Chapters 35, 8

1
Chapters 3-5, 8
Alkenes, Alkyl Halides, and Alcohols
Nucleophilic Substitution and Elimination
Reactions
2
Substitution and Elimination
Alcohols
Reactions of these different classes proceed by
related mechanisms
Other compounds
Alkenes
Alkyl halides
E2, SN2, E1, SN1 reactions Ch. 8, Ch. 4,
4.6-4.11 and A-Level!
E2 .. rate .. R .
alkyl group X Cl, Br, I or other leaving
group B is base may be uncharged (e.g.
ammonia) or negatively charged.
SN2 ... rate R
.. alkyl group X Cl, Br, I or other
leaving group Y is nucleophile (may be
uncharged, or negatively charged).
3
Substitution and Elimination (cont.)
E1 Elimination, 1st order rate k RX R is
2, 3 alkyl group X Cl, Br, I or other
group.
SN1 Substitution, Nucleophilic, 1st order rate
k RX R is 2, 3 alkyl group X Cl, Br, I
or other .. group.
Elimination decrease in of atom
undergoing reaction e.g. sp3 ? sp2 reverse of
addition
Substitution in hybridization state
at atom undergoing reaction e.g. sp3 ?? sp3
4
E2 Reactions
E2 Rate k RXB (Section 4.10).
. transition state

. reaction .. intermediate (Fig. 4.6, p.
109)
?
?
Transition State
?-Carbon atom bearing leaving group X attached
to ?-carbon atom with at least one hydrogen atom
?
- reaction
5
E2 Reactions Reaction Profile
intermediate (Fig. 4.6, p. 109)

Energy
Reaction Coordinate
6
E2 Reactions (cont.)
To inhibit competing SN2 reaction, base must be
., and/or .. effect
(base)
increasing E2
(CH3)3CO- gt(CH3)2CHO- gtCH3CH2O- gtCH3O-
increasing SN2
Rate depends upon strength of C-LG bond (LG
leaving group) ? .
..rate of E2
CH3CH2CH2F ltlt CH3CH2CH2Cl ltCH3CH2CH2Br ltCH3CH2CH2I
If base is small (unhindered), E2 reaction
tends to give more stable more substituted
alkene.
minor (23)
major (77)
7
E2 Reactions - Problems

• Do you expect the equatorial conformer of
  bromocyclohexane
• to undergo E2 elimination by the antiperiplanar
  pathway?

For Br equatorial, no antiperiplanar arrangement
of Br, H required for elimination.
8
E2 Reactions Problems (cont.)

• Rank the following compounds in order of expected
  rate of
• elimination by the E2 reaction upon treatment
  with potassium
• tert-butoxide in tert-butyl alcohol to give the
  corresponding
• alkene. Give reasons.

PhCH2I PhCH2CH2F PhCHClC(CH3)3 PhCH2CH2I
PhCH2CH2Br PhCH(CH3)CH2Br
9
E1 Reactions
E1 Elimination reaction, 1st order rate k
RX where R 2, 3 alkyl group X Cl, Br, I
or other leaving group (Section 4.11).
?
?

• Most important for . RX react by E1 and E2
  .. via E2.
• Strong base . required for 3 RX, ..base
  (e.g. NH3) effective.
• Rate determining step (RDS) is i..
  (elimination) to . intermediate.

Intermediate
10
E1 Reactions Reaction Profile

• Rate determining
• step (RDS) is
• .
• (elimination) to
• .
• intermediate

Intermediate
Energy

• The step is which involves removal
• of the ?-proton by base

Reaction Coordinate
11
E1 Reactions (cont.)

• Step b .. step involves removal of the
  ?-proton by base

• RDS is . rate is directly related to
  strength of C X bond ? ...

..increasing rate of E1
(CH3)3C-I gt (CH3)3C-Br gt (CH3)3C-Cl gtgt(CH3)3C-F

• Solvents which solvate ions e.g. water, other
  protic polar solvents, .. the energy of
  and enhance rate of reaction.

? see SN1 reactions
12
E2 and E1 Reactions
Other leaving groups acid catalyzed
dehydration of alcohols (Ch. 4, Sect. 4.8).

• 3 alcohols - via E1 (Fig. 4.4) 2 - via E1 and
  E2 pathways
• 1 - via E2 .
• Reactions catalyzed by Brønsted acids - H2SO4
  H3PO4 etc - dehydrating agents.
• Order of reactivity . alcohols for .,
  hot concentrated acid must be used.

13
Alcohol Dehydration
1 alcohol
does not occur OH- poor leaving group.
X
leaving group ability
measured by
..
- I gt - Br gt - Cl gt - F - OH2 gt - OH
HI gt HBr gt HCl gt HF H3O gt H2O
..related to strength of C LG bond (LG
leaving group)
Sec. 3.5, 3.6
14
Alcohol Dehydration (cont.)
3 alcohol
E1 dehydration is . of acid catalyzed
hydration of alkenes (Sect. 5.5)
does not occur poor leaving group.
Note
X
15
Alcohol Dehydration (cont.)

• More stable alkene is preferentially formed

• The function of the Brønsted acids is to convert
  into .., a better leaving group!

• Brønsted acid which have n may also
  be used for this purpose in SN1 and SN2 reactions
  of alcohols.
• ? conversion of alcohols into alkyl halides, Ch.
  3, Sec. 3.7-3.8

16
SN2 Reactions
SN2 rate k RXY, R 1, 2 alkyl group X
Cl, Br, I, OH2 or other leaving group Y
nucleophile (uncharged, or negatively charged)
(Section 8.1-8.5 Table 8.1).
i. via bimolecular trigonal bipyramidal
pentacoordinated TS

ii. C. .. intermediate see Fig. 8.1, p.
211
iii. Nucleophile attacks carbon bearing LG
(leaving group) along axis of C-LG bond on
opposite side (backside attack).
iv. For basic, hindered nucleophile, competing E2
reaction for alkyl halides with ?-hydrogen
atoms
E2
(CH3)3CO- gt(CH3)2CHO- gtCH3CH2O- gtCH3O-
.. SN2
17
SN2 Reactions Reaction Profile
SN2 Concerted no intermediate see Fig. 8.1,
p. 211
Reaction Profile
Energy
Reaction Coordinate
18
SN2 Reactions (cont.)
Rate depends upon
a. strength of C-LG bond ? leaving group
ability
.. of SN2
CH3CH2CH2F ltlt CH3CH2CH2Cl lt CH3CH2CH2Br lt
CH3CH2CH2I
b. steric effect - degree of substitution at
carbon atom bearing LG (Fig. 8.2)
Increasing .at C bearing leaving group
. rate of SN2
19
SN2 Reactions (cont.)

• Increasing .at C bearing leaving group,
  rate of SN2

Steric or van der Waals interaction with
nucleophile
N
Br
C
Br
Br
N
C
N
C
For 3, no SN2!
20
SN2 Reactions (cont.)
Rate depends upon c. strength of nucleophile -
nucleophilicity
rate of SN2
F- ltlt Cl- lt Br- lt I-

• Nucleophiles with negative charge
• on larger atom are more reactive

HO- lt HS- lt HSe-

• Nucleophiles with negative charge
• or lone pair on. electronegative
• atom are .. reactive

F- lt HO- lt H2N-
H2O lt H3N
NO3- ltlt NO2-

• The more a negative
• charge is on a nucleophile, the
• .. reactive it is

HSO4- ltlt HSO3-
CH3COO- lt HO-
Solvent effects important, but are outside scope
of this course (Ch. 8, section 8.12 of reference
text)
21
SN2 Reactions Alcohols
-OH group must be .. (cf. Slide 15)
Conversion of alcohols into alkyl halides HBr,
HI for 1, 2? alcohols (3 react by SN1 reaction
2? react by both SN2, SN1 reactions Section 3.6,
3.7)
does not occur OH- is . leaving group ?
salt (NaCl) in beer!!
Rate of SN2 is related to nucleophilicity of
conjugate base
HI gt HBr gt HCl gt HF
22
SN1 Reactions
SN1 rate k RX where R 2, 3 alkyl group
X Cl, Br, I or other LG (Ch. 8, Section
8.5-8.7).
Hydrolysis of tert-butyl bromide
Several steps

• RDS a (elimination) to carbocation
  intermediate.

• fast step b .. of water to carbocation (sp2
  ? sp3)

• fast step c . reaction

• Nucleophile must not be basic, otherwise E1 for
  3 alkyl halides, use as nucleophile
  (cleavage by ..).

23
SN1 Reactions Reaction Profile
Intermediate
Energy
Reaction Coordinate
24
SN1 Reactions (cont.)

• RDS is ionization rate related to strength of
  CX bond ? leaving group ability.

. rate of SN1
(CH3)3CI gt (CH3)3CBr gt (CH3)3CCl gtgt(CH3)3CF

• Solvents which solvate ions e.g. water, other
  protic polar solvents, lower energies of ions
  produced - carbocation and halide -
• Enhance rate of reaction

• Ability to solvate ions measured by
  . ?

rate of SN1, .. ?
CH3COOH lt CH3OH lt HCOOH lt H2O
25
SN1 Reactions Alcohols
Acid catalyzed conversion of 3 and 2 alcohols
into alkyl halides (Ch. 3, Sec. 3.7-3.8)
First step same as E1 dehydration
In general
does not occur OH- is . leaving group.
26
SN1 Reactions Alcohols (cont.)

• Function of the Brønsted acid in SN1 reaction of
  alcohols
• i. converts OH into, a leaving group!

ii. generates a .. conjugate base on
ionization which reacts with the
carbocation intermediate e.g. HCl, HBr, HI
? Cl-, I-, Br-

• For Brønsted acids which do not generate .
  conjugate base on ionization e.g. H2SO4 H3PO4
  etc , carbocation intermediate undergoes
  elimination to give alkenes (see E1 reaction)

• For SN2 reactions of 1 and 2 alcohols with
  hydrogen halides,
• Normally use HBr, HI ? I-, Br-
• HCl slow reaction - Cl- less nucleophilic than
  Br-,I-

27
E2, SN2, E1, SN1 Reactions Examples
Ch. 8, Ch. 4, Section 4.6-4.11
-CN weak base, good nucleophile only SN2
-OCH3 good nucleophile, but also strong base SN2
and E2.
hot concentrated base enhances E2 over SN2
reaction
-OC(CH3)3 (tert-butoxide) is hindered base -
enhances E2 over SN2 reaction
28
E2, SN2, E1, SN1 Reactions Examples (cont.)
SN1 reaction requires -. nucleophile.
If nucleophile is basic, then E1 reaction is
greatly favoured.
29
E2, SN2 Reactions Summary.
Both reactions are .. - .. intermediate

SN2
.. attacks at carbon

E2
. attacks at hydrogen abstraction of
proton
30
E1, SN1 Reactions Summary
RDS is generation of carbocation intermediate
E1
SN1
Note SN1 proceeds via . to carbocation,
followed by .. to give final product
. .. overall substitution!
31
E2, SN2, E1, SN1 Reactions Summary
Alkyl halides Primary Secondary
Tertiary Elimination E2 E2 and E1
E1 Substitution SN2 SN2 and SN1 SN1
SN1 Reaction requires non-basic nucleophile
(e.g. H2O vs. HO-) E1 Basic conditions
greatly favour E1 over SN1. SN2 For
nucleophiles which are also basic, e.g. HO-,
dilute conditions, low temperature favour SN2
E2 i. Hot concentrated base, e.g. 10M NaOH
at elevated temperature favours E2 over
SN2 ii. Use of large or hindered bases, e.g.
(CH3)3C-O- - tert-butoxide, favours E2 over SN2.
?check examples in notes, textbook and reference
text!
32
E2, SN2, E1, SN1 Reactions Summary
Alcohols All require 'activation' of -OH group
by protonation Primary Secondary
Tertiary Elimination E2 E2 and E1
E1 Substitution SN2 SN2 and SN1 SN1
SN1 Reaction requires Brønsted acid whose
conjugate base is nucleophilic, e.g. I- from HI
E1 Reaction requires 'dehydrating agent',
usually a Brønsted acid whose conjugate base is
non-nucleophilic, e.g. HSO4- from H2SO4. SN2
Reaction requires Brønsted acid whose conjugate
base is nucleophilic, e.g. I- from HI E2
Reaction requires 'dehydrating agent', usually a
Brønsted acid used under hot concentrated
conditions whose conjugate base is
non-nucleophilic, e.g. HSO4- from H2SO4.
33
E2, SN2, E1, SN1 Reactions Problems

• Arrange isomers of C4H9Cl in order of decreasing
  rate of
• reaction with NaI in acetone solvent

Isomers are
Reaction conditions NaI in acetone these are
good conditions for SN2 reaction normal order of
reactivity 1 gt 2 gtgtgt 3
? slide 18-20
Order is chlorobutane (1, no steric hindrance)gt
isobutyl chloride (1, branching at ?-carbon
atom) gt 2-chlorobutane (2) gtgtgt tert-butyl
chloride (3).
34
Problems (cont)
2. Identify the organic product of the following
reactions
a.
For SN2 reaction, 1 alkyl halide reacts much
more rapidly than 2.
b.
Two possibilities i. SN2 followed by
intramolecular SN2 reaction
The intramolecular SN2 is concentration
independent! However, in order to suppress
intermolecular SN2 (polymerization) (next slide),
and favour intramolecular SN2 above, use dilute
solution of BrCH2CH2Br and Na -SCH2CH2S-Na .
35
Problems (cont)
2.b (cont.)
ii. SN2 followed by intermolecular SN2 reactions
The intermolecular series of SN2 reactions may
lead to polymer!
36
Problems (cont)
2.b (cont.)
Intermolecular SN2 reactions and polymerization!
(cont.)
The probability that intermediate oligomers
cyclize is very low formation of rings much
larger than six-membered by SN2 is difficult? !
The intermolecular SN2 reactions are favoured if
concentrated solutions of BrCH2CH2Br and Na
-SCH2CH2S-Na are used.
37
Problems (cont)
2. Identify the organic product of the following
reactions (cont.)
c.
d.
As in question 2b, products of this reaction are
dependent upon concentration of reactants use of
dilute solutions give cyclized product
(especially favoured)
38
Problems (cont)
2. d (cont.)
As in question 2b, products of this reaction are
dependent upon concentration of reactants use
of concentrated solutions may also lead to
competing formation of polymers
As in question 2b, probability of cyclization of
intermediates to give rings larger than
five-membered is very low.
39
Problems (cont)
3. The compound KSCN potassium thiocyanate -
reacts with 1-bromobutane in dimethyl sulfoxide
(DMSO) as solvent to give two constitutional
isomers of formula C5H9NS. Give structures

• Draw Lewis structures for resonance contributors
  to structure
• of thiocyanate

ii. SN2 reaction will take place with 1 alkyl
halide. Two possible reactions can take place
involving either S or N atom
99
1
iii. DMSO is a polar aprotic solvent, especially
good for SN2 reactions. Major product arises by
attack though larger, more polarizable (more
nucleophilic) sulfur atom.
40
Problems (cont)
4. Select the combination of alkyl bromide and
potassium alkoxide that would be most effective
for synthesis of the following ethers
i. For tert-butyl methyl ether A
or
must use reaction 1 methyl bromide undergoes SN2
reaction (elimination impossible) 3 alkyl
halide undergoes exclusively elimination in
presence of strong base (KOCH3) ? what products?
41
Problems (cont)
ii. For cyclopentyl methyl ether B
4. (cont.)
or
Use combination of reagents which contain least
hindered alkyl halide ? reaction 2. For
reaction 1, both E1 and E2 elimination compete
with substitution ? what products?
42
Problems (cont)
4. (cont.)
iii. For 2,2,-dimethylpropyl ethyl ether C
or
Reaction 2 Alkyl halides 1, SN2 reaction on
BrCH2C(CH3)3 (neopentyl bromide) is prevented by
steric hindrance to attack by nucleophile
CH3CH2O-
O-
Br
O-
Br
For reaction 2, some E2 elimination will compete
with SN2, as nucleophile is also a large strong
base!
Neopentyl halides do not normally undergo SN2
substitution reactions!
43
Problems (cont)
5. Indicate by means of equations giving details
of reagents and conditions how the following
transformation is carried out

• Br is attached to 1 and 3 carbon atoms 3 will
  react via SN1 reaction with non-basic nucleophile
  as solvent (solvolysis), 1 will not react

ii. Treat the product of the above reaction with
CH3CH2S-Na
SN2 reaction on 1 alkyl halide !
44
SN2 Reactions Stereochemistry
Section 7.11 8.4 8.8
SN2 Inversion of configuration
Always for SN2 reactions. Note that (R)- and
(S)- descriptors may not always change depending
upon priority (a, b or c) of newly introduced
group ? problems
45
Stereochemistry of SN2 Reactions Problem
6. Give the stereostructure of the product
obtained when (R)-2- iodopentane is treated with
sodium acetate in acetone
(R)- 2-iodopentane CH3CH(I)CH2CH2CH3 chiral
centre (C) at C2 ? groups at C are I- , CH3-,
CH3CH2CH2, H- .
Priorities I- a, CH3CH2CH2- b, CH3- c, H-
d
(R)- 2-iodopentane
SN2 reaction with acetate inversion of
configuration
Stereostructure must be unambiguously indicated
(S)-2-pentyl acetate
46
SN1 Reactions Stereochemistry
SN1 For enantiomerically pure 3 alkyl
halide(Section 8.8)
Carbocation planar and achiral in absence of
Br-, equal probability of addition of H2O from
top (retention) and bottom(inversion) to
give 50 (R)-, 50 (S)-products (complete
racemization).
However Br- associated with top face,
preference for H2O to add from bottom -
slightly more of (S)-2-phenyl-2-butanol is
obtained! (partial racemization)