CHEM 109A
CLAS
Substitution Reactions - KEY
1. Define and understand the following terms. (I will go over these if you have
questions, but will expect that you have attempted to understand them on your
own.)
a. Hyperconjugation
b. Basicity
c. Nucleophile
d. Nucleophilicity
e. Electrophile
f. Polarizability
g. Aprotic solvent (give an example)
h. Protic solvent (give an example)
2. Determine the product that would be formed from the SN2 reaction of
a. (R)-2-bromobutane and hydroxide ion (aprotic solvent)
HO-
OH
Br
(R)-2-bromobutane
Br-
(S)-2-butanol
b. (S)-3-chlorohexane and hydroxide ion (aprotic solvent)
HO-
Cl
(S)-3-chlorohexane
OH
Cl-
(R)-3-hexanol
3. For each of the following pairs of SN2 reactions, indicate which reaction occurs
faster.
a. CH3CH2Br + H2O
or
CH3CH2Br + HOB/C HO- is better nuc than H2O
CH3CH2Cl + CH3S- in ethanol
b. CH3CH2Cl + CH3O- or
Ethanol is protic solvent, so CH3S- is better nuc than CH3Oc. CH3CH2Cl + Ior
CH3CH2Br + I- in aprotic solvent
B/C Br- is better LG (weaker base) than Cl4. Determine the product(s) and indicate the probably mechanism (SN1 or SN2) for
the following reactions
a. (R)-2-bromobutane and water (in water)
Page 1 of 8
CHEM 109A
CLAS
Substitution Reactions - KEY
H
H
O
H
O
O+
Br
H
H
H
Br(R)-2-bromobutane
H 3O+
Br-
OH
(R and S)-2-butanol
a.k.a. HBr
SN1 – good LG (Br-) in polar protic solvent
b. 1-bromo-2-butene and ethanol (in ethanol)
SN1
Br
1-bromo-2-butene
carbocation
rearrangement
BrOH
HO
tiny bit of
SN2
HO
1-hydroxy-2-butene
<
O
HBr
O
HBr
(R and S)-
SN1 – Good LG (Br-) in polar protic solvent (maybe a bit of SN2)
Cl
and water (in water).
c.
H 2O
HCl
Cl
OH
SN1 – Good LG (Cl-) in polar
protic solvent w/ extremely hindered substrate
(R and S)
Page 2 of 8
CHEM 109A
CLAS
Substitution Reactions - KEY
5. Which alkyl halide would you expect to be more reactive in an 1) SN1 reaction 2)
SN2 reaction with a given nucleophile? And why ?
Br
Cl
or
a.
1) bromide is weaker base, so better LG and more reactive
2) bromide is weaker base, so better LG and more reactive
Br
Br
b.
or
1) both will form 2o carbocations, so equally reactive
2) 2-bromobutane b/c less steric hindrance
Br
Br
c.
or
1) 2-bromopentane b/c 2o carbocation is more stable
2) 1-bromo-2-methylbutane b/c 1o alkyl halide is less sterically hindered
d.
1)
2)
Br
Br
or
Br
b/c 2o carbocation
Br
b/c less steric hindrance
Additional Information:
Definitions
Hyperconjugation: Delocalization of e-s by overlap of a C-H or C-C σ bond with an
empty/ ½ empty p-orbital. Stabilizes carbocations/radicals.
Basicity: Measure of how well a base shares its lone pair electrons with a proton (accept
a proton by making a covalent bond).
Nucleophile: An e- rich atom or molecule. “Likes” nuclei b/c they have protons.
Nucleophilicity: Measure of how readily an atom or molecule with a pair of nonbonding
e-s attacks an atom (electrophile).
Electrophile: An e- deficient atom or molecule.
Polarizability: Indication of the ease with which the e- cloud of an atom can be distorted.
Page 3 of 8
CHEM 109A
CLAS
Substitution Reactions - KEY
Solvent Affects – Table 8.7, pg 376 gives common solvents w/ dielectric constants.
Protic solvent – H bonded to an O or N (can hydrogen bond). Makes a strong base less
nucleophilic by solvating the ion (ion-dipole interaction)/shielding it from reacting.
HO
EX. water, ammonia, ethanol,
O
all polar
acetic acid
Aprotic solvent – NO H bonded to an O or N (can NOT hydrogen bond).
EX.
polar
nonpolar
O
S
O
N
N,N-dimethylformamide
DMF
dimethyl sulfoxide
DMSO
Cl
H
Cl
Cl
O
chloroform
diethyl ether
hexane
SN2 vs. SN1 Rxns:
SN2: bimolecular nucleophilic substitution: Concerted rxn where nuc replaces LG
w/ inversion of R stereochem (b/c of “back side” attack of nuc).
Factors:
Structure of Alkyl Halide:
SN2:Less substituted alkyl halides are more reactive b/c less steric hindrance (↓
‡
∆G )
methyl halide > 1o > 2o > 3o (too unreactive w/ SN2)
Table 8.1 Rates of SN2 Reaction w/ Alkyl Bromides
Alkyl Halide
Br
Br
Class of Alkyl Halide
methyl
1o
Rel. Rate
1200
40
1o
16
Br
Br
o
2
1
3o
Too slow
Br
Leaving Group (LG):
W/ same alkyl halide and same nuc in aprotic solvent: Weaker bases are better LGs
I- > Br- > Cl- > F- (worst LG, ~ NO SN2)
Nucleophile (Nuc):
W/ same attacking atom/ atom of similar size: Stronger bases are better nucs
Stronger Base/Better Nuc
compared to →
HO-
Weaker Base/Poorer Nuc
H2O
Page 4 of 8
CHEM 109A
CLAS
Substitution Reactions - KEY
CH3ONH2
CH3CH2NH-
CH3OH
NH3
CH3CH2NH2
-
NH2 > HO- > F-
Solvent
A protic solvent makes a strong base less nucleophilic by solvating the ion (iondipole interaction)/shielding it from reacting (reverses trend in nucleophilicity;
can think of nucleophilicity in terms of size/polarizability).
Size
Nucleophilicity
in PROTIC
solvent
↓
↓
Base
↑
↑
Nucleophilicity
in APROTIC
solvent
Basicity
FClBrI-
Steric Affects
A bulky nuc is not as good attacking an electrophile and a steric nuc is not as easy
to attack.
Tbl 8.3, pg 358: The Acidities of the Conjugate Acids of some LGs
Acid
HI
HBr
HCl
pKa
-10.0
-9.0
-7.0
SO3H
-6.5
H2SO4
CH3O+H2
H3O+
HF
-5.0
-2.5
-1.7
3.2
HO
4.8
O
H2S
HCN
N+H4
CH3CH2SH
(CH3)3N+H
CH3OH
H2O
HC
CH
Conjugate Base (LG)
IBrCl-
7.0
9.1
9.4
10.5
10.8
15.5
15.7
25
SO3-
HSO4CH3OH
H2O
F-
In Protic Solvent
↑↓
Better
LG
Better
Nuc
-O
O
HSCN
NH3
CH3CH2S(CH3)3N
CH3OH
HOHC
C-
Page 5 of 8
CHEM 109A
CLAS
Substitution Reactions - KEY
NH3
H2
36
~40
-
NH2
H-
Reversibility of SN2 rxn:
Depends on basicity of nuc and LG: SN2 proceeds in direction that allows the
stronger B (better nuc) to displace the weaker B (better LG), but if the basicity isn’t that
different, rxn will be reversible.
SN1: unimolecular nucleophilic substitution
2-step reaction where LG leaves, generates a cabocation intermediate (w/
possible rearrangement) and nuc attacks from “top or bottom” to give racemation.
Factors:
Structure of Alkyl Halide:
More substituted alkyl halides more reactive b/c carbocation formed is more
stable (hyperconjugation).
3o > 2o > 1o * & methyl halide* (*too unreactive w/ SN1, can do SN2)
Table 8.4 Rates of SN1 Reaction w/ Alkyl Bromides
Alkyl Halide
Class of Alkyl Halide
3o
Rel. Rate
1,200,000
Br
2o
11.6
Br
1o
1.00*
methyl
1.05*
Br
Br
Carbocation Rearrangement:
Carbocation will rearrange to form a more stable ion and then you may get BOTH SN1
and SN2 (constitutional isomers).
Leaving Group (LG):
W/ same alkyl halide and same nuc in aprotic solvent: Weaker bases are better LGs
I- > Br- > Cl- > FNucleophile (Nuc):
NO effect on rate of SN1 rxn b/c NOT involved in r.d.s.; usu. solvent is nuc (solvolysis:
rxn w/ solvent).
*Benzylic and allylic nucs: undergo SN2 (unless 3o) and SN1 (if stable carbocations).
Br
Cl
Vinylic and aryl nucs: do NOT undergo SN2 (b/c π e- cloud –dbl bond or aromatic ring
– repels nuc) or SN1 (b/c sp carbocation is not stable and sp2 C-H bonds are strong).
Page 6 of 8
CHEM 109A
CLAS
Substitution Reactions - KEY
Br
Cl
Table 8.5 Comparison of SN1 and SN2 Rxns
SN1
2-step mech w/ carbocation intermed.
Unimolecular r.d.s.
Carbocation rearrangement
Racemization
Most reactive 3o > 2o > 1o & methyl halide*
* unreactive
SN2
Concerted mech
Bimolecular r.d.s.
NO rearrangement
P has inverted configuration
Most reactive methyl halide > 1o > 2o > 3o*
How do I decide SN1 vs. SN2?
Look at alkyl halide
Table 8.6 Summary of Reactivity of Alkyl Halides in Nucleophilic Substitution Reactions
SN2 only
Methyl and 1o alkyl halides
3o alkyl halides
SN1 only
o
3 benzylic and allylic halides
SN1 only
2o alkyl halides
SN1 and SN2
o
o
1 and 2 benzylic and allyic halides SN1 and SN2
Vinylic and aryl halides
Neither
Look at reaction conditions
1.
2.
3.
[nuc]
Reactivity of nuc
(good or poor?)
Solvent*
Inc. rate of SN2
Inc. [nuc]
Good nuc
Inc. rate of SN1
Aprotic polar (if nuc (-))
Protic polar
Poor nuc
*In general: inc. polarity of solvent
Dec. rxn rt if 1 or more R in r.d.s. is charged.
Inc. rxn rt if no R in r.d.s. is charged.
The greater the charge on the solvated species, the stronger interaction w. polar
solvent and the more stabilized.
If charged R
If charged T.S. (neutral R)
Stabilize R more
Stabilize T.S. more
‡
Inc. ∆G
Dec. ∆G‡
Dec. rxn rt.
Inc. rxn rt.
w/ SN1:
R (usu. neutral) → T.S. (carbocation, so charged)
T.S. more stabilized by polar solvent, so inc. rxn rt.
w/ SN2:
IF Nuc (usu. (-)) + R (usu. neutral) → T.S. ((-) over 2 atoms)
R more stabilized by polar solvent, so dec. rxn rt.
Page 7 of 8
CHEM 109A
CLAS
Substitution Reactions - KEY
IF Nuc (neutral) + R (usu. neutral) → T.S. ((-))
T.S. more stabilized by polar solvent, so inc. rxn rt.
Look at…
Reactant
Nuc
LG
Solvent
Products
SN1
3o > 2o
Weak
Good-Excellent
Polar protic
Racemate and carbocation
rearrangement
SN2
1o > 2 o
Strong-Excellent
Bad-Excellent
Aprotic
Inversion of reactant
stereochemistry
Page 8 of 8