Nucleophilic Substitution

Functional Group
Transformation By Nucleophilic
Substitution
 Previous Nucleophilic
Substitution Reaction

R-OH + HX -> R-X + H2O

X- ; Nucleophilic Atom
Carbon bond to O; Electrophilic Atom
H2O (protonated –OH) ; Leaving Group
 Nucleophilic Substitution

– –
Nu : + R L Nu R + :L
H-L
Nu :H + R L Nu R +
 Nucleophilic Substitution

Substrate cannot be an a vinylic halide or an

aryl halide, except under certain conditions to
be discussed in Chapter 23.

L
C C L
 Recognize

1. Good Leaving Group (X-, OTos, neutral

molecules)
2. Nucleophiles
3. Electrophile is sp3 C bond to Leaving Group
 Nucleophiles
Group VI
Oxygen Nucleophiles

-
O H H O H K (OH)

-
O R H O R Li (OCH3)
 Nucleophiles
Group VI
Sulfur Nucleophiles

- Na (SH)
S H S H
H

-
S R H S R Rb (S-CH2CH3)
 Nucleophiles
Group V
Nitrogen Nucleophiles

(N3)-
H N H H N R
-
- -
H H +
N N N

H N R R N R
NaN3
R R
 Nucleophiles
Group IV
Carbon Nucleophiles

-
-
C R
C N

K(CN) NaC CH2CH3

 Nucleophiles
Group VII
Halogen Nucleophiles

-
X

-
Cl HCl NaCl
-
Br HBr KBr

-
I HI CsI
Table 8.1 Examples of Nucleophilic Substitution

Alkoxide ion as the nucleophile

..–
R' O
.. : + R X

gives an ether
.. –
R' O
.. R + :X
Example

(CH3)2CHCH2ONa + CH3CH2Br

Isobutyl alcohol

(CH3)2CHCH2OCH2CH3 + NaBr

Ethyl isobutyl ether (66%)

Table 8.1 Examples of Nucleophilic Substitution

Carboxylate ion as the nucleophile

O
..–
R'C O .. : + R X

gives an ester
O
.. –
R'C O R + :X
..
Example
O
CH3(CH2)16C OK + CH3CH2I

acetone, water

O
CH3(CH2)16C O CH2CH3 + KI

Ethyl octadecanoate (95%)

Table 8.1 Examples of Nucleophilic Substitution

Hydrogen sulfide ion as the nucleophile

..–
H S
..: + R X

gives a thiol
.. –
H S
.. R + :X
Example

KSH + CH3CH(CH2)6CH3

Br

ethanol, water

CH3CH(CH2)6CH3 + KBr

SH

2-Nonanethiol (74%)
Table 8.1 Examples of Nucleophilic Substitution

Cyanide ion as the nucleophile

–
:N C: + R X

gives a nitrile

:N + –
C R :X
Example

NaCN + Br

DMSO

CN + NaBr

Cyclopentyl cyanide (70%)

Table 8.1 Examples of Nucleophilic Substitution

Azide ion as the nucleophile

– + –
:N N .. :
N + R X
..

gives an alkyl azide

– + –
:N N N R + :X
.. ..
Example

NaN3 + CH3CH2CH2CH2CH2I

2-Propanol-water

CH3CH2CH2CH2CH2N3 + NaI

Pentyl azide (52%)

Table 8.1 Examples of Nucleophilic Substitution

Iodide ion as the nucleophile

..–
: ..I: + R X

gives an alkyl iodide

.. –
: ..I R + :X
Example

CH3CHCH3 + NaI

Br

acetone

CH3CHCH3 + NaBr NaI is soluble in acetone;

NaCl and NaBr are not
soluble in acetone.
I
63%
Relative Reactivity of Halide
Leaving Groups
 Leaving Group Trends

Reactivity of halide leaving groups in

nucleophilic substitution is the same as
for elimination.
RI most reactive

RBr

RCl

RF least reactive
 Leaving Group Trends
The weaker the C-L bond; the better the
leaving group

Bond Type Bond Strength

(kcal/mole)
C-F 110

C-Cl 85

C-Br 71

C-I 57
 Leaving Group Trend
Weak bases make better leaving groups.

Strong Acids; Weak Conjugate Base; Good

Leaving
HI, HBr, HCl I-, Br-, Cl- Group

Weak Acid; Strong Conjugate Base Poor

Leaving
HF F- Group
Strong Bases (Derived from Weak Conjugate
Acids) Make Poor Leaving Groups

Weak Acids or Neutral Poor (not a ) Leaving Group

Molecule (Strong Conjugate Base)
R-OH RO-

H2O OH-

NH3 NH2-

H2 H-

RH R-
Neutral Molecules are Good Leaving Groups

Poor Leaving Group Good Leaving Group

OH- H2O

NH2- NH3
 The Tosylate Anion, OTos,
is a Good Leaving Group

O
-

O S CH3

O
 Problem

A single organic product was obtained when

1-bromo-3-chloropropane was allowed to react
with one molar equivalent of sodium cyanide in
aqueous ethanol. What was this product?

BrCH2CH2CH2Cl + NaCN

Br is a better leaving
group than Cl
 Problem

A single organic product was obtained when

1-bromo-3-chloropropane was allowed to react
with one molar equivalent of sodium cyanide in
aqueous ethanol. What was this product?

BrCH2CH2CH2Cl + NaCN

:N C CH2CH2CH2Cl + NaBr