophilic substitution reactions.
This is a “substitution” reaction : ….. of course there are a few special cases that do react,
Nu substitutes for X (takes its place). but we won’t discuss them in this chapter.
 EXAMPLE 1

* acetone
NaI + CH3 Br CH3 I + NaBr (s)
soluble insoluble
EXAMPLES

iodide displaces bromide at carbon

* NaI is soluble in acetone, NaCl and NaBr are not

CH3 E1
EXAMPLE 2 H2C C
competes
DISPLACEMENT REACTIONS
more about
CH3 this later

NUCLEOPHILIC SUBSTITUTION REACTIONS

CH3 CH3
( substitution at carbon )
H3C C Cl + 2 H2O H3C C OH + H3O+ + Cl-
CH3 CH3
can be compared to …..

solvolysis of t-butyl chloride in water

ACID-BASE REACTIONS
water displaces chloride at carbon
( substitution at hydrogen )

*The extra proton is taken by a second water molecule.

 COMPARE THESE SUBSTITUTIONS
DISPLACEMENT AT CARBON

Nu:- + R X R Nu + :X-

nucleophile substrate product leaving

group

DISPLACEMENT AT HYDROGEN
THESE REACTIONS HAVE A
WIDE RANGE OF SUBSTRATES
B:- + H X B H + :X
-

base acid conjugate conjugate

acid base

COMMON SUBSTRATES
( Leaving group varies ) see Table 10-3

alkyl halides alcohols

+
R Cl R OH R O H

R Br H alcohols
require acid
R I and then
H2O leaves THERE IS ALSO A
WIDE RANGE OF NUCLEOPHILES
tosylates
ABBREVIATION
O R O Ts
R O S CH3
A WIDE VARIETY OF COMPOUNDS CAN BE MADE
O
alkyl p-toluenesulfonate
 NUCLEOPHILES see Table 10-4
THE NUCLEOPHILE DOES NOT HAVE TO BE CHARGED
A WIDE SELECTION OF NUCLEOPHILES MAKES POSSIBLE THE SYNTHESIS
OF MANY TYPES OF ORGANIC COMPOUNDS: +
H O + R Br H O R + Br -
R-Y + Nu R-Nu + Y H H
Nucleophile Product Class O H
Under some circumstances
H
water will react.
Cl-,Br-,I- R X alkyl halides -
H O R + H3O + + Br
-
OH R OH alcohols
‘ -
RO R O R‘ ethers Nucleophile Product Class
C N - R C N nitriles H O H R O H alcohols
O O
esters R‘ O H R‘ O R ethers
R' C R' C
- O R R NH2 amines
O NH3
-
R' C C: R' C C R alkynes R' NH2 R' NH R amines
-
SH R SH thiols

TWO “LOOK-ALIKE” REACTIONS

RBr + NaOH ROH + NaBr

80% ethanol -
“LOOK-ALIKE” REACTIONS 1) CH3 Br + NaOH
20% water 55oC
CH3 OH + Br

rate = k2 [RBr] [NaOH]

high conc. NaOH
RBr + NaOH ROH + NaBr
2)
Two reactions follow.... CH3 CH3
80% ethanol -
Both appear to be identical and follow H3C C Br + NaOH H3C C OH + Br
20% water 55oC
the general pattern shown above. CH3 CH3
( + some alkene by E1,E2 )
However, they are different !
rate = k1 [RBr]
low conc. NaOH
 Notice that substrate in reaction 1 has
no β-hydrogens ….. why not?
REACTION 1
THE SN2 REACTION

80% ethanol - Concerted (one step) reaction

CH3 Br + NaOH CH3 OH + Br
20% water 55oC
transition
rate = k2 [RBr] [NaOH] state TS
SN2
k2 = 0.022 liter/mole-sec
E
N
E Ea
H O
- R
80% ethanol - G
CH3 Br CH3 OH + Br
20% water Y
starting
∆H
material
bimolecular product
concerted SN2 substitution
nucleophilic
bimolecular
 CH3 CH3
80% ethanol -
H3C C Br + NaOH H3C C OH + Br
20% water 55oC
CH3 CH3
rate = k1 [RBr]
k1 = 0.010 liter/mole-sec

CH3 CH3
REACTION 2 H3C C Br + NaOH
80% ethanol
20% water
H3C C OH + Br
- unimolecular
two steps
THE SN1 REACTION CH3 CH3

slow

CH3
O H
fast SN1
-
H3C C + + Br substitution
also
CH3 alkene (via E1) nucleophilic
unimolecular

TWO STEP REACTION

carbocation
TS1
intermediate SN1
E TS2
N
E Ea2
R
G Ea1
Y

starting step 1 step 2

∆H
material

product
 RECALL FROM LAST LECTURE

Two similar reactions,

RBr + NaOH ROH + NaBr different kinetics.

1) First Case
A QUICK REVIEW OF
80% ethanol -
TWO SUBSTITUTION REACTIONS CH3 Br + NaOH
20% water 55oC
CH3 OH + Br

primary
SN1 / SN2
SN2 rate = k2 [RBr] [NaOH]

RECALL FROM LAST LECTURE

QUESTION
2) Second Case

CH3 CH3 SN1 SN2

80% ethanol -
H3C C Br + NaOH H3C C OH + Br
20% water
55oC rate = k1 [RBr] rate = k2 [RBr] [NaOH]
CH3 CH3
tertiary Is this difference significant, or is it just a
“mathematical illusion” of some kind?
SN1 rate = k1 [RBr]
 HUGHES AND INGOLD ca. 1940
It was found experimentally that :

Most primary compounds undergo SN2 reactions

with second order kinetics.

Most tertiary compounds undergo SN1 reactions

THE WORK OF with first order kinetics.
HUGHES AND INGOLD
Most nucleophilic substitution reactions fit one
or the other of these two patterns.

Is this significant, or is it just a mathematical

illusion of some kind?

2-BROMOOCTANE
*
CH3CH2CH2CH2CH2CH2 CH CH3
Br
R = C6H13

2-BROMOOCTANE abbreviation

chiral
*
R CH CH3
A STUDY IN STEREOCHEMISTRY
can react both
Br SN1 and SN2
Let’s use an optically-active compound. secondary
DIFFERENT KINETICS AT DIFFERENT BASE CONCENTRATIONS SN1 SN2

SN1 k1[RBr] Total Rate = k1 [RBr] + k2 [RBr] [OH-]

H low conc [ OH- ] H TOTAL
< 0.1 M
R C CH3 R C CH3 dominates at
S N2
+ k2 [RBr] [OH-]
low [OH-]
Br
high conc [ OH- ]
SN2 >1M
dominates at
high [OH-]
1) H2O Rate
2) -H+
S N1
H k1 [RBr]
R C CH3 The two mechanisms
OH compete.
k2[RBr][OH] [ OH- ]
[RBr] constant

STEREOCHEMICAL RESULTS STEREOCHEMISTRY CHANGES

R-(-)-2-bromooctane
[α]D = -36.0o complete
* R inversion
CH3CH2CH2CH2CH2CH2 CH CH3 SN2 conditions R
high [OH-]
Br CH3 HO
Br CH3 S
H H
2-Bromooctane is chiral .....
R S-(+)-2-octanol
SN1 conditions
low [OH-] [α]D = +10.3o
What if we start with an enantiomerically pure
compound (one enantiomer only)? R R
R + S
CH3 HO
OH CH3
Is the stereohemical result the same in H H
complete
each case :
SN1 and SN2 ? racemization enantiomers
racemic mixture [α]D = 0o
 THE MECHANISMS

SN1
Can we explain the stereochemical results
with our proposed mechanisms for
SN1 and SN2 reactions?

Let’s Try .......

SN1 MECHANISM
50%
R sp2
+ R
CH3 CH3 C -O H
Br planar H
H carbocation
attacks top
(R) and bottom
50% equally

SN2
RACEMIZATION OH OH
+
CH3 R
R CH3
H H
(S) enantiomers (R)
racemic mixture
 CONCEPTUAL ANALOGY 1
SN2 MECHANISM
nucleophilic attack LIKE POOL OR BILLIARDS
1) two balls at rest
R (R)-config
.. X and touching
..
.. :
2) forceful shot
H O
C : Br : directly on axis Similar in concept
.. to an attack from
Nu X the back forcing
CH3 the nucleophile to
R leave.
attacks H
back lobe
.. 3) straight-on
.. :
Nu
H O C X
collision

INVERSION CH3 4) momentum

(S)-config
Nu X
H transfer

CONCEPTUAL ANALOGY 2
THE INVERSION sp2
R 2p
HO C B
INVERSION OF AN UMBRELLA IN THE WIND PROCESS
partial bonding
HO C Br
activated complex
CH3 H is trigonal planar (sp2 )

configuration
.. R sp3
is inverted
..:
H O R
sp3
C : Br
Inversion of the Ea HO : C
umbrella is CH3
similar in concept H CH3
to the inversion of
an SN2 atom. (R)-configuration
H
(S)-configuration
ACTIVATED COMPLEX FOR SN2
MIDPOINT OF THE REACTION

trigonal planar (sp2)

forming
R breaking

HO C Br

5 bonds to Carbon

CH3 H … but the bonds to

Br and OH are only
half-formed and
are not full bonds.

NOT A STABLE SPECIES

 NUCLEOPHILIC SUBSTITUTION
MANY FACTORS INFLUENCE SN1 AND SN2 REACTIONS

SOME PARAMETERS :
a) solvent
b) temp.
Nu:- + R X R Nu + :X-
MANY PARAMETERS INFLUENCE c) pH
d) ∆H
NUCLEOPHILIC SUBSTITUTION a) structure a) structure of R, a) bond strength a) nature of X
stereochemistry
b) atom used b) atom used
b) concentration
c) concentration c) base strength
c) bond strength
d) base strength

e) solubility

f) size

SN1 - SUBSTRATE AND CARBOCATION

slow
R-X R+ + X-

R+ + Nu- R-Nu
STRUCTURE OF THE SUBSTRATE fast

SN1
The energy of the carbocation
intermediate is an important
factor for an SN1 reaction.
The better ion
3o < 2o < 1o will have the
lower energy
pathway.
 SOLVOLYSIS OF t-BUTYL BROMIDE
1)
SOLVOLYSIS OF tert-BUTYL BROMIDE CH3 CH3
.. _
slow
H3C C CH3 H3C C CH3 + : Br :
+ ..
: Br:
..
CH3 CH3 tertiary
acetone
CH3 C Br + H2O CH3 C OH + HBr 2)
CH3 CH3
CH3 CH3 H
fast
H3C C CH3 + :O: H3C C CH3
+ H +
:O H

SN1 H
3)
CH3 CH3
fast
H3C C CH3 H3C C CH3 + H3O+ + Br-
+
:O H :O H
H ..
H + :O:
H 1935: Hughes & Ingold

EFFECT OF INCREASING SUBSTITUTION - SN1

100%
RBr + H2O ROH + HBr
HCOOH

methyl primary secondary tertiary

H H H CH3
H C Br CH3 C Br CH3 C Br CH3 C Br
H H CH3 CH3 HYPERCONJUGATION
1.0 1.7 45 Guess
108 ?
relative
rate CARBOCATION STABILITY
increasing rate

rate
rel rate =
EFFECT OF SUBSTRATE ON RATE rate CH3Br
 CARBOCATION STABILITY
HYPERCONJUGATION
REVIEW

H electrons in an adjacent
.. C-H σ bond help to stabilize
+ R the positive charge of the
C C carbocation by proximity

H
(overlap) BENZYL AND ALLYL
R
CARBOCATIONS
H
R
lowest highest THESE ARE GOOD CARBOCATIONS
energy R C
+ R
<< R CH R < R CH2 energy
+ +
tertiary secondary primary

BENZYL AND ALLYL CARBOCATIONS

SOLVOLYSIS RATES
BENZYL RESONANCE 80% Ethanol-water at 50°
STABILIZATION
+ RCl + H2O ROH + HCl
+
CH2 CH2 etc ( RCl + EtOH ROEt + HCl )
both reactions take place
ALLYL +
+
CH2 CH2 etc krel
Ethyl chloride very small good but
Systems that are similar in form to benzyl and allyl are called benzylic and allylic. Isopropyl chloride 1 not as good
Allyl chloride 74 as tertiary
+ Benzyl chloride 140
H3C O CH2
tert-Butyl chloride 12,000
+ + isoelectronic
(benzylic) (allylic)
with allylic
 WILL NOT REACT - SN1

X
+
Br
SOME CARBOCATIONS
cannot become
CANNOT FORM + planar

+
“steric rigidity”

SN2 - SUBSTRATE

.. R
..:
H O large groups
introduce steric
C : Br hindrance

R
STRUCTURE OF THE SUBSTRATE
R
SN2
.. H
..:
H O easy access
C : Br no steric
hindrance

H
H
EFFECT OF DEGREE OF SUBSTITUTION - SN2 EFFECT OF BULKY SUBSTITUENTS - SN2
( substitution on the α carbon )
acetone ethanol
RBr + NaI RI + NaBr RBr + NaOEt ROEt + NaBr
H2O H2O NEOPENTYL
slower than
t -butyl
methyl primary secondary tertiary
CH3 α α α α
CH3
CH3 Br CH3 CH2 Br CH3 CH Br CH3 C Br CH3 Br CH3 CH2 Br CH3 CH CH2 Br CH3 C CH2 Br
CH3 CH3 CH3 CH3
150 1 0.01 0.001
17 1 0.03 3 x 10-6

decreasing rate decreasing rate

rate rate
rel rate = rel rate =
EFFECT OF SUBSTRATE ON RATE rate EtBr ALL ARE PRIMARY ! rate EtBr

COMPARATIVE STERIC HINDRANCE

STERIC HINDRANCE

isopropyl t-butyl neopentyl

 WILL NOT REACT - SN2
backside
attack is
difficult

Steric
Hindrance

Br
BENZYL SUBSTRATES

BENZYL ( GOOD FOR SN1 )

acetone
IS ALSO A GOOD SN2 SUBSTRATE RCl + NaI RI + NaCl SN2
primary, but faster
CH3 CH Cl 0.0076
than other primary
CH3
CH2 Br + NaI CH2 I + NaBr
increasing
CH3CH2CH2 Cl 0.37
rate
I overlap in
the activated CH3CH2 Cl 1.0
H complex
lowers the CH2 CH CH2 Cl 33
activation
energy
CH3 Cl 93
H
rate
rel rate =
Br CH2 Cl 93 rate EtBr
critical
overlap
 SUMMARY Notice that benzyl
and allyl are good
SN1 SN2 for both SN1 and SN2

(fastest) tertiary methyl** (fastest)

BEST BEST
benzyl benzyl
allyl allyl ** In SN2 reactions
benzyl is actually
better than methyl,

SUMMARY secondary primary but allyl is not. For

illustration purposes
benzyl and allyl

primary secondary were grouped in the

yellow box.

WORST bridgehead tertiary

(slowest) (bicyclic)
neopentyl

APPROXIMATE bridgehead WORST

RATE ORDERS (bicyclic) (slowest)

AND DON’T FORGET:

SN1 and SN2 reactions occur only at sp3 (tetrahedral) carbon atoms.

sp3 sp2 sp

C C C C C X
X X X
yes no

acetone
+ NaCN no reaction
Cl
(attempted SN2 reaction)

CH3CH2-C=CH-Br + H2O no reaction

(attempted SN1 solvolysis)
 NUCLEOPHILES AND BASES
THE FUNDAMENTAL DISTINCTION

Nucleophilicity kinetic (or rate) parameter

Basicity thermodynamic (or equilibrium)

NUCLEOPHILICITY parameter.

All nucleophiles are bases …...

WHAT IS A NUCLEOPHILE ? A BASE ? and all bases are nucleophiles.

WHAT MAKES A GOOD NUCLEOPHILE?

A good base is not necessarily
HOWEVER :
a good nucleophile, and vice versa.

NUCLEOPHILE VERSUS BASE DIFFERENT PLACES ON THE ENERGY PROFILE

DETERMINE NUCLEOPHILICITY AND BASICITY
Nu1 Nu2 is a better
nucleophile
Nucleophilicity = Kinetic NUCLEOPHILES
( FASTER RATE )
Nucleophilicity is
Rate = k2[RX][Nu]
Nu2 determined here

activation energy
good nucleophile
and rate (kinetics)
increases k2
(I.e., the rate) faster is better
BASES
Basicity is
Nu1 is a
determined here
better base
Basicity = Thermodynamic
( STRONGER BOND )
B:- + H+ B-H strength of bonds
strong base and position of
shifts equilib. equilibrium
lower energy is better
 NUCLEOPHILES
IMPORTANCE IN SN1 AND SN2 REACTIONS

Nucleophiles are unimportant in an SN1 reaction;

they are not involved in the rate-determining step.

SN1 rate = K1 [RX]

IS THE NUCLEOPHILE IMPORTANT
IN BOTH SN1 AND SN2 REACTIONS ?
The nature of a nucleophile is only important to
an SN2 reaction.

SN2 rate = K2 [RX][Nu]

WHAT IS THE IDEAL NUCLEOPHILE ?

SN2 REACTIONS
LARGE
..
:Y
.. : STERIC PROBLEMS
no way ! bad

R
WHAT IS A SMALL
.. -
:..
X: C : Br
GOOD NUCLEOPHILE ? good

R
R
SN2 REACTIONS Smaller
is better !
For an SN2 reaction the nucleophile must find
the back lobe of the sp3 hybrid orbital that the
leaving group is bonded to.
 EXPECTED “IDEAL” NUCLEOPHILES OUR NAÏVE EXPECTATION
cyanide We would expect the halides to be good nucleophiles:
ROD OR SPEAR - :C N:
ionic radii:
SHAPED - + -
:N N N: 1.36 A 1.81 A 1.95 A 2.16 A
smallest
azide
ion

F- Cl- Br - I-
These types SMALL
should be
SPHERES .. - .. -
able to find :F:
.. :Cl:
.. etc.
the target ! and we would expect the smallest one (fluoride)
to be the best nucleophile,
….. however, that is not usually the case.
Generally this idea is correct.

EXPERIMENTAL RESULTS
RELATIVE RATES OF REACTION FOR THE HALIDES
MeOH
CH3-I + NaX CH3-X + NaI

Rate = k [CH3I] [X-]

SN2
k
SOLVATION
F- 5 x 102 slowest
Cl- 2.3 x 104
Br- 6 x 105 Solvation reverses our ideas of size.

I- 2 x 107 fastest
* MeOH solvates like water but dissolves everything better.
 HEAT OF SOLVATION HALIDE IONS
ENERGY IS RELEASED WHEN AN ION IS PLACED IN WATER IONIC
RADIUS 1.36 A 1.81 A 1.95 A 2.16 A

F- gas phase smallest

ion
F- Cl- Br - I-
- 120 Kcal / mole HEAT OF SOLVATION
F- (g) F- (aq) Heats of
solvation
O H H O
in H2O - 120 - 90 - 75 - 65
The interaction between
Kcal / mole
F-
SOLVATED the ion and the solvent
H H is a type of weak bond.
ION Energy is released when
H H it occurs. -
X(H2O)n
O H H O Solvation lowers the increasing solvation
potential energy of the larger n smaller n
water solution
nucleophile making it
less reactive. SMALL IONS SOLVATE MORE THAN LARGE IONS

WATER AS A SOLVENT SMALL IONS SOLVATE MORE HEAVILY THAN LARGE ONES

F
- I
-
H H
H O BETTER
δ+ δ- O O H H O H NUCLEOPHILE
H O δ- H
M +
H O X -
H
H H O
H H O ...smaller
O H H
Hδ+ H
-
H O H H solvent shell
H O

polar OH bonds
H
H H O O
H H
H H O
H
- H ...escapes
H O H easily
O O H O
H solvent
H shell
…more
potential
energy
Water is a polar molecule. “Effective size” is larger.
Negative on the oxygen end, and positive on the hydrogen end. Heavy solvation lowers the
It can solvate both cations and anions. potential energy of the nucleophile.
It is difficult for the solvated nucleophile
to escape the solvent shell.
This ion is less reactive.
 PROTIC SOLVENTS LARGER IONS ARE BETTER NUCLEOPHILES
IN PROTIC SOLVENTS
H THREE FACTORS ARE INVOLVED :
H O CH3 O CH3CH2 O R N
H
H H H In protic solvents the larger ions are solvated less
water methanol ethanol amines
1 (smaller solvent shell) and they are, therefore,
effectively smaller in size and have more potential
energy.
Water is an example of a “protic” solvent.
Since the solvent shell is smaller in a larger ion
Protic solvents are those that have
O-H, N-H or S-H bonds.
2 it can more easily “escape” from the surrounding
solvent molecules during reaction. There is more
potential energy.

Protic solvents can form hydrogen bonds and can

solvate both cations and anions.
3 The larger ions are thought (by some) to be
more “polarizable”.
see the next slide …..

POLARIZABILITY BASICITY
Polarizability assumes larger ions are able to easily
distort the electons in their valence shell, and that
smaller ions cannot. If everything else is equal, the stronger base is
the better nucleophile.

This principle shows up in a period, where

C Br atoms do not vary appreciably in size, and
solvate to similar extents.

VERY
HYPOTHETICAL
OH- is a better nucleophile than F-
The distortion of large ions is easier because the
orbital clouds are more diffuse.

The nucleophile “flows” into the reactive site.

 OBSERVED NUCLEOPHILICITY TRENDS
H2O OR OTHER “PROTIC” SOLVENTS

GROUP IV V VI VII
increasing nucleophilicity (ROWS) basicity

CH3- NH2- OH- F- increasing

NUCLEOPHILICITY TRENDS nucleophilicity
PH2- SH- Cl-
IN PROTIC SOLVENTS (COLUMNS)
Br-
I-
basicity
more solvation,
larger effective size,
lower potential energy

RELATIVE RATES OF SOME NUCLEOPHILES

MeOH
CH3-I + Nu: CH3-Nu + I-
SN2
Rate = k [CH3I] [X-]

CH3OH 1.0 (solvolysis is faster)

F- 5 x 102
CH3COO- 2 x 104 NH3 3.2 x 105
Cl- 2.3 x 102 (CH3)2S 3.5 x 105
C6H5NH2
C6H5SH
5 x 105
5 x 105
APROTIC SOLVENTS
C6H5O- 5.6 x105
N3 - 6 x 105
Br- 6 x 105 these are the good
CH3O- 2 x 106 nucleophiles, but
CN- 5 x 106 watch out, some
I- 2 x 107 are strong bases
C6H5S- 8 x 109
CHARGED NEUTRAL
 APROTIC SOLVENTS APROTIC SOLVENTS SOLVATE CATIONS,
- BUT NOT ANIONS (NUCLEOPHILES)
O
- O O
+
H3C +
CH3
CH3 S CH3 H C N CH3 N P N H3C
H3C CH3 S + CH3
CH3 N crowded
dimethylsulfoxide H3C CH3
H3C O CH3
“DMSO” dimethylformamide -
“DMF” hexamethylphosphoramide S O M+ O S X-
O “HMPA”
- +
H3C O CH3
CH3 C CH3 CH3 C N The nucleophile is
“free” (unsolvated),
acetone acetonitrile APROTIC SOLVENTS CH3 S CH and therefore is small
3
DO NOT HAVE and not hindered by
if scrupulously OH, NH, OR SH BONDS a solvent shell.
free of water
They do not form
hydrogen bonds.

DIMETHYLFORMAMIDE
DIMETHYLSUFOXIDE
space-filling
CH3
H3C N C H

+ O
O M X-
S O
H H nucleophile is “free”
H C N CH3 (unsolvated)

CH3
density - electrostatic potential plot
 OBSERVED NUCLEOPHILICITY
APROTIC SOLVENTS
WHY NOT ALWAYS USE
APROTIC SOLVENTS FOR SN2 ?
GROUP IV V VI VII
Mostly, it is a matter of expense.
increasing nucleophilicity (ROWS)
Water, ethanol, methanol and acetone are much
CH3- NH2- OH- F- increasing cheaper, especially water.
nucleophilicity
PH2- SH- Cl-
(COLUMNS)
Br- Water “free” DMSO $47.50 / L
Methanol $14.70 / L DMF $33.75 / L
I- Ethanol $15.35 / L HMPA $163.40 / L
decreasing basicity Acetone $16.60 / L
ionic size
The direction of the red arrow (COLUMNS) represents a Cheapest grades available, Aldrich Chemical Co., 2000.
different order than in protic solvents.

SN1 SOLVENTS = POLAR

SN1 reactions prefer polar-protic solvents that
can solvate the anion and cation formed in the
rate-determining step.

ions

SOLVENTS R-X rate-determining

R+ + X-
step solvation of both ions
speeds the ionization

WHAT ARE GOOD SOLVENTS FOR SN1 AND SN2 ?

Carbocation
 CF3COOH
POLAR POLAR
SN2 SOLVENTS = NONPOLAR APROTIC
SOLVENTS
H2O

OR POLAR-APROTIC CF3CH2OH

O- HCOOH
S N1
SN2 reactions prefer “non-polar” solvents, or CH3
+
S CH3
polar-aprotic solvents that do not solvate the O CH3OH
nucleophile. H C N CH3
CH3CH2OH
CH3
O overall
CH3COOH
CH3 C CH3 polarity
.. R S N2 POLAR
X:
:.. CH3CH2 O CH2CH3
PROTIC
CCl4 SOLVENTS
SMALL, C : Br
UNSOLVATED

R CH3CH2CH2CH2CH3
smaller is better ! R NONPOLAR
SOLVENTS NONPOLAR

SOLVENT MIXTURES ARE VERY COMMON

RX Alkyl halides don’t dissolve in water,

but dissolve in most organic solvents.

NaX Nucleophile salts don’t dissolve in most

organic solvents, but dissolve in water.

SOLVENT MIXTURES
Both dissolve in a mixed solvent.
miscible solvents
50% EtOH
CH3CH2CH2CH2 Cl + NaBr
50% H2O
soluble in EtOH soluble in H2O
EXCEPTIONS THE BOTTOM LINE
SN1
NaX Dissolve in polar-aprotic organic solvents:
DMF, DMSO, HMPA.
CARBOCATIONS REACT WITH ALL NUCLEOPHILES EQUALLY
NaI and NaCN dissolve in acetone,
but NaCl and NaBr do not The nucleophile is not involved in the rate-determining step.

SN2
BETTER NUCLEOPHILES REACT FASTER GIVING MORE PRODUCT

The nucleophile is involved in the rate-determining step.

 SN1 REACTIONS
IN SN1 REACTIONS ALL NUCLEOPHILES REACT
EQUALLY WELL

CH3 CH3
HOH, H+
H3C C CH3 H3C C CH3 .. -
solvolysis + :Br:
..
OH slow ..
COMPETITIVE NUCLEOPHILES :Cl:
..
-
.. -
: ..I :

All react equally with the

carbocation. The amounts of
RCl, RBr and RI reflect their
starting concentrations in
the solution.

SN2 REACTIONS EXPERIMENT 1

Acid-assisted but
primary substrate = SN2

FOR SN2 REACTIONS, THE SIZE AND NATURE OF SN2

THE NUCLEOPHILE IS IMPORTANT
CH3CH2CH2 CH2 Br
H2SO4 (8M)

Cl - CH3 CH3CH2CH2 CH2 OH

NH4+ Cl (3.5M)
+
CH3CH2CH2 CH2 Cl
NH4+ Br (3.5M)
H Cl
Br - I - CH3CH2
Ammonium salts
are more soluble
equimolar
than Na salts, NaX

Different amounts of
RCl, RBr, and RI are found WHAT HAPPENS ? Under these conditions
even when they are equi- secondary and tertiary alcohols
molar in the original solution. would give predominantly SN1
 SN2 RESULT Same conditions,
EXPERIMENT 2 tertiary substrate = SN1
NUCLEOPHILES PARTICIPATE IN THE RATE CONTROLING STEP
SN1

primary CH3 CH3 CH3

H+ .. more RBr (8M)
CH3CH2CH2 CH2 OH CH3CH2CH2 CH2 O H H2SO4
+ slow less RCl CH3 C OH CH3 C Br + CH3 C Cl
H NH4+ Cl (3.5M)
Br- ~ 80/20 CH3
NH4+ Br (3.5M) CH3 CH3
The better Nu Cl- Observed
reacts faster
tertiary equimolar

In this experiment we get more RBr than RCl. WHAT HAPPENS ?

Rate = k [ROH] [X-]

SN1 RESULT THE BOTTOM LINE

NUCLEOPHILES DO NOT PARTICIPATE IN THE RATE-CONTROLLING
STEP
SN1
50/50
Observed CARBOCATIONS REACT WITH ALL NUCLEOPHILES EQUALLY

CH3 CH3 CH3 Cl-

H+ .. slow
equal amounts The nucleophile is not involved in the rate-determining step.
CH3 C OH CH3 C O H CH3 C + RBr + RCl
+
H
CH3 CH3 CH3
Br-
react equally SN2
BETTER NUCLEOPHILES REACT FASTER GIVING MORE PRODUCT
In this experiment we get nearly the same amounts
of RBr and RCl. The nucleophile is involved in the rate-determining step.

Rate = k [ROH]
 SUBSTITUTION
VERSUS
ELIMINATION SN1
In SN1 and SN2 reactions, you always get
elimination too!

COMPETING REACTIONS SUBSTITUTION VERSUS ELIMINATION

When you do solvolysis you CH3 HIGHER TEMPERATURE FAVORS MORE ELIMINATION
always get a mixture of the H3C C CH2
SN1 and E1 reactions.
take β-H
Carbocations do both ! E1 ..
: O Et
CH3 CH3 CH3
EtOH
CH3 C Cl CH2 C + CH3 C OEt (+ROH)
H H2O
CH3 CH3 CH3
EtOH
CH3 CH3
H3C C CH3 H3C C CH3 or
solvolysis + 25oC 17% 83%
Br ..
:O You get the same 60oC 36% 64%
Et
SN1 ratios for both
H R-Br and R-I !
CH3 CH3
E1 / SN1
add to Both RCl and RBr
H3C C CH3 H3C C CH3 C+ ion give the same C+ ion !
OEt O+
Et H
 SUBSTITUTION VERSUS ELIMINATION

SN2 - ..
:O-H
..
H
H3C C CH3
- ..
SN2 Br
E2 :O-H
..

Better nucleophiles give

more substitution.
Both SN2 and E2 Stronger bases give
occur simultaneously. more elimination
(break the C-H bond)

SUBSTITUTION VERSUS ELIMINATION

HIGHER TEMPERATURE FAVORS MORE ELIMINATION

EtO
H
CH3 CH CH3 CH2 CH CH3 + CH3 CH OEt
H2O
CH3
Br CH3 (+ ROH) TEMPERATURE
+ NaOH
45oC 53% 47%
100oC 64% 36%
ACTIVATION ENERGIES
E2 / SN2
 SUBSTITUTION vs ELIMINATION SUBSTITUTION vs ELIMINATION
Elimination reactions generally have a higher Elimination reactions generally have a higher
ACTIVATION ENERGY (are more difficult) than ACTIVATION ENERGY (are more difficult) than
substitution substitution

SN2 / E2 SN1 / E1
elimination E2
elimination E1

substitution SN2 substitution SN1

carbocation
intermediate
HIGHER TEMPERATURE HIGHER TEMPERATURE
GENERALLY INCREASES GENERALLY INCREASES
THE AMOUNT OF THE AMOUNT OF
ELIMINATION
ELIMINATION

Strong Bases Give Mostly

E2 (+ some SN2)

Weak Bases Give Mostly

SN1 (+ some E1)
secondary
EtO
H
CH3 CH CH3 CH2 CH CH3 + CH3 CH OEt
BASICITY VS. NUCLEOPHILICITY CH3
H2O
CH3 (+ ROH)
Br

E2 / E1 reactants (20o C) E1 S N1
weak base
good nucleophile
(solvolysis) CH3CH2OH 3% 97%
NaOCH2CH3 / CH3CH2OH 79% 21% strong base
good nucleophile
E2 S N2
STRONG BASES FAVOR E2, ESP. IF 2o or 3o SUBSTRATE TERTIARY SUBSTRATES FAVOR E2 WITH STRONG BASE
strong base Hydrogens are on the surface of the molecule, but the
S N2 E2 sp3 orbital is buried in the center.
EtOH
R Br + NaOEt ether + alkene
50o C .. H H
TERTIARY SUBSTRATES
Et-O:
.. H C
Substitution Elimination Lots of β-hydrogens for H
*You can obtain E2 easy
elimination ….. but the
CH3CH2CH2 Br * SN2 reaction with
back lobe of sp3 orbital C C Br
91 % 9% a 1o substrate
is difficult to reach S N2 H
even with a
strong base (use (steric hinderance) difficult X H C
CH3 CH Br heat to get E2). for substitution by SN2. H H
25 % 75 %
H
CH3
Thus, the substrate preference for E2
CH3 reactions is reversed from that for SN2.
# #Tertiary with a
CH3 C Br 0% 100 % strong base will
give mostly E2. E2 : tertiary >> secondary > primary
CH3
SN2 : primary > secondary >>> tertiary

ALL OF THESE REACTIONS COMPETE !

weak Nu solvolysis 3o >> 2o > 1o

SN1 E1 weak base

weak Nu
YOU GET BOTH
3o >> 2o > 1o (SN1 & E1) inseparable
increased temp

SUMMARY good Nu
favors E1 / E2

SN2 E2 if Nu is a
strong base
- strong bases can be used
must have
and avoid E2 if 1o substr. used
anti coplanar
1o > 2o >> 3o beta H 3o >> 2o > 1o

HOW CAN YOU TELL WHICH REACTION WILL PREDOMINATE?

HOW CAN YOU TELL IF IT IS SN1 OR SN2 ? SOME HELPFUL HINTS ! DECISION CHART

LOOK FIRST AT THE NUCLEOPHILE, THEN THE SUBSTRATE

1) LOOK FIRST AT THE NUCLEOPHILE
GOOD NUCLEOPHILE
You cannot do a reasonable SN2 reaction without a good Nu.
If your “good” nucleophile is a strong base, E2 will be a problem.
If you have a poor nucleophile, (SN1 + E1) is probable. * Good Nucleophile in high concentration = S 2
unless it is a strong base = E2
N

however, 1o substrates
2) NEXT CHECK THE SUBSTRATE can give SN2 at low T RO-
HO-
…. however, SN2 needs a 1o or 2o H2N-
Primary is bad for SN1 / E1….. Tertiary is bad for SN2 SUBSTRATE
substrate (or 1o benzylic) not 3o
…. prefers a nonpolar solvent
3) FINALLY LOOK AT THE SOLVENT SOLVENT but will proceed even in a
polar solvent (aprotics best) strong bases like
all substrates with STRONG
SN2 is best in nonpolar and polar aprotic solvents, but can also a beta hydrogen
happen in water or EtOH. higher T BASE
(anti-coplanar)
favors E2
3o >> 2o > 1o
SN1 needs a polar solvent.
see next slide …..

SOME HELPFUL HINTS ! DECISION CHART STUDY THESE !

LOOK FIRST AT THE NUCLEOPHILE, THEN THE SUBSTRATE
THE KEY IS IN THE TABLES IN THE TEXT
POOR NUCLEOPHILE
Table 10-6 (p. 911)
Factors Which Influence Nucleophilicity
Poor nucleophile (solvolysis) = SN1 + E1 (always occur together)
* or low concentration higher T gives more E1 Table 10-10 (p. 936)
A Comparison of SN1 and SN2 Reactions

Table 10-16 (p. 963)

…. however, the
substrate needs SUBSTRATE Comparison of Substitution and Elimination Reactions
to be 3o or benzylic
or allylic (or 2o) Table 10-18 (p. 982)
…. also, in SN1 the Summary of Reactions of Alkyl Halides
carbocation needs a SOLVENT
reasonably polar solvent
Table 10-19 (p. 984)
watch for rearrangements REARRANGEMENT Rules to Predict Nucleophilic Substitution Mechanisms
(SN1 or SN2)
 PRODUCT AND MECHANISM ?
Br (R)
acetone
1) CH CH3 + NaCN

Br (R)
EtOH
2) CH CH3 + EtOH

SOME PROBLEMS 3) CH3CH2CH2CH2CH2CH2Br + NaCl

DMSO

CH3 4M
4) Br + NaOH
50 o C

0.01 M H2O
5) CH2 Br + NaOH

H3C CH3
OH
H2SO4
6)
50 oC
Ph
(S) acetone
7) C + NaI
H Br
CH3
Ph ACCELERATING THE SN1 REACTION
(R) 4M H2O
C + NH4Br
8) CH3CH2 OH H2SO4
CH3 TESTS FOR “LABILE” HALIDES
CH3
9) AgNO3
H3C C CH2 Br + EtOH easily displaced,
EtOH very reactive
CH3
SILVER HALIDES ARE NOT SOLUBLE IN WATER SILVER CATION AIDS IONIZATION
(or alcohols)
Recall from general chemistry :

CH3 CH3
.. EtOH δ+ .. δ- δ+
NaCl (aq) + AgNO3 (aq) NaNO3 (aq) + AgCl (s) CH3CH2 C Cl : + Ag+ CH3CH2 C Cl Ag
.. AgNO3 ..
precipitate H H

The other silver halides (AgBr, AgI) are insoluble also.

CH3
Silver ion (Ag+) has a strong affinity for halide ions. EtOH
SN1 + E1 CH3CH2 C+ + AgCl (s)
H insoluble
.. in ethanol
This fact can be use to help the ionization of SN1 Et -O:
substrates. Ag+ helps the ionization.
H

THE SILVER NITRATE-ETHANOL TEST SODIUM IODIDE IN ACETONE

EtOH THIS TEST MEASURES REACTIVITY IN AN SN2 REACTION
R-Cl + AgNO3 R-OEt + AgCl (s)
Recall : Although NaI is soluble in acetone,
NaCl and NaBr are not.
appearance of a ppt.
benzylic indicates a reactive halide
allylic acetone
R-Cl + NaI R-I + NaCl (s)
tertiary secondary primary aromatic
acetone
R-Br + NaI R-I + NaBr (s)
RATE fast > slower > slowest > unreactive
Once again we watch the rate of precipitate formation.
This is an SN1 reaction and those substrates that neopentyl
make good carbocations react fastest. primary secondary tertiary aromatic
If the precipitate appears quickly (immediately), RATE fast > slower > slowest > unreactive
it implies a tertiary or benzylic compound is reacting.