Chemistry S-20ab Week 2

Chemistry E-2a: Lecture 6 October 30, 2008

Alkyl Halides: Substitution and Elimination

• There are two particularly important reactions of alkyl halides:

Substitution involves replacing the halide with some other group:

Y:–

Br

Elimination involves removing the halide and an adjacent hydrogen atom to yield an alkene:

B:–

Br

Reading: Section 9.1

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Chemistry E-2a: Lecture 6 October 30, 2008

Nucleophilic Substitution: The SN2 Reaction

• Can you predict the product and the mechanism of the following reaction:

CN– + Br

• What would be the rate law of this reaction? (Do you remember rate laws?)

• Why is this referred to as the SN2 reaction?

Reading: Section 9.4

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Chemistry S-20ab Week 2

Chemistry E-2a: Lecture 6 October 30, 2008

Stereochemistry of the SN2 Reaction

• Can you predict the product of the following reaction (including stereochemistry)?

H H3C
O + C Br
H
(CH2)5CH3
100% (R)-2-bromooctane

• Can you explain why that stereochemical result is observed for all SN2 reactions?

• Let’s take a look at the transition state for the SN2 reaction:
Nucleophile
approaches along
"proper" trajectory a
Nuc C LGp
c
b
Nucleophile
begins to bond a
Leaving group – carbon
Nuc C LGp bond begins to break
c
b
sp2 C
Transition state - a
Nucleophile – Transition state - Leaving
carbon bond
"halfway made" Nuc C LGp group – carbon bond
"halfway broken"
c
b

a
Past the Past the transition
transition state - Nuc C LGp state - Leaving
Nucleophile – group – carbon bond
carbon bond c b "almost broken"
"almost complete"
a
Nucleophile – carbon Leaving group
bond "complete" the Nuc C LGp
nucleophile's electron has left with its
c electron pair
pair now forms the new b
bond
Reading: Section 9.4

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Chemistry S-20ab Week 2

Chemistry E-2a: Lecture 6 October 30, 2008

Steric Effects on SN2 Reactions

• Because of the “backside attack” required for the SN2 mechanism, these reactions are
quite sensitive to steric effects (“crowding”). For example:

space-filling models the nucleophile's

of the halides view of its "target"
"target atom" "target atom"

H
Br
HH
methyl bromide
rapid SN2

H3C
Br
H3C H
isopropyl bromide
slow SN2

H3C
Br
H3C
CH3
tert-butyl bromide
noSN2

H3C
CH3
H3C
Br
HH
neopentyl bromide
VERY slow SN2
Reading: Section 9.4

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Chemistry S-20ab Week 2

Chemistry E-2a: Lecture 6 October 30, 2008

Nucleophiles in the SN2 Reaction

• Can you explain the relative nucleophilicity of the following nucleophiles in an SN2
reaction?

Species Name Rel. Nucleophilicity

EXCELLENT NUCLEOPHILES
N C cyanide 126,000
H S thiolate 126,000
I iodide 80,000
GOOD NUCLEOPHILES
H O hydroxide 16,000
Br bromide 10,000
N N N azide 8,000
H3N ammonia 8,000
MODERATE/POOR NUCLEOPHILES
Cl chloride 1,000
CH3COO acetate 630
F fluoride 80
H2O water 1

Reading: Section 9.4

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Chemistry E-2a: Lecture 6 October 30, 2008

Leaving Groups in the SN2 Reaction

• What is the leaving group in an SN2 reaction?

• Can you explain the relative leaving group ability of the following leaving groups?

Conjugate acid pKa Leaving Group Name

GOOD LEAVING GROUPS
H I –10 I iodide
H Br –9 Br bromide
H Cl –7 Cl chloride
H OSO2R –6.5 OSO2R sulfonate*
H3O –1.7 H2O water

*NOTE: Alkylsulfonic esters (R–OSO3R') react like alkyl halides

towards nucleophiles (and bases).
X X
Nuc C OSO3R' Nuc C + OSO3R'
ZY YZ

POOR LEAVING GROUPS

H F +3.2 F fluoride
H2S +7 HS thiolate
H C N +9.2 C N cyanide
H2O +15.7 HO hydroxide
H OR +15 to 18 RO alkoxide

Reading: Section 9.4

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Chemistry S-20ab Week 2

Chemistry E-2a: Lecture 6 October 30, 2008

Summary of Reactivity in SN2 Reactions

• Mechanism:

• Stereochemistry:

• What makes for a rapid SN2 reaction?

Steric Effects:

Nucleophilicity:

Leaving-Group Ability:

Reading: Section 9.4

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Chemistry S-20ab Week 2

Chemistry E-2a: Lecture 6 October 30, 2008

Elimination: The E2 Reaction

• Here is an example of an E2 reaction. Can you draw a curved-arrow mechanism?

H3C Br H3C H
Ph
C2H5O Na + + C2H5OH + Na Br
H
sodium H Ph Ph Ph
ethoxide

• Examine the stereochemistry of the above reaction. Why is this an example of anti-
elimination?

• What transition state and product would lead to syn-elimination?

• What would be the rate law for this reaction?

Reading: Section 9.5

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Chemistry E-2a: Lecture 6 October 30, 2008

Frontier Orbitals in the E2 Reaction

• Let’s take a close look at the frontier orbitals involved in the E2 reaction. There are in
fact two important interactions:

H3C Br
Ph
H
H Ph

• Note the contrast between anti- and syn-elimination:

FMO considerations
donor orbital - ! C–H acceptor orbital - !* C–Br
anti transiton state syn transiton state

H3C Br H Br
Ph
H H3C H
H Ph Ph
Ph
donor acceptor donor acceptor
best overlap poor overlap

Reading: Section 9.5

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Chemistry S-20ab Week 2

Chemistry E-2a: Lecture 6 October 30, 2008

Alkene Isomers Formed by the E2 Reaction

• Many E2 reactions can give more than one possible isomer. Can you explain the
distribution of products in the following reaction?

KOEt
+ +
EtOH
Br 41% 14% 25%

• You may notice that the above percentages do not add to 100%. What do you suppose is
the other product that emerges from the above reaction?

• The choice of base can affect the distribution of products. For example:
Br KOEt
+
EtOH
71% 29%

Br KOtBu
+
tBuOH

28% 72%

Reading: Section 9.5

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Chemistry S-20ab Week 2

Chemistry E-2a: Lecture 6 October 30, 2008

E2 vs. SN2: The “GFP” Reaction Hierarchy

• To help decide which reaction will predominate, apply the “GFP” (good-fair-poor)
reaction hierarchy. If all else is equal, choose the reaction that is at the top of the list:

1. SN2 reactions: Require good steric interactions

Good if the halide is methyl or 1°

Fair if the halide is 2°
Poor if the halide is 3° or if the nucleophile is very bulky (e.g. tBuO–)

2. E2 reactions: Require a strong base

Good if the base is at least as strong as OH–

Fair if the base is between H2O and OH– in strength
Poor if the base is weaker than H2O
• Let’s see some examples: Determine the primary product (and identify possible
secondary products) for each of the following reactions:

CH3I + OH–

CH3I +
O–

Br + OH–

Br + CN–

Br +
O–

Br + OH–

Br + CN–

Reading: Section 9.5

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Chemistry S-20ab Week 2

Chemistry E-2a: Lecture 6 October 30, 2008

Reactions Involving Carbocations: SN1 and E1

• Consider the following reaction. Why is it unlikely that this reaction proceeded by either
an SN2 or E2 mechanism?

Br EtOH O
+
25°C
81% 19%

• Can you propose a mechanism for this reaction?

Hint: the rate law for this reaction is simply: rate = k[tBuBr]

• What do you suppose is a requirement for this reaction?

Reading: Section 9.6

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Chemistry S-20ab Week 2

Chemistry E-2a: Lecture 6 October 30, 2008

The Stereochemistry of the SN1 Reaction

• Given that the SN1 mechanism proceeds through a carbocation intermediate, what would
you expect to find when you subject the following alkyl halide to SN1 conditions:
H Cl H OH HO H

H 2O
+

S S R

• In fact, the products are: 33% S and 67% R. How can we explain this observation?

• Can we make any generalizations about the stereochemical outcome of SN1 reactions?

Reading: Section 9.6

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Chemistry S-20ab Week 2

Chemistry E-2a: Lecture 6 October 30, 2008

SN1 vs. E1 Reactions

• In general, whenever SN1 and E1 reactions take place, a mixture of both mechanisms is
observed. Why might this be the case?

• It is often the case that higher temperatures favor elimination. For instance:

Br EtOH O
+

at 25°C: 81% 19%

at 55°C: 72% 28%

• One can ensure elimination by starting with an alcohol, instead of an alkyl halide, and
treating it with concentrated sulfuric acid. Can you propose a mechanism for this
reaction? Does this mechanism resemble any mechanism you have seen before?
conc.
OH H2SO4

Reading: Section 9.6

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Chemistry S-20ab Week 2

Chemistry E-2a: Lecture 6 October 30, 2008

SN1 / E1 / SN2 / E2: The “GFP” Hierarchy Revisited

• We can now extend the hierarchy to include SN1 and E1 reactions:

1. SN2 reactions: Require good steric interactions

Good if the halide is methyl or 1°

Fair if the halide is 2°
Poor if the halide is 3° or if the nucleophile is very bulky (e.g. tBuO–)

2. E2 reactions: Require a strong base

Good if the base is at least as strong as OH–

Fair if the base is between H2O and OH– in strength
Poor if the base is weaker than H2O
3. SN1 / E1 reactions: Require a stable carbocation

Good if the halide is 3°

Fair if the halide is 2°
Poor if the halide is methyl or 1°

(Note that SN1 and E1 reactions almost always occur together, although you can ensure
elimination by treating an alcohol with concentrated H2SO4.)

• Use the hierarchy to determine the primary product (and identify possible secondary
products) for each of the following reactions:

Br + CN–

Br + OH–

Br + H 2O

+ OH–
Br

+ CH3OH
Br

+ H2SO4
OH
Reading: Section 9.7

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