ChapterII AlkylHalogen (CMII)

Nucleophilic Substitution Reactions
at the Saturated C Atom
Prof. Carlos Mario Meléndez Gómez Qco, Ph.D

Alkyl Halides and Nucleophilic Substitution
The Polar Carbon-Halogen Bond
• The electronegative halogen atom in alkyl halides creates a polar C—X bond,
making the carbon atom electron deficient. Electrostatic potential maps of
four simple alkyl halides illustrate this point.
Electrostatic potential maps of four halomethanes (CH3X)

The Polar Carbon-Halogen Bond
General Features of Nucleophilic Substitution:
• Three components are

necessary in any
substitution reaction.
4
• Negatively charged nucleophiles like HO¯ and HS¯ are used as salts
with Li+, Na+, or K+ counterions to balance the charge. Since the
identity of the counterion is usually inconsequential, it is often
omitted from the chemical equation.
• When a neutral nucleophile is used, the substitution product bears a

positive charge.
• Furthermore, when the substitution product bears a positive charge and also
contains a proton bonded to O or N, the initially formed substitution product readily
loses a proton in a BrØnsted-Lowry acid-base reaction, forming a neutral product.
• To draw any nucleophilic substitution product:

Find the sp3 hybridized carbon with the leaving group.
Identify the nucleophile, the species with a lone pair or  bond.
Substitute the nucleophile for the leaving group and assign charges (if
necessary) to any atom that is involved in bond breaking or bond formation.
Nucleophiles and Electrophiles; Leaving Groups
Stated with some exaggeration, organic chemistry is comparatively

simple to learn because most organic chemical reactions follow a single
pattern. This pattern is
Contain an electron pair that is easily available because it is nonbonding or

Nucleophile they must contain a bonding electron pair that can be donated from the
bond involved and thus be made vailable to the reaction partner.
Are electron pair acceptors. They therefore contain either a deficiency in

Electrophile the valence electron shell of one of the atoms they consist of or they are
indeed valence-saturated but contain an atom from which a bonding
electron pair can be removed as part of a leaving group
For most organic chemical reactions, the pattern just
specified can thus be written more briefly as follows:
Alkyl groups are transferred to the nucleophiles. Organic electrophiles of this type are
referred to as alkylating agents. The group X is displaced by the nucleophile agent.
Consequently, both the bound group X and the departing entity X are called leaving
groups.
Some uncharged and a few positively charged three-membered heterocycles also

react as alkylating agents. The most important heterocyclic alkylating agents of this
type are the epoxides.When there are no Brønsted or Lewis acids present, epoxides
act as hydroxy alkylating agents with respect to nucleophiles.
This reaction can also be considered to be an addition reaction. An intermolecular addition reaction
is one that involves the combination of two molecules to form one new molecule. …
at the Saturated C Atom.
Good and Poor Nucleophiles
As emerges from these definitions, good and poor nucleophiles, high and low
nucleophilicity, good and poor alkylating agents, good and poor electrophiles, and high
and low electrophilicity are kinetically determined concepts.
Answers to all these questions are obtained via pairs of SN
reactions, which are carried out as competition experiments. In a
competition experiment two reagents react simultaneously with
one substrate…. The nucleophile that reacts to form the main
product is then the “better” nucleophile.
With this as the basic idea, the experimentally observable nucleophilicity gradations
can be interpreted as follows……
Within a group of nucleophiles that attack at the electrophile with the same atom,
the nucleophilicity decreases with decreasing basicity of the nucleophile
Decreasing basicity is equivalent to decreasing affinity of an electron pair for a proton, which to
a certain extent, is a model electrophile for the electrophiles of SN reactions...
With this as the basic idea, the experimentally observable
nucleophilicity gradations can be interpreted as
follows……
This parallel between nucleophilicity and basicity can be reversed by steric effects.
Less basic but sterically unhindered nucleophiles therefore have a higher
nucleophilicity than strongly basic but sterically hindered nucleophiles.
This is most noticeable in reactions with sterically demanding alkylating agents or

sterically demanding epoxides…..
With this as the basic idea, the experimentally observable
nucleophilicity gradations can be interpreted as follows……
Nucleophilicity decreases with increasing electronegativity of the attacking atom.

This is true both in comparisons of atomic centers that belong to the same period
of the periodic table of the elements.
and in comparisons of atomic centers from the same group of the periodic table:
The nucleophilicity of a given nucleophilic center is increased by attached heteroatoms that

possess free electron pairs (-effect):
The reason for this is the unavoidable overlap of the orbitals that accommodate the free
electron pairs at the nucleophilic center and its neighboring atom.
Leaving Groups and the Quality of Leaving Groups
The Hammond postulate implies that a good leaving group is a stabilized species, not a
high-energy species. Therefore good leaving groups are usually weak bases, not strong
bases.
Good leaving groups: RHal and

epoxides can be further activated
with Lewis acids.
Very basic leaving groups are produced relatively slowly according to

Hammond. In other words, strong Brønsted bases are poor leaving
groups; weak Brønsted bases are good leaving groups!!!!!!
HOW CAN WE EXPLAIN?
A 1:1 mixture of a strong base with protons would be high in energy relative to the
corresponding conjugate acid. From this we can conclude that a mixture of a strongly basic
leaving group with the product of an SN reaction is also relatively high in energy.. !!!!
Alcohols, ethers, and carboxylic acid esters do not enter into any SN reactions with
nucleophiles.The reason for this is that poor leaving groups would have to be released (OH, OR,
O2CR).
in situ activation of the leaving group

necessary!!!!
These compounds can enter into SN reactions with nucleophiles when they are activated as
oxonium ions, for example via a reversible protonation, via bonding of a Lewis acid (LA), or via a
phosphorylation. Thus, upon attack by the nucleophile, better leaving groups (e.g., HOH, HOR,
HO2CR, O“PPh3) can be released.
Poor leaving group. The effect of nucleophiles on substrates of the latter
type does result in a reaction, but it is not an SN reaction.
Very poor leaving group or not a leaving

group..!!!
The nucleophile abstracts an acidic proton in

the alpha- position to the functional group
instead of replacing the functional group.
Another reaction competing with the substitution of a functional

group by a nucleophile is an attack on the functional group by
the nucleophile.
Hammond’s Postulate
“If two states, for example, a transition state and an

unstable intermediate, occur consecutively during a
reaction process and have nearly the same energy
content, their interconversion will involve only a
small reorganization of the molecular structures”
George S. Hammond, J. Am. Chem. Soc. 1955, 77, 334-338.

“The structure of the transition state for an

exothermic reaction is reached early in the reaction,
so it resembles reactants more than products.
Conversely, the structure of the transition state for
an endothermic reaction step is reached relatively
late, so it resembles products more then reactants.”
• In reactions where the

starting material is
higher in energy (A), the
transition state more
closely resembles the
starting material
• In reactions where the
product is higher in
energy (B), the
transition state more
closely resembles the
product
George S. Hammond, J. Am. Chem. Soc. 1955, 77, 334-338.

SN2 Reactions: Kinetic and Stereochemical Analysis—Substituent

Effects on Reactivity
Energy Profile and Rate Law for SN2

Reactions: Reaction Order.
An SN2 reaction refers to an SN
reaction. in which the nucleophile and
the alkylating agent are converted into
the substitution product in one step,
that is, via one transition state.
Rate laws establish a relationship between…..

• The change in the concentration of a product, an intermediate, or a
starting material as a function of time.
• The concentrations of the starting material(s) and possibly the catalyst
• The rate constants of the elementary reactions that are involved in the
overall reaction.
With the help of the rate laws that describe the elementary reactions involved,
it is possible to derive…
If the right-hand side of Equation does not contain any sums or differences, the
sum of the powers of the concentration(s) of the starting material(s) in this
expression is called the order m of the reaction….
Energy Profile and Rate Law for SN2 Reactions:

Reaction Order.
This reaction is a bimolecular substitutions. And

referred to a SN2 mechanism .The bimolecularity
makes it possible to distinguish between this type
of substitution and SN1 reactions.

The attack by potassium acetate

on the trans-tosylate A gives exclusively the
cyclohexyl acetate cis-B. No trans-isomer
is formed…..!!!
In the substitution product cis-B the acetate is axial and the adjacent H atom is
equatorial. Thus a 100% inversion of the configuration has taken place in this SN2
reaction.
The reason for the inversion of configuration is that SN2 reactions

take place with a backside attack by the nucleophile on the bond
between the C atom and the leaving group.

The SN2 reactions take place with a backside attack

by the nucleophile on the bond between the C atom
and the leaving group.
The SN2 mechanism is casually also referred to as an “umbrella mechanism.”The

nucleophile enters in the direction of the umbrella handle and displaces the leaving
group, which was originally lying above the tip of the umbrella.
The geometry of the transition state corresponds to the geometry of the umbrella, which
is just flipping over.
A Refined Transition State Model for the SN2 Reaction; Nucleophilic Substitution Reactions
Crossover Experiment and Endocyclic Restriction Test at the Saturated C Atom.
Determination of the mechanism of one-step SN

reactions on methyl (arenesulfonates): intra- or
intermolecularity.
Experiment 1. The perprotio-sulfonyl anion [H6]-A reacts to

form the methylated perprotio-sulfone [H6]-B.
Experiment 2. The sulfonyl anion [D6]-A, (perdeuterated in

both methyl groups), reacts to form the hexadeuterated
methylsulfone [D6]-B.
INTRAMOLECULAR O INTERMOLECULAR REACTION?
The intramolecular methylation of the substrate, (not

observed), would had to take place through a six-
membered cyclic transition state. Why a cyclic
transition state not able to explain the SN reactions in
Figure?
In other cases cyclic six-membered transition states of intramolecular reactions are so favored that
intermolecular reactions usually do not occur.
The conformational degrees of freedom of cyclic transition states are considerably limited or
“restricted” relative to the conformational degrees of freedom of noncyclic transition states
(cf. the fewer conformational degrees of freedom of cyclohexane vs n-hexane).
Mechanistic investigations of this type are

therefore also referred to as endocyclic
restriction tests. They prove or refute in a
very simple way certain transition state
geometries because of this conformational
restriction.
The endocyclic restriction imposes limitations of the conceivable geometries on cyclic transition
states. These geometries do not comprise all the possibilities that could be realized for intermolecular
reactions proceeding through acyclic transition states.
In the SN reactions of Figure, the endocyclic restriction would therefore impose a geometry in an
intramolecular substitution that is energetically disfavored relative to the geometry that can be obtained in
an intermolecular substitution.
In an intramolecular substitution the

The colinear geometry can be obtained
nucleophile, the attacked C atom, and the
in an intermolecular way!!!!!
leaving group cannot lie on a common axis.
In the SN reactions of Figure, the endocyclic restriction would therefore impose a geometry in an
intramolecular substitution that is energetically disfavored relative to the geometry that can be obtained in
an intermolecular substitution
This approach path is preferred in order to achieve a transition state with optimum bonding
interactions. Let us assume that in the transition state, the distance between the nucleophile and
the attacked C atom and between the leaving group and this C atom are exactly the same.
• The geometry of the transition state would

then correspond precisely to the geometry of
an umbrella that is just flipping over.
• The attacked C atom would be—as shown

in Figure (left)—sp2-hybridized and at the
center of a trigonal bipyramid.
• The nucleophile and the leaving group

would be bound to this C atom via sigma
bonds, both suffer a overlap with one lobe
of the 2pz AO. A linear arrangement of the
nucleophile, the attacked C atom, and the
leaving group is preferred in the transition
state of SN reactions.
The figure shows that in a bent transition state of the SN reaction neither the nucleophile nor the leaving
group can form similarly stable bonds by overlap with the 2pz AO of the attacked C atom. Because the
orbital lobes under consideration are not parallel Bent bonds are weaker than linear bonds because
of the smaller orbital overlap
Substituent Effects on SN2 Reactivity
How substituents in the alkylating agent influence the rate constants of SN2 reactions can be
explained by means of the transition state model developed previously. This model makes it
possible to understand both the steric and the electronic substituent effects.
• The bond angle between these

substituents and the leaving group
decreases from approximately the
tetrahedral angle 109 to approximately 90.
• The attacking nucleophile approaches the

inert substituents until the bond angle that
separates it from them is also
approximately 90.
The resulting increased steric interactions destabilize the transition state. It should be noted that this
destabilization is not compensated for by the simultaneous increase in the bond angle between the inert
substituents from approximately the tetrahedral angle to approximately 120.
The effect of the substituent in the transition state has various consecuences…..
• The SN2 react alkylating agent decreases with an increasing number of the alkyl substituents at
the attacked C ativity of an aom. In other words, alpha branching at the C atom of the alkylating
agent reduces its SN2 reactivity. This reduces the reactivity so much that tertiary C atoms can no
longer be attacked according to an SN2 mechanism at all:
• The SN2 reactivity of an alkylating agent decreases with an increase in size of the alkyl
substituents at the attacked C atom. In other words, beta branching in the alkylating agent
reduces its SN2 reactivity. This reduces the reactivity so much that a C atom with a tertiary C atom
in the position can no longer be attacked at all according to an SN2 mechanism:
Besides these rate-reducing steric substituent effects, in SN2 reactions there is a rate increasing
electronic substituent effect. It is due to facilitation of the rehybridization of the attacked C atom from
sp3 to sp2.
Electronic effects on SN2 reactivity:

conjugative stabilization of the transition
state by suitably aligned unsaturated
substituents.
This effect is exerted by unsaturated substituents bound to the attacked C atom!!!
These include substituents, such as alkenyl,

aryl, or the C=O double bond of ketones or
esters.
When it is not prevented by the occurrence of strain, the p-electron system

of these substituents can line up in the transition state parallel to the 2pz AO
at the attacked C atom!!!
SN1 Reactions: Kinetic and Stereochemical Analysis;
Substituent Effects on Reactivity
Energy Profile and Rate Law of SN1 Reactions;

Steady State Approximation
Take place in two steps. In the first and slower step, heterolysis of the bond between the C
atom and the leaving group takes place. A carbenium ion is produced as a high-energy, and
consequently short-lived, intermediate. In a considerably faster second step, it combines with
the nucleophile to form the substitution product Nu¬R.
Mechanism and energy profile of SN1

reactions: Ea,het designates the activation
energy of the heterolysis, khet and kattack
designate the rate constants for the
heterolysis and the nucleophilic attack on the
carbenium ion, respectively.
In a substitution according to the SN1 mechanism, the nucleophile does not activel attack
the alkylating agent.The reaction mechanism consists of the alkylating agent dissociating
by itself into a carbenium ion and the leaving group
The energy profile shows that here—as everywhere else—the rate-determining step of a multistep
sequence is the step in which the highest activation barrier must be overcome.
• Both take place via the

benzhydryl cation Ph2CH. In
the first experiment, this
cation is intercepted by
Rate and selectivity of SN1 pyridine as the nucleophile to
reactions.vBoth reactions 1 and form a pyridinium salt. In the
2vtake place via the benzhydryl second experiment, it is
cation. Both reactions (with pyridine intercepted by triethylamine to
and triethylamine) take place with the form a tetraalkylammonium
same rate constant. The higher salt.
nucleophilicity of pyridine
does not become noticeable until
experiment 3, the “competition • In experiment 3, both SN1
experiment”: The pyridinium salt is reactions are carried out as
by competitive reactions:
far the major product. benzhydryl chloride
heterolyzes (just as fast as
before) in the presence of
equal amounts of both amines.
The benzhydryl cation is now
intercepted faster by the more
nucleophilic pyridine. The
major product is the pyridinium
salt
Stereochemistry of SN1 Reactions; Ion Pairs
In the carbenium ion intermediates R1R2R3C+, the valence-unsaturated C atom has a
trigonal planar geometry. These intermediates are therefore achiral (if the substituents Ri
themselves do not contain chiral centers).
The carbenium ions react with achiral

nucleophiles to form chiral substitution
products R1R2R3C-Nu. These must be
produced as a 1:1 mixture of both enantiomers
(i.e., as a racemic mixture).
Stereochemistry of an SN1 reaction

that takes place via a contact ion pair.
The reaction proceeds with 66%
inversion of configuration and 34%
racemization.
The SN1 reaction with optically pure R-2-bromooctane carried out as a solvolysis. By
solvolysis one means an SN1 reaction performed in a polar solvent that also functions as the
nucleophile
The reacting carbenium ion is still almost in contact with this bromide ion. Thus it exists
as part of a so-called contact ion pair (the emphasis is on ion pair) R1R2HC. . . Br.
The solvolysis reaction takes place in a water/ethanol mixture. In the rate-

determining step a secondary carbenium ion is produced.
• In this ion pair, the bromide ion adjacent to the

carbenium ion center partially protects one side of the
carbenium ion from the attack of the nucleophile.
• The nucleophile preferentially attacks from the side

that lies opposite the bromide ion. Thus the solvolysis
product in which the onfiguration at the attacked C
atom has been inverted is the major product.
When in an SN1 reaction the nucleophile

attacks the contact ion pair, the reaction
proceeds with partial inversion of configuration
(or alternatively, with partial but not complete
racemization).
The reacting carbenium ion is still almost in contact with this bromide ion. Thus it exists
as part of a so-called contact ion pair (the emphasis is on ion pair) R1R2HC. . . Br.
The solvolysis reaction takes place in a water/ethanol mixture. In the rate-
determining step a secondary carbenium ion is produced.
The bromide ion moves so far away from the

alpha-methylbenzyl cation intermediate that it
allows the solvent to attack both sides of the
carbenium ion with equal probability!!!!!
When in an SN1 reaction the nucleophile

attacks the carbenium ion after it has
separated from the leaving group, the
reaction takes place with complete
racemization.This is the case with more
stable and consequently longer-lived
carbenium ions.
Solvent Effects on SN1 Reactivity
Heterolyses of alkylating agents, and consequently SN1 reactions, therefore,

succeed only in highly solvating media. These include the polar protic solvents
such as methanol, ethanol, acetic acid, and aqueous acetone as well as the polar
aprotic solvents acetone, acetonitrile, DMF, NMP, DMSO, and DMPU.
It is important to note that the use of polar solvents is only a necessary but not a sufficient
condition for the feasibility of SN1 substitutions or for the preference of the SN1 over the
SN2 mechanism.
The effects of group substitution in the SN1 reactivity are compared with
the carbocation stability as well.
Carbocation Stability
Stability: Stabilization via alkyl substituents (hyperconjugation)
Order of carbocation stability: 3Þ>2Þ>1Þ

R H H H
> H C > H C Due to increasing number of substituents
R C > R C
capable of hyperconjugation
R R R H
The relative stabilities of various carbocations

Hydride ion
can be measured in the gas phase by their affinities
affinity for hydride ion.
CH3+ 314
CH3CH2+ 276
R + H R–H + HI
(CH3)2CH+ 249
Hydride Affinity = –G° (CH3)3C+ 231
HI increases  C(+) stability decreases H2C=CH+ 287
H C C+ 386
Note: As S-character increases, cation stability PhCH2+ 239
decreases due to more electronegative carbon.
J. Beauchamp, J. Am. Chem. Soc. 1984, 106, 3917.

Carbocation Generation
Carbocation Generation
Removal of an energy-poor anion from a neutral precursor via Lewis Acids
R3C X + LA R3C + LA–X LA: Ag , AlCl3, SnCl4, SbCl5, SbF5, BF3, FeCl3, ZnCl2, PCl3, PCl5, POCl3 ...
X: F, Cl, Br, I, OR
Acidic dehydratization of secondary and tertiary alcohols
- H2 O R: Aryl + other charge stabilizing substituents

R3C OH + H–X R3C + X
X: SO42-, ClO4-, FSO3-, CF3SO3-
From neutral precursors via heterolytic dissociation (solvolysis) - First step in SN1 or E1 reactions
solvent
R3C X R3C + X Ability of X to function as a leaving group:
-N2+ > -OSO2R' > -OPO(OR')2 > -I • -Br > Cl > OH2+ ...
Addition of electrophiles to š-systems
R R H R R H R
H R R R
R R R R H
Hydride abstraction from neutral precursors
H H RS R2 N
+ Lewis-Acid H H
R3C H R3C R3 C H = etc.
H H H H
RS R2 N
Lewis-Acid: Ph3C BF4, BF3, PCl5

Vinyl & Phenyl Cations: Highly Unstable
+21 +81
H3C CH2 H2C CH HC C
276 287 386 Hydride ion affinities (HI)
+11
H2C CH Phenyl Cations
287
298
Allyl & Benzyl Carbocations

Carbocation Stabilization via -delocalization
Br
Stabilization by Phenyl-groups
The Benzyl cation is as stable as a t-Butylcation. This is shown in the
subsequent isodesmic equations:
Hydride ion affinities (HI) Ph CH2 Me3 C

239 231
Carbocations in Bridged Systems at the Saturated C Atom.
Carbocations In Bridged Systems
Cyclopropyl Carbocations Solvolysis rates represent the extend of that cyclopropyl orbital overlap
contributing to the stabiliziation of the carbenium ion which is involved as a
reactive intermediate:
OTs
Me OTs
Cl
Me
krel = 1 krel = 1 krel = 1
OTs
OTs
Cl
krel = 106 krel = 108 krel = 10-3
Bridgehead Carbocations Me
Me OTs why so
Me reactive?
TsO TsO TsO
1 10-7 10-13 104

Bridgehead carbocations are highly disfavored due to a strain increase in
achieving planarity. Systems with the greatest strain increase upon passing
from ground state to transition state react slowest.
Carbocation [1,2][1,2]
Carbocation Sigmatropic
SigmatropicRearrangements
Rearrangements
1,2 Sigmatropic shifts are the most commonly encountered cationic rearrangements. When
either an alkyl substituent or a hydride is involved, the term Wagner-Meerwein shift is
employed to identify this class of rearrangments.
Stereoelectronic requirement for migration....
retention of stereochemistry
C C
A D A D
B bridging T.S. B
C
A D
B
Carbocation [1,2] Sigmatropic Rearrangements
Demjanov-rearrangement (Driving force: relief of ring strain)
Me H
Me
Me
H2SO4 H
Me Me Me
Me OH H Me
Me H OH
Me
Me
H H
equiv to Me Me
HO Me
Me H Me
E. J. Corey J. Am. Chem. Soc. 1964, 86, 1652. -caryophyllene alcohol
Factors that influence carbocation formation
Nature of the leaving group
R Z heterolytic R
+
+ Z
cleavage
The leaving group may be a stable, neutral atom or molecule
 -decay 3 +1 -1 3 0
i) CH 3 T ( CH 3 He ) + 1e CH 3 + + He
gas phase
KNO 2 + + -
ii) C6 H 5 NH 2 C6 H 5 N 2 + Cl - C6 H 5 + N 2 + Cl C6 H 5 Cl
HCl
HX +
- + -
iii) ROR' ROR' + X R + X + R'OH RX
H
+
+
iv) R NR 3 R + NR 3
Factors that influence carbocation formation at the Saturated C Atom.
Anionic leaving
+
groups
-
R Z R + Z
The greater the ability of the departing anionic species to

stabilize negative charge, the better a leaving group it is .
Ease of displacement of common anionic leaving groups:
O O O
- - -
O2 N S O > Br S O > H 3C S O
O O O
nosylate brosylate tosylate
O
S O > I > Br > Cl > F ~= CH 3 COO- > OH - ~
= OR - > NR 2 -
- - - - -
Z
O
Other particularly good anionic leaving groups :
O NO 2
O
CF3 S O- O2 N O- CF3 C
O-
O NO 2
triflate picrate trifluoroacetate
s that influence carbocation formation
Structural factors
Alkyl substitution - The greater the degree of alkyl substitution at the cationic center,
the greater will be the stability of the carbocation produced.
o o o +
3 > 2 > 1 > CH 3
Aryl substitution - The greater the degree of conjugation of the cationic center with
delocalizing groups, the greater will be the stability of the carbo-
cation produced.
+
(C6 H 5 )3 C+ > (C6 H 5 )2 CH > C6 H 5 CH 2 +
Conjugation with heteroatoms:

H 3C + H 3C +
C OR C OR R = H or alkyl
H 3C H 3C
H 3C + H 3C +
C NR 2 C NR 2 R = H or alkyl
H 3C H 3C
Steric factors - Carbocations prefer a planar geometry: Any structural feature that
o
interferes or prevents the attainment of 120 interbond angles
will hinder (retard) carbocation formation.
+ +
(CH 3 )3 C+ > > CH 3 (all are 3
o
)
o o o
120 ~ 105 ~ 60
Factors that influence carbocation formation
Solvent effects: Any property of a solvent

system that can lower the energy of
activation for heterolytic bond cleavage
will favor carbocation formation.
The role of solvent in carbocation formation
• Dielectric constant - a rough measure of

the ability of the solvent to separate
oppositely charged ions.
• Hydrogen-bonding ability
• Acid-base properties
• Nucleophilicity: As the nucleophilicity of
a solvent decreases, the likelihood of
discrete carbocation formation
increases.
Preparatively Useful SN2 Reactions: Alkylations
synthetically important reactions, shows the various nucleophiles that can be

alkylated according to the SN2 mechanism.
Enolate Synthesis
C-nucleophiles
N-nucleophiles
S-nucleophiles
Hal-nucleophiles
P-nucleophiles
O-nucleophiles
Preparation of methyl
esters from carboxylic
acids and
diazomethane.
Mitsunobu inversion
With its reactions is possible to invert the configuration of a stereocenter equipped with an OH group.
The enantiomers of optically pure alcohols, which contain a single stereocenter that bears an OH group,
are easily accessible through a Mitsunobu inversion process.
Mitsunobu inversion
Mechanism of
the Mitsunobu
inversion
Additions to the Olefinic C=C
Double Bond
Reactivity of C=C at the Saturated C Atom.
• Electrophiles are attracted to the pi electrons.

• Carbocation intermediate forms.
• Nucleophile adds to the carbocation.
• Net result is addition to the double bond.
Electrophilic Addition
 Step 1: Pi electrons attack the electrophile.
E
+
C C + E C C +
• Step 2: Nucleophile attacks the carbocation.
E E Nuc
_
C C+ + Nuc: C C
Chapter 8 =>
Addition of HX (1)
Protonation of double bond yields the most stable carbocation.

Positive charge goes to the carbon that was not protonated.
CH3
CH3 C CH CH3
CH3 +
H
CH3 C CH CH3 _
+ Br
H Br CH3
X
CH3 C CH CH3
H
+
Chapter 8
MECHANISM
STEP-BY-STEP ACCOUNT OF WHAT HAPPENS
:X-
X
step 1 step 2
C C C C C C
+
E E
+
E
intermediates are
Intermediate formed during a
reaction but are
not products
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ENERGY PROFILE
two step reaction
intermediate
TS1
E
N TS2
E
R -
G X
Y
C C
+
E
step 1 step 2
C C H X
product C C
+
E E
WWU -- Chemistry
ACTIVATED COMPLEXES
correspond to transition states for each step
-
X X
C C C C C C
+
E E
+ intermediate
E
-
X
+
C C C
+ C
+ E
E
ACTIVATED show bonds in the process of breaking or forming

COMPLEXES (bonds are half formed or half broken)
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Regiospecificity
• Markovnikov’s Rule: The proton of an acid

adds to the carbon in the double bond that
already has the most H’s. “Rich get richer.”
• More general Markovnikov’s Rule: In an
electrophilic addition to an alkene, the
electrophile adds in such a way as to form the
most stable intermediate.
• HCl, HBr, and HI add to alkenes to form
Markovnikov products.
Chapter 8
MARKOVNIKOV RULE
When adding HX to a double bond the

hydrogen of HX goes to the carbon
which already has the most hydrogens
CH 2 CH 3
Cl
+ HCl
..... conversely, the anion X adds to the most

highly substituted carbon ( the carbon with
most alkyl groups attached).
WWU -- Chemistry
REGIOSELECTIVE
REACTION
CH3 CH3 CH3

HCl
CH3 C CH2 CH3 C CH3 + CH3 CH CH2
Cl Cl
major minor
one of the possible products is formed

in larger amounts than the other one
Compare
REGIOSPECIFIC
only one of the possible products is
formed (100%).
WWU -- Chemistry
Mechanism (Markovnikov)
+ slow
1) R CH CH2 + H R CH-CH2 H
Secondary C+
+
Electrophile
_ fast
2) R CH-CH2 H + Br R CH CH2 H
+ Br
Nucleophile
Major product
WWU -- Chemistry
Mechanism (anti-Markovnikov)
CH CH2+
+ slow
1) R CH CH2 + H R
H
Primary carbocation
+ _ fast
2) R CH CH + Br R CH CH2 Br
2
H H
Minor!
WWU -- Chemistry
COMPETING PATHWAYS at the Saturated C Atom.
rate-determining step
slower Higher energy

intermediate
faster Lower energy

1o intermediate
2o
rate-determininng
(slow) step
WWU -- Chemistry
SOME ADDITIONAL EXAMPLES
only major product is shown
CH3 CH3
Cl
+ HCl
CH2 CH3
Cl
+ HCl
CH CH2 CH CH3
+ HCl Cl
WWU -- Chemistry
Free-Radical Addition of HBr
• In the presence of peroxides, HBr adds to

an alkene to form the “anti-Markovnikov”
product.
• Only HBr has the right bond energy.
• HCl bond is too strong.
• HI bond tends to break heterolytically to
form ions.
Chapter 8
Free Radical Initiation
• Peroxide O-O bond breaks easily to form

free radicals.
heat
R O O R R O + O R
• Hydrogen is abstracted from HBr.
R O + H Br R O H + Br
Chapter 8
Propagation Steps
• Bromine adds to the double bond.
Br + C C C C
Br
• Hydrogen is abstracted from HBr.
C C + H Br C C + Br
Br Br H
Chapter 8
Anti-Markovnikov ??
CH3
CH3 C CH CH3
CH3 Br
CH3 C CH CH3 + Br CH3
X CH3 C CH CH3
Br
• Tertiary radical is more stable, so that

intermediate forms faster.
Chapter 8
β-Eliminations
Concepts of β-Elimination Reactions
The Concepts of α,β- and 1,n-Elimination
Reactions in which two atoms or atom groups X and Y are removed from a
compound are referred to as eliminations
In many eliminations X and Y are removed in such a way that they do not
become constituents of one and the same molecule. In other eliminations they
become attached to one another such that they leave as a molecule
of type X-Y or X=Y.
Concepts of β-Elimination Reactions
The Concepts of α,β- and 1,n-Elimination
Reactions in which two atoms or atom groups X and Y are removed from a
compound are referred to as eliminations
1,n-Eliminations (n 1–4) of
two atoms or groups X and
Y, which are bound to sp3-
hybridized C atoms.
Depending on the distance between the atoms or groups X and Y removed from the
substrate, their elimination has a distinct designation. If X and Y are geminal, their
removal is an a-elimination. If they are vicinal, it is a b-elimination. If X and Y are
separated from each other by n atoms, their removal is called 1,n-elimination, that
is, 1,3-, 1,4-elimination, and so on
Elimination Reactions, E1 and E2:
•We have seen that alkyl halides may react with basic nucleophiles such as NaOH via
substitution reactions.
H H
.. H .. .. .. .. ..
:O H + C Br : H ..O C Br : H C + : Br :
..
H
.. .. ..O ..
H
H HH H
transition state
•Also recall our study of the preparation of alkenes. When a 2° or 3° alkyl halide is
treated with a strong base such as NaOH, dehydrohalogenation occurs producing an
alkene – an elimination (E2) reaction.
KOH in ethanol + KBr + H2O

Br
-HBr
• bromocyclohexane + KOH  cyclohexene (80 % yield)
•Substitution and elimination reactions are often in competition. We shall consider the
determining factors after studying the mechanisms of elimination.
78
E2 Reaction Mechanism
• There are 2 kinds of elimination reactions, E1 and E2.
• E2 = Elimination, Bimolecular (2nd order). Rate = k [RX] [Nu:-]

 E2 reactions occur when a 2° or 3° alkyl halide is treated with a strong base such
as OH-, OR-, NH2-, H-, etc.
H
 C C + Br- + HO H
OH- + C C

Br
The Nu:- removes an H+ from a -carbon & the
halogen leaves forming an alkene.
 All strong bases, like OH-, are good nucleophiles. In 2° and 3° alkyl
halides the -carbon in the alkyl halide is hindered. In such cases, a
strong base will ‘abstract’ (remove) a hydrogen ion (H+) from a -
carbon, before it hits the -carbon. Thus strong bases cause
elimination (E2) in 2° and 3° alkyl halides and cause substitution (SN2)
in unhindered methyl° and 1° alkyl halides.
E2 Reaction Mechanism
•In E2 reactions, the Base to H  bond formation, the C to H  bond breaking, the C
to C  bond formation, and the C to Br  bond breaking all occur simultaneously.
No carbocation intermediate forms.
B:- 
+
B
H R H R R R
C C R C C C C + B H + X-
R R R R
R X R R
X-

•Reactions in which several steps occur simultaneously are called ‘concerted’

reactions.
•Zaitsev’s Rule:
•Recall that in elimination of HX from alkenes, the more highly substituted (more
stable) alkene product predominates.
Br CH3CH2O-Na+
CH3CH2CHCH3 CH3CH CHCH3 + CH3CH2CH CH2
EtOH 2-butene 1-butene
major product minor product

( > 80%) ( < 20%)
E2 Reactions are ‘antiperiplanar’ at the Saturated C Atom.
 E2 reactions, do not always follow Zaitsev’s

rule.
 E2 eliminations occur with anti-periplanar

geometry, i.e., periplanar means that all 4
reacting atoms - H, C, C, & X - all lie in the
same plane. Anti means that H and X (the
eliminated atoms) are on opposite sides of
B:- 
+
the molecules. H R
B
H R R R
C C R C C C C + B H + X-
R R R
 R R
X R X- R

 Look at the mechanism again and note the

opposite side & same plane orientation
81 of
Antiperiplanar E2 Reactions in Cyclic Alkyl Halides
 When E2 reactions occur in open chain alkyl halides, the Zaitsev product is
usually the major product. Single bonds can rotate to the proper alignment to
allow the antiperiplanar elimination.
 In cyclic structures, however, single bonds cannot rotate. We need to be
mindful of the stereochemistry in cyclic alkyl halides undergoing E2 reactions.
• See the following example.
 Trans –1-chloro-2-methylcyclopentane undergoes E2 elimination with

NaOH. Draw and name the major product.
H H3C H
H3C H Na+ OH- NaCl
+
H H3C
H H + HOH H
H E2 H
H
Cl
Little or no Zaitsev (more stable)
Non Zaitsev product product is formed.
is major product.
3-methylcyclopentene 1-methylcyclopentene
82
E1 Reactions
 Just as SN2 reactions are analogous to E2 reactions, so SN1 reactions have an

analog, E1 reaction.
 E1 = Elimination, unimolecular (1st order); Rate = k  [RX]
CH3 CH3
slow H
rapid CH3
CH3 C Br CH3 C+ -
C C + B H + Br
- Br-
CH3 H C H
CH3 H
H B:-
 E1 eliminations, like SN1 substitutions, begin with unimolecular dissociation, but

the dissociation is followed by loss of a proton from the -carbon (attached to
the C+) rather than by substitution.
 E1 & SN1 normally occur in competition, whenever an alkyl halide is treated in
a protic solvent with a nonbasic, poor nucleophile.
 Note: The best E1 substrates are also the best SN1 substrates, and mixtures of
products are usually obtained.
83
E1 Reactions
 As with E2 reactions, E1 reactions also produce the more highly substituted

alkene (Zaitsev’s rule). However, unlike E2 reactions where no C+ is produced,
C+ rearrangements can occur in E1 reactions.
 e.g., t-butyl chloride + H2O (in EtOH) at 65 C  t-butanol + 2-methylpropene
CH3 H2O, EtOH CH3 CH3 H

CH3 C Cl CH3 C OH + C C
65ºC
CH3 CH3 CH3 H
36%
64%
E1
S N1
product
product
 In most unimolecular reactions, SN1 is favored over E1, especially at low

temperature. Such reactions with mixed products are not often used in
synthetic chemistry.
 If the E1 product is desired, it is better to use a strong base and force the E2
reaction.
 Note that increasing the strength of the nucleophile favors SN1 over E1. Can
you postulate an explanation?
84
Predicting Reaction Mechanisms
1. Non basic, good nucleophiles, like Br- and I- will cause substitution not
elimination. In 3° substrates, only SN1 is possible. In Me° and 1°
substrates, SN2 is faster. For 2° substrates, the mechanism of
substitution depends upon the solvent.
2. Strong bases, like OH- and OR-, are also good nucleophiles.
Substitution and elimination compete. In 3° and 2° alkyl halides, E2 is
faster. In 1° and Me° alkyl halides, SN2 occurs.
3. Weakly basic, weak nucleophiles, like H2O, EtOH, CH3COOH, etc.,
cannot react unless a C+ forms. This only occurs with 2° or 3°
substrates. Once the C+ forms, both SN1 and E1 occur in
competition. The substitution product is usually predominant.
4. High temperatures increase the yield of elimination product over
substitution product. (DG = DH –TDS) Elimination produces more
products than substitution, hence creates greater entropy (disorder).
5. Polar solvents, both protic and aprotic, like H2O and CH3CN,
respectively, favor unimolecular reactions (SN1 and E1) by stabilizing
the C+ intermediate. Polar aprotic solvents enhance bimolecular
reactions (SN2 and E2) by activating the nucleophile.
85
- - - -
good Nu good Nu good Nu very poor Nu
alkyl nonbasic strong base strong bulky base nonbasic
halide e.g., bromide e.g., ethoxide e.g., t-butoxide e.g., acetic acid
- - -
(substrate) Br C2H5O (CH3)3CO CH3COOH
Me SN2 SN2 SN2 no reaction
1° S N2 S N2 E2 (SN2) no reaction
2 S N2 E2 E2 SN1, E1
3 S N1 E2 E2 SN1, E1
Strong bulky bases like t-butoxide are hindered. They have difficulty
hitting the a-carbon in a 1° alkyl halide. As a result, they favor E2 over
SN2 products.
86
•The nucleophiles in the table on slide 30 are extremes. Some

nucleophiles have basicity and nucleophilicity in between these
extremes. The reaction mechanisms that they will predominate can be
interpolated with good success.
•Predict the predominant reaction mechanisms the following table.
-
v. gd. Nu-
……….. v. gd. Nu-
……….. ………..
fair Nu HI
alkyl ………. .base
moderate ……….. base
moderate ……….. base
weak alcohol HBr
halide e.g., cyanide e.g., alkyl sulfide e.g., carboxylate (substrate)
- HCl
(substrate) CN- RS-, also HS- RCOO
4.
pkb = ……… 6.0 /
pkb = ……… pkb = ………
9
7 7.0
Me S N2 SN2 SN2 Me S N2
1 S N2 S N2 S N2 1 S N2
2 S N2 S N2 E2 2 S N1
3 E2 E2 E2 3 S N1
HCl, HBr and HI are assumed to be in aqueous solution, a protic solvent.
87
Alkylation of Alkynides
• Recall the preparation of long alkynes.

1. A terminal alkyne (pKa = 25) is deprotonated with a very strong base…
• R-C º C-H + NaNH2 ® R-C º C:- Na+ + NH3
2. An alkynide anion is a good Nu:- which can substitute (replace) halogen

atoms in methyl or 1° alkyl halides producing longer terminal alkynes ¼
• R-C º C: - Na+ + CH3CH2-X ® R-C º C-CH2CH3 + NaX
 The reaction is straightforward with Me and 1 alkyl halides and proceeds

via an SN2 mechanism
 Alkynide anions are also strong bases (pKb = -11) as well as good Nu:-’s,
so E2 competes with SN2 for 2 and 3 alkyl halides
• CH3(CH2)3CC:- Na+ + CH3-CH(Br)-CH3  CH3(CH2)3CCCH(CH3)2 (7%
SN2)
• + CH3(CH2)3CCH + CH3CH=CH2 (93% E2)
88
Preparation of Alkyl Halides from Alcohols
• Alkyl halides can be prepared from alcohols by reaction with HX, i.e., the
substitution of a halide on a protonated alcohol.
3º - H2O
.. + ..
(Lucas Test) (CH3)3C Cl : + H2O
(CH ) C OH + H Cl (CH3)3C OH (CH3)3C + ..
SN1 3 3 .. .. 2
.. -
Rapid. 3° C+ is stabilized by protic sovent (H2O) : Cl :
..
 OH- is a poor leaving group, i.e., is not displaced directly by

nucleophiles. Reaction in acid media protonates the OH group
producing a better leaving group (H2O). 2 and 3 alcohols react by
SN1 but Me° and 1 alcohols react by SN2.
1º
.. +
SN2 CH3CH2 OH + H Cl CH3CH2 OH2 CH3CH2Cl + H2O
..  .. -
: Cl :
..
Very slow. Protic solvent inhibits the nucleophile.
 Draw the mechanism of the reaction of isopropyl alcohol with HBr.

 What products form if concentrated H2SO4 is used in place of aq. HCl?
89
Preparation of Alkyl Halides from Alcohols
• Alternative to using hydrohalic acids (HCl,

HBr, HI), alcohols can be converted to alkyl
halides by reaction with PBr3 which transforms
OH- into a better leaving group allowing
substitution (SN2) to occur without
rearrangement.
Br
:P
Br
1º
.. Br + PBr2
CH3(CH2)4CH2Br
SN2 CH3(CH2)4CH2 OH CH3(CH2)4CH2 O
.. ..
ether H
-
Br
90
Preparation of Alkenes from Alkyl Halides
• 2° and 3° alkyl halides can be dehydrohalogenated with a strong base such

as OH- producing an alkene.
KOH in ethanol + KBr + H2O

Br
-HBr
•bromocyclohexane + KOH  cyclohexene (80 % yield)
•Clearly, this is an E2 reaction.
 Predict the mechanism that occurs with a Me° or 1° alkyl halide.
 Predict the products and mechanism that occur with isopentyl chloride
and KOH
91
Summary of SN /Elimination Reactions
• Alkyl Halide Substrate Reactivity:

methyl 1º 2º 3º
H H CH3 CH3
H C Br CH3 C Br CH3 C Br CH3 C Br
H H H CH3
unhindered substrates favor S N2 hindered substrates. S N2 increasingly unfavorable, E2 is OK

do not form a stable C + form increasingly stable C +
do not react by S N1 or E1 favors SN1 and E1. E2 is OK
E2 reactions possible with strong bases
E2 reactions possible with strong bulky bases (t-butoxide)
92
Polar Reactions under
Basic Conditions
β-Elimination by the E2 and E1cb Mechanisms
C(sp3)–X electrophiles can undergo β -elimination reactions as well as

substitutions. -Elimination reactions proceed by the E2 or E1cb mechanism
under basic conditions.
The concerted E2 mechanism is
more common. The lone pair of
the base moves to form a bond
to a H atom on a C atom
adjacent to the electrophilic C
atom.
Because the H–C and the C–X bonds break simultaneously in the E2
mechanism, there is a stereoelectronic requirement that the orbitals making up
these two bonds be periplanar, (i.e., parallel to each other), in the transition state
of the elimination.
Acyclic compounds can orient

the two bonds in a periplanar
fashion in two ways,
synperiplanar (by eclipsing them
at a 0° dihedral angle) and
antiperiplanar (by staggering
them at a 180° angle).
In cyclic compounds, there are much greater restrictions on conformational flexibility. In six-
membered rings, the antiperiplanar requirement for E2 elimination is satisfied when both the
leaving group and the adjacent H atom are axial.
Moreover, two C–H bonds are antiperiplanar to the C–Cl bond in the reactive conformation
of neomenthyl chloride, so two products are obtained upon E2 elimination, whereas only
one C–H bond is antiperiplanar to the C–Cl bond in the reactive conformation of menthyl
chloride, so only one product is obtained.
Not only can 1° and 2° C(sp3)–X undergo -elimination by the E2 mechanism
under basic conditions, but so can 3° C(sp3)–X systems. Alkenyl halides
also undergo β -elimination readily. When there are H atoms on either side of
an alkenyl halide, either an alkyne or an allene may be obtained. Even alkenyl
ethers (enol ethers) can undergo -elimination to give an alkyne.
Draw a mechanism for the following reaction.

Substitution at C(sp2)–X Bonds
Substitution at Carbonyl C
Many carbonyl compounds, including esters, acyl chlorides, and acid anhydrides,
have leaving groups attached to the carbonyl C, and many reactions proceed
with substitution of this leaving group by a nucleophile
Primary amines react with many esters just upon mixing to give amides.
The
amines are sufficiently nucleophilic to add to the ester carbonyl.
After the nucleophilic N is

deprotonated, the alkoxy group is
a much better leaving group, so
collapse of the tetrahedral
intermediate occurs with
expulsion of OR to give the amide
as the product.
Transesterification of esters occurs by a mechanism very much like amide synthesis, but
the reaction requires a catalytic amount of base (usually the Na salt of the alcohol). The
nucleophile is the alkoxide. The reaction is driven in the forward direction by the use of a
large excess of the starting alcohol.
The reaction of alcohols with enolizable acyl chlorides or anhydrides can proceed by two
different mechanisms. One is the addition–elimination mechanism that has already been
discussed.
The other is a two-step, elimination–addition mechanism. In the elimination step,

-elimination occurs by an E2 mechanism to give a ketene, a very reactive
compound that is not usually isolable.
In the addition step, the alkoxide adds to the electrophilic carbonyl C of the ketene to
give the enolate of an ester. Acyl chlorides lacking -hydrogens (t-BuCOCl, ArCOCl), of
course, can react only by the addition–elimination mechanism.
Often a nucleophilic catalyst such as DMAP (4-dimethylaminopyridine) is
added to accelerate the acylation of alcohols ROH with acyl chlorides. The
catalyst is a better nucleophile than RO, so it reacts more quickly with the
acyl chloride than RO to give an acylpyridinium ion by addition–elimination.
The acylpyridinium ion, though, is more reactive than an acyl chloride, so RO
adds more quickly to it than to the acyl chloride.
Draw mechanisms for the following two acylation reactions.
Substitution by the Elimination–Addition Mechanism
A third mechanism for substitution at C(sp3)–X bonds under basic conditions,
elimination– addition, is occasionally seen. The stereochemical outcome of the
substitution reaction shown in the figure tells us that a direct SN2 substitution is not
occurring
An elimination–addition mechanism can be proposed. MeO is both a good nucleophile

and a good base. It can induce -elimination of HBr to give a compound that is now -
electrophilic at the C atom that was formerly -electrophilic. Another equivalent of MeO
can now undergo conjugate addition to the electrophilic C atom; the addition occurs
from the bottom face for steric reasons.
Base-Promoted Rearrangements
A rearrangement is a reaction in which C–C bonds have both broken and

formed in the course of a reaction involving just a single substrate. It is often
more difficult to draw a reasonable mechanism for a rearrangement than for
any other kind of reaction. When you draw a mechanism for a rearrangement
reaction, it is especially important to determine exactly which bonds are being
broken and which are formed.
Migration from C to C
In the benzylic acid rearrangement of 1,2-diketones, HO adds to one ketone.

The tetrahedral intermediate can collapse by expelling HO, giving back
starting material, or it can expel Ph. The Ph group leaves because there is an
adjacent electrophilic C to which it can migrate to give the product.
Diazomethane (CH2N2) reacts with ketones to insert a CH2 unit between the carbonyl
and -carbon atoms. The diazo compound acts as a nucleophile toward the electrophilic
carbonyl C, and migration of R to the diazo C then occurs with expulsion of the great
leaving group N2
In the Wolff rearrangement, an -diazoketone is heated to give a ketene. The mechanism of

the Wolff rearrangement consists of one step: the carbonyl susstituent migrates to the
diazo C and expels N2. When the reaction is executed in H2O or an alcohol, the ketene
reacts with solvent to give a carboxylic acid or an ester as the ultimate product.
Migration from C to O or N
Ketones react with peracids (RCO3H) to give esters in the Baeyer–Villiger
oxidation. The peracid is usually m-chloroperbenzoic acid (m-CPBA);
peracetic acid and trifluoroperacetic acid are also commonly used.
Peracids have an O–OH group attached to the carbonyl C.
The terminal O of the peracid then adds to the carbonyl C. The O–O bond is very weak,
so migration of R from the carbonyl C to O occurs, displacing the good leaving group
carboxylate. (Proton transfer occurs first to transform the carboxylate into an even
better leaving group.) The product ester is obtained after final loss of H from the
carbonyl O.
Mitsunobu inversion
Mitsunobu inversion
Mechanism of
the Mitsunobu
inversion
Polar Reactions under
Acidic Conditions
In the rearrangement reaction shown next, a 1,2-shift occurs concerted
with loss of a leaving group. Draw a mechanism for this reaction. FeCl3
is a Lewis acid. What by-products might be obtained if the migration
were not concerted with loss of the leaving group?
Draw a reasonable mechanism for the following substitution reaction.
Which O is protonated first?
Elimination of small molecules like water and MeOH is often carried out
under acidic conditions. The reaction is often driven to completion by
azeotropic distillation with benzene or petroleum ether.
Dihydropyran (DHP) reacts with alcohols under acid catalysis to give
tetrahydropyranyl (THP) ethers. The alcohols can be released again by
treating the THP ether with MeOH and catalytic acid. Thus, the THP group
acts as a protecting group for alcohols. Draw mechanisms for the formation
and cleavage of the THP ether.
Electrophilic Aliphatic Substitution
Alkenes undergo electrophilic substitution reactions by the same

addition–fragmentation mechanism as do arenes.
The Sakurai reaction
TiCl4 is a Lewis acid; it coordinates to the carbonyl O, making the

carbonyl and -carbons into cations. The alkene then attacks the -carbon
in such a way as to put the new carbocation on the C adjacent to the C–
Si bond. Fragmentation of the C–Si bond gives a Ti enolate. Aqueous
workup protonates the enolate to give the observed product.
TiCl4 is a Lewis acid; it coordinates to the carbonyl O, making the
carbonyl and -carbons into cations. The alkene then attacks the -carbon
in such a way as to put the new carbocation on the C adjacent to the C–
Si bond. Fragmentation of the C–Si bond gives a Ti enolate. Aqueous
workup protonates the enolate to give the observed product.
Carbon Nucleophiles
The carbocation that is formed upon protonation of a carbonyl compound

canlose H from the -carbon to give an enol. Enols are good nucleophiles.
Thus,under acidic conditions, carbonyl compounds are electrophilic at the
carbonyl C and nucleophilic at the -carbon and on oxygen, just like they are
under basicconditions. Resonance-stabilized carbonyl compounds such as
amides and esters are much less prone to enolize under acidic conditions
than less stable carbonyl compounds such as ketones, aldehydes, and acyl
chlorides; in fact, esters and amides rarely undergo reactions at the -carbon
under acidic conditions.
Halogenuros de alquilo: sustitución nucleofílica y eliminación
Polarización del enlace en el haluro de alquilo
En un haluro de alquilo el átomo de halógeno está enlazado a un

átomo de carbono con hibridación sp3. El halógeno es más
electronegativo que el carbono, y el enlace C-X está polarizado con
una carga parcial positiva en el carbono y una carga parcial negativa
en el halógeno
Cuanto más electronegativo es el átomo de halógeno, mayor es la

polarización entre el enlace carbono-halógeno.
Representaciones con modelos CPK de los haluros de alquilo
Los halógenos más pesados son

más voluminosos, con áreas
superficiales mucho más
grandes
La electronegatividad aumenta
hacia la derecha y hacia arriba
en la tabla periódica.
El tamaño aumenta hacia la derecha y hacia abajo, por lo que el tamaño

de los halógenos incrementa en el orden de F < Cl < Br < I.
Sustitución nucleofílica y reacciones de eliminación.
 Los haluros de alquilo se convierten fácilmente en otros grupos funcionales. El átomo

de halógeno puede salir con su par de electrones de enlace para formar un ión haluro
estable; se dice que un haluro es un buen grupo saliente.
 Cuando otro átomo reemplaza al ión haluro, la reacción es una sustitución.
 Si el ión haluro abandona la molécula junto con otro átomo o ión (con frecuencia el
H+), la reacción es una eliminación
 En una reacción de sustitución nucleofílica, el átomo de haluro se sustituye por un

nucleófilo.
 En una reacción de eliminación, el haluro se "elimina" de la molécula después de la

abstracción de un hidrógeno por medio de una base fuerte. Las reacciones de
eliminación producen alquenos.
Sustitución nucleofílica y reacciones de eliminación.

Sustitución nucleofílica del yodometano con ión hidróxido.
Al yodometano se le denomina sustrato, es decir, el compuesto que es atacado por

el reactivo. El átomo de carbono del yodometano es electrofílico, ya que va unido a
un átomo de yodo electronegativo. La densidad electrónica se representa alejada
del carbono debido a la inducción ejercida por el átomo de halógeno, lo que hace
que el átomo de carbono tenga una cierta carga positiva parcial. La carga negativa
del ión hidróxido es atraída hacia esta carga positiva parcial.
El ión hidróxido es un nucleófilo fuerte porque el átomo de oxígeno tiene

pares de electrones no compartidos y una carga negativa .
El ión hidróxido ataca a la molécula de yodometano desplazando al ión yoduro

y formando un enlace de carbono-oxígeno !!!!
Mecanismo SN2
El mecanismo siguiente muestra el ataque por el nucleófilo (ión
hidróxido), el estado de transición y el desprendimiento del grupo
saliente (ión yoduro).
El ión hidróxido ataca al carbono de la molécula de yodometano. En el estado

de transición, existe un enlace que comienza a formarse entre el carbono y el
oxígeno, y el enlace carbono-yoduro se rompe. La reacción produce un alcohol.
Éste es un mecanismo concertado en el que todo pasa en un único paso.
Diagrama de energía de reacción
El diagrama de energía de reacción

muestra sólo un máximo de energía,
(estado de transición); no hay
intermedios
La formación y ruptura de enlaces

tiene lugar al mismo tiempo.
Solamente hay un estado de
transición formado por las dos
moléculas (el ión hidróxido y el
yodometano). No hay intermedios en
esta reacción
El mecanismo SN2 es un ejemplo de reacción concertada!!!

Reacciones de intercambio de halógenos
El yoduro es un buen nucleófilo y muchos cloruros de alquilo reaccionan con yoduro de

sodio para obtener yoduros de alquilo. Los fluoruros de alquilo son difíciles de sintetizar
directamente, por lo que con frecuencia se obtienen tratando cloruros o bromuros de alquilo
con KF; utilizando un éter y un disolvente aprótico que aumente la nucleofilia normalmente
débil del ión fluoruro.
El haluro de un haluro de alquilo se pueden intercambiar por un haluro diferente. Esta

reacción de intercambio a menudo se utiliza para sintetizar los fluoruros de alquilo. El ión
fluoruro no es un buen nucleófilo, pero su nucleofilicidad se puede aumentar llevando a
cabo la reacción en disolventes apróticos y utilizando un éter corona para "apartar" al
catión del fluoruro.
Estados de transición para ataques del nucleófilo fuerte y débil.

Basicidad y nucleofilicidad
• Podríamos pensar que el metóxido es mucho mejor nucleófilo

porque es mucho más básico. Esto sería un error, ya que la
basicidad y la nucleofilicidad son propiedades diferentes. La
basicidad viene determinada por la constante de equilibrio para
abstraer un protón. La nucleofilicidad se define por la velocidad
de ataque sobre un átomo de carbono electrofílico para dar
sustituciones o adiciones. En ambos casos, el nucleófilo (o base)
forma un nuevo enlace; si el nuevo enlace lo forma un protón,
ha reaccionado como una base, si el nuevo enlace lo forma con
el carbono, ha reaccionado como un nucleófilo.
Basicidad y nucleofilicidad
• Predecir de qué forma puede reaccionar una especie

podría ser difícil. La mayoría de los buenos nucleófilos
(pero no todos) también son bases fuertes, y viceversa.
• Observando el producto formado podemos decidir si

la base conjugada ha actuado como una base o como
un nucleófilo. Si el nuevo enlace es un protón, ha
reaccionado como una base; si el nuevo enlace lo
forma con el carbono, ha reaccionado como un
nucleófilo.
Basicidad y nucleofilia
Nucleófilos comunes
Una base es un nucleófilo más fuerte que su ácido conjugado. En general, cuanto más
electronegativo es el átomo, menos nucleofílico es.
Efecto de la polarizabilidad del nucleófilo en las

reacciones SN2
Comparación de los iones
fluoruro y yoduro como
nucleófilos en las reacciones
SN2. El fluoruro retiene
fuertemente los electrones,
que no pueden formar enlace
C-F hasta que los átomos
están próximos.
El yoduro retiene los electrones externos con menos fuerza, por lo que es más
fácil que se forme un enlace en la reacción !!!
Influencia del disolvente en la nucleofilicidad.
• En un disolvente prótico, los aniones pequeños se solvatan

más fuertemente que los grandes, ya que el disolvente se
aproxima más a un ión pequeño y forma enlaces de hidrógeno
más fuertes.
• Si el ión es más pequeño, como el fluoruro, se requiere más
energía para poder separar el disolvente de este ión que está
fuertemente solvatado que de otro ión más grande, que está
más débilmente solvatado, como el yoduro.
• Los disolventes próticos polares rodearán al nucleófilo y
reducirán su nucleofilia. Cuanto más pequeño sea el átomo,
más solvatado estará y mayor será la reducción de la
reactividad.
Influencia del disolvente en la nucleofilicidad

Grupos salientes comunes
Los sulfonatos, los sulfatos y los fosfatos son buenos grupos salientes porque pueden
deslocalizar la carga negativa sobre los átomos de oxígeno. Las moléculas neutrales son
grupos salientes cuando la reacción se lleva a cabo en medios ácidos.
Influencia estérica del sustrato sobre las reacciones SN2
El ataque SN2 en un haluro de alquilo primario sencillo no está impedido; el ataque en un

haluro de alquilo secundario está impedido, y el ataque en un haluro de alquilo terciario es
imposible.
Para formar un enlace, el nucleófilo tiene que encontrarse dentro de la distancia enlazante
del carbono. Un haluro de alquilo estéricamente impedido evitará que el nucleófilo se
acerque lo suficiente como para reaccionar.
Vista molecular de un ataque SN2

La reacción SN2 tiene lugar a través del ataque del nucleófilo sobre el lóbulo posterior del
OM antienlazante del enlace C-Br. El ataque posterior o dorsal invierte el tetraedro del
átomo de carbono, de forma similar a como el viento invierte un paraguas.
El nucleófilo ataca al carbono desde la parte posterior, opuesto al grupo saliente. Las
reacciones SN2 siempre tendrán como resultado una inversión de la configuración del carbono
que está siendo atacado. Los estereocentros que no están involucrados en la reacción no se
invertirán
Mecanismo de inversión
El estado de transición de la reacción SN2 tiene una geometría

bipiramidal trigonal con el nucleófilo y el grupo saliente a 180º de
cada uno.
Inversión de la configuración
En algunos casos, la inversión de la configuración es muy clara; por ejemplo,

cuando el cis-1-bromo-3-metilciclopentano experimenta un desplazamiento SN2
por el ión hidróxido, la inversión de la configuración da lugar al trans-3-
metilciclopentanol
La inversión de la configuración no sólo puede cambiar la configuración

absoluta, en el caso de los compuestos cíclicos también cambiará la geometría
del cis al trans o viceversa. Las reacciones SN2 son estereoespecíficas
Mecanismo de una reacción SN1
El término unimolecular quiere decir que sólo una molécula
está implicada en el estado de transición del paso limitante
de la velocidad de reacción
El primer paso del mecanismo es la formación del carbocatión. Es paso es lento y es el paso
limitante de la velocidad. El segundo paso es el ataque nucleofílico del nucleófilo en el
carbocatión. Si el nucleófilo fuera una molécula de agua o alcohol, se tendría que perder un
protón con objeto de obtener un producto neutro
Pasos clave del mecanismo SN1
El mecanismo SN1 es un proceso de múltiples pasos. El primer paso es una

ionización lenta para formar un carbocatión. El segundo paso es un ataque rápido
de un nucleófilo al carbocatión. El carbocatión es un electrófilo fuerte y reacciona
rápidamente tanto con un nucleófilo fuerte como con uno débil. En el caso de
ataque de una molécula de alcohol o de agua (como nucleófilos), la pérdida de un
protón da lugar al producto neutro final.
El mecanismo principal está formado por dos pasos: formación de un carbocatión

y ataque nucleofílico. Dependiendo del nucleófilo se puede necesitar un tercer
paso. Si actúa una molécula de alcohol o agua como un nucleófilo, se tendrá que
perder un protón con objeto de obtener un producto neutro.
Diagramas de energía de las reacciones SN1 y SN2
• La reacción SN1 tiene un mecanismo que consta de dos pasos, con dos estados de
transición (‡1 y ‡2) y un carbocatión intermedio. La reacción SN2 sólo tiene un
estado de transición y no tiene intermedios.
• La reacción SN1 tiene un carbocatión intermedio y proporcionará una mezcla de
enantiómeros. La reacción SN2 tendrá como resultado una inversión de la
configuración.
Efecto inductivo e hiperconjugación
El paso limitante de la velocidad de la reacción SN1 es la ionización para formar un
carbocatión, proceso fuertemente endotérmico. El estado de transición para este proceso
endotérmico se asemeja al carbocatión (postulado de Hammond), por lo que las
velocidades de las reacciones SN1 tienen una dependencia de la estabilidad del
carbocatión.
Los cationes alquilo del carbocatión estan estabilizados por la donación de

electrones a través de los enlaces sigma (efecto inductivo), además mediante
el solapamiento de los orbitales llenos (hiperconjugación); por tanto, los
carbocationes altamente sustituidos son más estables.
Estado de transición de la reacción SN1.
En el estado de transición de la ionización SN1, el grupo saliente

forma parte de la carga negativa. El enlace C-X se rompe y un grupo
saliente polarizable todavía puede mantener un solapamiento
sustancial
El estado de transición se asemeja al carbocatión

Disolución de los iones

La reacción SN1 está favorecida en disolventes polares, que estabilizan los iones
intermedios. El paso limitante de la velocidad forma dos iones y la ionización tiene lugar en
el estado de transición.
Los disolventes polares solvatan estos iones debido a la interacción de los

dipolos del disolvente con la carga del ión. Los disolventes próticos como los
alcoholes y el agua son incluso disolventes más efectivos, ya que los aniones
forman enlaces de hidrógeno con el átomo de hidrógeno del grupo -OH y los
cationes, complejos con los electrones no enlazantes del átomo de oxígeno del
grupo -OH.
Racemización en la reacción SN1
Un átomo de carbono asimétrico experimenta racemización cuando

se ioniza y se transforma en un carbocatión aquiral, plano. Un
nucleófilo puede atacar al carbocatión desde cualquier cara, dando
lugar, como producto, a cualquier enantiómero.
Racemización en la reacción SN1
• Los carbocationes tienen orbitales híbridos sp2 y un

orbital vacío p. El nucleófilo puede aproximarse al
plano del carbocatión desde arriba o desde abajo. Si
el nucleófilo ataca por el mismo lado del grupo
saliente, habrá una retención de configuración, pero
si el nucleófilo ataca por el lado opuesto del grupo
saliente la configuración se invertirá. Las reacciones
SN1 forman mezclas de enantiómeros (racemización).
Reacción SN1 sobre un anillo
• En la reacción SN1 del cis-1-bromo-3-

deuteriociclopentano con metanol, el carbocatión
puede ser atacado por cualquier cara. Como el
grupo saliente (bromuro) bloquea parcialmente la
cara frontal cuando se desprende, el ataque
posterior (inversión de configuración) está
ligeramente favorecido.
• El átomo de deuterio se utiliza para distinguir las

caras del ciclopentano.
Reacción SN1 sobre un anillo
En la reacción SN1 del cis-1-bromo-3-deuteriociclopentano con metanol, el carbocatión
puede ser atacado por cualquier cara.
Como el grupo saliente (bromuro) bloquea parcialmente la cara frontal

cuando se desprende, el ataque posterior (inversión de configuración) está
ligeramente favorecido!!!
Transposición de hidruro en una reacción SN1
El producto reordenado, 2-etoxi-2-metilbutano, es el resultado de una transposición

de hidruro: movimiento de un átomo de hidrógeno con su par de electrones de
enlace.
Una transposición de hidruro se representa por el símbolo ~H. En este

caso, la transposición de hidruro convierte el carbocatión secundario
inicialmente formado en un carbocatión terciario más estable. El ataque
del disolvente a este último da lugar al producto de reordenamiento.
Transposición del metilo en una Halogenuros
reacciónde Salquilo: sustitución nucleofílica y eliminación
N1
Cuando se calienta el bromuro de neopentilo con etanol, la reacción sólo da un producto de

sustitución reordenado. Este producto es debido a la transposición del metilo (representada
por el símbolo ~CH3), la migración de un grupo metilo junto con su par de electrones.
La formación de un carbocatión primario no es posible, por lo que la transposición

del metilo y la formación del carbocatión se produce en un único paso para formar
un carbocatión terciario. El ataque por el nucleófilo sobre el carbocatión proporciona
el único producto obtenido de esta reacción.
Reacciones de eliminación: E1 y E2.
• Una eliminación implica la pérdida de dos átomos o grupos del

sustrato, generalmente con la formación de un enlace pi.
Dependiendo de los reactivos y de las condiciones en las que se
encuentren, una eliminación debería ser un proceso de primer
orden (E1) o de segundo orden (E2). Los siguientes ejemplos
ilustran los tipos de eliminación que se tratarán en este capítulo.
• De la misma forma que existe un SN1 y un SN2, existen dos

mecanismos de eliminación, E1 y E2. Qué eliminación se
producirá es una cuestión de las condiciones empleadas durante
la reacción.
Reacciones de eliminación: E1 y E2
Mecanismo E1
En un segundo paso rápido, una base abstrae un protón del átomo de carbono
adyacente al C+. Los electrones que antes formaban el enlace carbono-hidrógeno
ahora forman el enlace pi entre dos átomos de carbono.
Competencia entre las reaccionesHalogenuros
SN1 y E1 de alquilo: sustitución nucleofílica y eliminación
El primer producto (2-metilpropeno) es el resultado de la

deshidrohalogenación, eliminación de hidrógeno y un
átomo de halógeno.
Bajo estas condiciones de
primer orden (ausencia de
base fuerte), se produce la
deshidrohalogenación por
un mecanismo E1.
El producto de sustitución es el resultado del ataque nucleofílico al carbocatión. El

etanol sirve como base para la eliminación y como nucleófilo en la sustitución.
Competencia entre las reacciones SN1 y E1
• El primer paso de los dos mecanismos es el mismo:

formación del intermedio carbocatiónico. El alcohol
puede actuar como una base o como un nucleófilo. Si
actúa como una base, la abstracción de un protón
producirá un alqueno. Si el alcohol actúa como un
nucleófilo, se obtendrá el producto de sustitución.
Modelo orbital para la eliminación E1
En el segundo paso del mecanismo E1, el átomo de carbono adyacente debe
rehibridarse a sp2 cuando la base ataca al protón y los electrones fluyen hacia
el nuevo enlace pi.
Las bases débiles se pueden utilizar en las reacciones E1, puesto que no se
encuentran implicadas en el paso limitante de la velocidad de la reacción.
Diagrama de energía de reacciónHalogenuros
para lasde reacciones
alquilo: sustituciónE1
nucleofílica y eliminación
Diagrama de energía de reacción. El primer paso es una ionización

limitante de la velocidad de reacción. Compare este perfil de energía con
el de las reacciones SN1.
El mecanismo E1 conlleva dos pasos y un intermedio. La formación del carbocatión

intermedio tiene la energía de activación más elevada, por lo que será el paso
limitante de la velocidad de la reacción.
Reordenamiento en el mecanismo E1.
Como en otras reacciones mediadas por un carbocatión intermedio, en la E1 se

pueden producir reordenamientos. Compare la siguiente reacción E1 (con
reordenamiento) con la reacción SN1 del mismo sustrato
Cuando la reacción conlleva intermedios carbocatiónicos, habrá una posibilidad

de reordenamiento, por lo que se obtendrá la mezcla de productos
Las reacciones E2
La eliminación también puede ser bimolecular en presencia de una base fuerte. A manera de
ejemplo, considérese la reacción del bromuro de terc-butilo con ión metóxido en metanol
E2 muestra la misma preferencia de sustrato como E1, 3o > 2o > 1o . E2 necesita una base
fuerte.
Mecanismo E2
La velocidad de esta eliminación es proporcional a las concentraciones tanto del

haluro de alquilo como de la base, dando lugar a una ecuación de velocidad de
segundo orden. Esto es un proceso bimolecular; ya que participan el haluro de
alquilo y la base en el estado de transición, por lo que este mecanismo se expresa
como E2, forma abreviada de eliminación bimolecular.
La reacción tiene lugar en un único paso, por lo que es una reacción

concertada !!!
Mezcla de productos en las reacciones E2
Las reacciones E2 requieren la abstracción de un protón de un átomo de carbono próximo
al carbono que lleva el halógeno. Si hay dos o más posibilidades, se obtienen mezclas de
productos. Los ejemplos siguientes muestran cómo la abstracción de protones diferentes
puede dar lugar a productos diferentes.
En general, el alqueno más sustituido será el producto principal de la reacción !!!

Estado de transición para las Halogenuros
reacciones E2
de alquilo: sustitución nucleofílica y eliminación
Estados de transición concentrados de la reacción E2. Los orbitales del átomo de hidrógeno
y el haluro deben estar alineados para que puedan comenzar a formar un enlace pi en el
estado de transición.
El hidrógeno que se va a abstraer debería ser anti-coplanar al grupo saliente para

minimizar cualquier impedimento estérico entre la base y el grupo saliente. Una
orientación sin-coplanar entre el hidrógeno y el grupo saliente creará una interacción
repulsiva y aumentará la energía del estado de transición !!!
Mitsunobu inversion
Mitsunobu inversion
Mechanism of
the Mitsunobu
inversion

ChapterII AlkylHalogen (CMII)

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Nucleophilic Substitution Reactions

at the Saturated C Atom

Prof. Carlos Mario Meléndez Gómez Qco, Ph.D

Electrostatic potential maps of four halomethanes (CH3X)

General Features of Nucleophilic Substitution:

• Three components are

General Features of Nucleophilic Substitution:

• When a neutral nucleophile is used, the substitution product bears a

• To draw any nucleophilic substitution product:

Stated with some exaggeration, organic chemistry is comparatively

Contain an electron pair that is easily available because it is nonbonding or

Are electron pair acceptors. They therefore contain either a deficiency in

Some uncharged and a few positively charged three-membered heterocycles also

Good and Poor Nucleophiles

This is most noticeable in reactions with sterically demanding alkylating agents or

Nucleophilicity decreases with increasing electronegativity of the attacking atom.

The nucleophilicity of a given nucleophilic center is increased by attached heteroatoms that

Good leaving groups: RHal and

Very basic leaving groups are produced relatively slowly according to

HOW CAN WE EXPLAIN?

in situ activation of the leaving group

Very poor leaving group or not a leaving

The nucleophile abstracts an acidic proton in

Another reaction competing with the substitution of a functional

“If two states, for example, a transition state and an

George S. Hammond, J. Am. Chem. Soc. 1955, 77, 334-338.

“The structure of the transition state for an

• In reactions where the

George S. Hammond, J. Am. Chem. Soc. 1955, 77, 334-338.

SN2 Reactions: Kinetic and Stereochemical Analysis—Substituent

Energy Profile and Rate Law for SN2

Rate laws establish a relationship between…..

Energy Profile and Rate Law for SN2 Reactions:

This reaction is a bimolecular substitutions. And

SN2 Reactions: Kinetic and Stereochemical Analysis—Substituent

The attack by potassium acetate

The reason for the inversion of configuration is that SN2 reactions

SN2 Reactions: Kinetic and Stereochemical Analysis—Substituent

The SN2 reactions take place with a backside attack

The SN2 mechanism is casually also referred to as an “umbrella mechanism.”The

Determination of the mechanism of one-step SN

Experiment 1. The perprotio-sulfonyl anion [H6]-A reacts to

Experiment 2. The sulfonyl anion [D6]-A, (perdeuterated in

INTRAMOLECULAR O INTERMOLECULAR REACTION?

The intramolecular methylation of the substrate, (not

Mechanistic investigations of this type are

In an intramolecular substitution the

• The geometry of the transition state would

• The attacked C atom would be—as shown

• The nucleophile and the leaving group

• The bond angle between these

• The attacking nucleophile approaches the

Substituent Effects on SN2 Reactivity

Electronic effects on SN2 reactivity:

This effect is exerted by unsaturated substituents bound to the attacked C atom!!!

These include substituents, such as alkenyl,

When it is not prevented by the occurrence of strain, the p-electron system

Energy Profile and Rate Law of SN1 Reactions;

Mechanism and energy profile of SN1

• Both take place via the

The carbenium ions react with achiral

Stereochemistry of an SN1 reaction

The solvolysis reaction takes place in a water/ethanol mixture. In the rate-