Chapter 9 Outline

9.1: Nucleophilic Substitution

o A substitution reaction is one in which one functional group replaces another functional
group. In this chapter, we will discuss nucleophilic substititution. In this reaction, a
nucleophile (electron donor) will replace a leaving group.
o We have already studied one example of this type of reaction. The alkylation of acetylide
anions with alkyl halides. The acetylide anion acts as a nucleophile and replaces the
halide leaving group on the alkyl carbon.
o Anything that can be a lone pair donor, can potentially act as a nucleophile in a
substitution reaction.
The nucleophile is often an anion (OH, CN, etc). In this case, the resulting
substitution product is neutral.

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Neutral nucleophiles (NH3, H2O) can also be involved in substitution reactions. The

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resulting product is a cation, although deprotonation may occur to eventually give a

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neutral product.

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See Table 9.1 for examples of common nucleophiles and their substitution products.
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9.2: Mechanisms of substitution reactions
o There are two basic mechanism for a substitution reaction. In each case, a new bond is
formed with the nucleophile and the bond to the leaving group is broken. The difference
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in the mechanisms is the order in which these occur.

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o SN2 mechanism. Reaction of hydroxide with bromomethane.

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The SN2 name stands for Substitution, Nucleophilic, 2nd order (we'll see what this
means later).
The hydroxide attacks the methyl bromide carbon, which is the electrophile.
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As the hydroxide nucleophile comes in, the C-Br bond starts to break. In the
transition state, the carbon is bonded to both the hydroxide and bromide and is sp2
hybridized.
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The hydroxide must attack from the back side of the C-Br bond. This allows it to add
to the large lobe of the * orbital of the C-Br bond.
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The other substituents on the carbon fold away from the incoming hydroxide.
o SN1 mechanism. Reaction of 2-bromo-2-methylpropane with water
The SN1 name stands for Substitution, Nucleophilic, 1st order (we'll see what this
means later).
The mechanism in this case involves two steps
First, the leaving group leaves to form a carbocation. This is generally the slow
step in the reaction.

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 Second, the nucleophile adds to the carbocation. In this case, water adds to give a
cartion. Loss of a proton gives the neutral alcohol product.
o Key differences between the SN1 and SN2 mechanisms.
SN1: Two step mechanism with a carbocation intermediate.
SN2: Single step without a carbocation intermediate. Nucleophile directly attacks
carbon.
9.3: Experimental evidence for SN1 and SN2 mechanisms.
o Reaction kinetics.
For every reaction there is a specific equation to tell you how fast the reaction will go.
This equation is known as the rate law.
The rate of the reaction depends on a constant (k, the rate constant) and the

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concentrations of the reactants involved up until the rate determining step. If the

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concentration of a reactant in the rate law is increased, the reaction will be faster.

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By determining which reactants are involved in the key reaction step.

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In the reaction of hydroxide with methyl bromide to give methanol, we can make the

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following observations.
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If we double the concentration of hydroxide, the reaction rate doubles. Thus, the
dependence is first order in hydroxide
If we double the concentration of methyl bromide, the reaction rate also doubles.
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The reaction has a first order dependence on methyl bromide.

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Therefore, the reaction involves the reaction of one molecule of hydroxide and
one molecule of methyl bromide in the key step.
Since the reaction depends on two concentration terms, it is called a second order
or bimolecular reaction.
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These observations are consistent with our SN2 mechanism, which has a single
step involving both the alkyl halide and the nucleophile.
In the reaction of water with 2-bromo-2-methylpropane to give 2-methyl-2-propanol,
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we can make the following observations.

If we double the concentration of 2-bromo-2-methylpropane, the reaction rate
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doubles. The reaction has a first order dependence on methyl bromide.

If we double the concentration of water, there is no change in the reaction rate.
Thus, the dependence is zero order in hydroxide
Since the reaction depends on two concentration terms, it is called a first order or
unimolecular reaction.
Since the rate only depends on the alkyl halide, the nucleophile (water) must not
be involved in the rate determining step. Only the alkyl halide is involved.
These observations are consistent with our SN1 mechanism, which has two steps.
The first step, which is rate determining, involves only the alkyl halide. The

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 nucleophile then reacts with the carbocation intermediate after the rate limiting
step.
o Reaction Stereochemistry
SN1 reaction: Here, we are forming a carbocation intermediate. Carbocations are sp2
hybridized, so the carbocation intermediate is achiral. Therefore, we would expect
racemization to occur.
SN2 reaction: In this case, the nucleophile must attack from the back side of the C-X
bond. This results in an inversion of the stereocenter. If we start with a chiral alkyl
halide, the stereochemistry will be inverted (R to S or S to R).
o Electrophile (RX) structure
SN2 Reaction
In the SN2 reaction of chloride with an alkyl bromide, the rate of the reaction

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increases going from a tertiary alkyl bromide (relative rate of <1) to isopropyl
bromide (500), ethyl bromide (40,000), and methyl bromide (2,000,000).

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The reaction occurs much faster with less hindered alkyl bromides

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This trend is seen because the chloride nucleophile must add to the back side of
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the C-Br bond. In methyl, there is little steric hindrance to the approach of the
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chloride. In t-butyl bromide, the tertiary carbon is shielded by the methyl groups,
so the chloride cannot get in to attack.
The SN2 reaction only works well with methyl, 1, or 2 carbons.
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The SN2 reaction also will not work with sp2 or sp C-X bonds. In these cases, the
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back side is blocked by the groups attached to the sp2 or sp carbon.

SN1 Reaction
If we compare other alkyl bromides, we find the following trend: methyl (relative
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rate < 1) ethyl bromide (1), isopropyl bromide (12), tert-butyl bromide (1.2
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million).
The key step is formation of a carbocation. Thus, the rate of an SN1 reaction
depends on the stability of the carbocation intermediate. The more stable the
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intermediate, the faster the reaction.

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Usually tertiary and possibly secondary carbons can do SN1 reactions

Resonance stabilization of the carbocation can also make SN1 reactions possible
even on primary carbons. Allylic and benzylic positions can also do SN1
reactions because the carbocation is resonance stabilized. A primary allylic or
benzylic carbocation is about as stable as a normal secondary carbocation.
Benzylic is the position next to a benzene ring. It is analogous to allylic.
The overall trend for SN1 reactivity is: methyl << 1 << 2 alkyl, 1 allylic, 1
benzylic < 3 alkyl, 2 allylic, 2 benzylic < 3 allylic, 3 benzylic
o Nucleophile

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 SN2 reaction: The nucleophile must be good enough to attack the carbon and displace
the leaving group. For a table of nucleophile strengths, see Table 9.7.
Anionic nucleophile will be more reactive than a neutral one (i.e. OH vs. H2O).
Therefore, SN2 reactions are usually run under basic conditions rather than neutral
or acidic.
Nucleophile strength is roughly comparable to basicity, at least when considering
atoms in the same row.
Hydroxide is more nucleophilic than water, because hydroxide is a stronger
base.
Hydroxide is also a stronger nucleophile than acetate, again because
hydroxide is more basic.
Nucleophilicity increases as you go down a column in the periodic table

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This trend is opposite to the basicity. Basicity decreases moving down the
periodic table because the elements are less electronegative.

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HS is more nucleophilic than HO

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For the halides, the order is I > Br > Cl >> F
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SN1 reaction: The identity of the nucleophile is less important, because it is not
involved in the rate limiting step.
Generally weak nucleophiles (H2O, ROH, RCO2H) give the best results.
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Basic nucleophiles will often promote elimination reactions discussed later.

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o Leaving group: The leaving group is the group displaced by the incoming nucleophile
Leaving group ability increases with increasing stability of the resulting anion (or in
some cases neutral molecule)
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More stable anions are better leaving groups and will give faster substitution
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reactions. The general trend is:

OH, OR, NR2 << F << Cl < Br < I
I, Br, and Cl are the most common leaving groups.
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Oxygen and nitrogen anions are rarely used in substitution reactions as the leaving
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groups.
The trend roughly follows the basicity of the anions. Weaker bases are better
leaving groups.
SN1 and SN2 reactions have the same trends for leaving group ability. Both rely on a
good leaving group.
o Solvent:
Rates of SN2 reactions are strongly dependent upon the solvent. Polar solvents are
needed because the reagents are typically ionic

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 Typical reaction rates in various solvents are: methanol (1) < water (7) <
DMSO (1300) < DMF (2800) < CH3CN (5000)
Polar protic solvents, such as water and alcohols, are poor solvents for SN2
reactions.
Protic solvents are those with OH or NH bonds that can be involved in
hydrogen bonding.
These solvents hydrogen bond to the lone pairs of nucleophile. These inhibit
the nucleophile from reacting because it stabilizes it as well as shielding the
nucleophile from the electrophile.
Polar aprotic solvents (DMSO, DMF, HMPA) are good solvents for SN2
reactions.
They are polar enough to stabilize ions, but do not engage in hydrogen

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bonding with nucleophiles.

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SN1 reaction: Like the SN2 reaction, solvent is critical to the success

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Polar protic solvents were bad in the SN2 reaction because they stabilized the

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reactant nucleophile.
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In the SN1 reaction, polar protic solvents are generally the best solvents because
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they can stabilize the carbocation intermediate as well as the leaving group to help
form the carbocation.
Water is usually the best solvent for SN1 reactions followed by alcohols.
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Polar aprotic solvents are usually not great solvents for SN1 reactions.
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o Skeletal rearrangements
Because the SN1 reaction proceeds through a carbocation intermediate, carbocation
rearrangements (CH 6) can occur.
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Rearrangement will only occur if a more stable carbocation can be formed by

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moving a H or alkyl group from a neighboring carbon.

SN2 reactions do not involve rearrangements because there is not a carbocation
intermediate.
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o Summary of SN2 vs. SN1 reactions

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Methyl: only SN2 possible

Primary R-X: only SN2 possible
Secondary R-X: SN2 favored with strong, non-basic nucleophiles in polar aprotic
solvents. SN1 favored with weak nucleophiles (i.e. H2O or ROH) in protic solvents.
Tertiary R-X: Only SN1 possible.
Stereochemistry: SN1 gives racemization. SN2 gives inversion.
Kinetics: SN1 is first order depending only on RX. SN2 is second order and depends
on both RX and the nucleophile.

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 9.4: Deciding which mechanism will occur
o See examples from the book. The substitution elimination flow chart on the class web
site will also help you here.
o Key things to look for:
Substitution of the alkyl halide
Type of nucleophile
Solvent
9.5: -Elimination
o In addition to substitution, alkyl halides can also undergo an elimination reaction in the
presence of basic nucleophiles leading to an alkene product
This is essentially the reverse of the alkene addition reactions we discussed before

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(i.e. HBr addition to an alkene).

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Treatment of an alkyl halide with hydroxide can lead to removal of the proton next to

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the bromine by hydroxide to give water and eliminate bromide.

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o If we do the reaction with 2-bromobutane, two possible alkenes can be formed: 1-butene
or 2-butene rs e
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2-Butene is formed in 80% yield and 1-butene in 20%. In general, the more
substituted alkene will be formed preferentially
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Why is the more substituted alkene preferred? Recalled that more substituted alkenes
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are thermodynamically more stable, so there is a preference to make the most stable
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alkene.
This preference was originally noted by Zaitsev, so the rule is named for him.
9.6: Mechanisms of -elimination
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o Like substitution, there are several different ways that the elimination can occur. These
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different mechanism include the same steps, but in different orders. We will discuss
three major mechanisms.
E1: The C-X bond breaks first to give a carbocation, which then loses a proton to
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give the alkene.

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E2: The C-H and C-X bonds are broken at the same time in a bimolecular reaction
with the base
9.7: Experimental evidence of E1and E2 mechanisms
o Kinetics:
The 2 in E2 stands for bimolecular as it does in the SN2 mechanism.
The rate of the elimination depends on both the base and the alkyl halide,
therefore both are involved in the rate limiting step.

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 The mechanism occurs in a single step. The base begins to break the C-H bond at
the same time that the C-Br bond is being broken. Thus both the base and alkyl
halide are involved in the key (and only) step.
The E1 reaction is a unimolecular reaction like the SN1 reaction.
The loss of the leaving group to form the carbocation is the slow step. The rate
only depends on the alkyl halide.
o Regioselectivitywhere will the alkene be formed?
As discussed above, the more substituted alkene is preferred
E1 always gives the Zaitsev (more substituted) product.
E2 usually gives the Ziatsev product, unless this is not possible (discussed below).
o Stereochemistry:

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E1 reactions, like SN1 reactions, are not stereoselective

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The intermediate carbocation does require that the C-H bond being eliminated be

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parallel to the empty p-orbital. Since the p-orbital is symmetric there is no
difference between syn or anti

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In addition, the single bonds can freely rotate before the proton is removed,
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allowing a mixture of E and Z alkene stereoisomers to be formed in most cases.
The E2 reaction, like the SN2 reaction, is stereoselelective.
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Because all of the bond breaking and bond forming steps occur at one time
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(concerted process), the stereochemistry of the starting material will affect the
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stereochemistry of the alkene product.

Because the reaction concerted, the C-H bond and the C-Br bond involved most
be parallel or coplanar.
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The bonding orbital of the C-H bond must be parallel to the * C-X
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antibond. These orbitals will form the new bond, so they must be coplanar.
The C-H and C-Br bonds could be parallel in the same direction (syn
coplanar) or in opposite directions (anti coplanar).
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The anti conformation is preferred because it provides the best overlap

between the bonding orbital of the C-H bond must be parallel to the * C-X
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antibond. In addition, this conformation is staggered. The syn coplanar

conformation requires the substituents to be eclipsed.
Therefore, we can look at a alkyl halide and determine whether the product will
be E- or Z-configured
To do this, draw the reactant with the C-H and C-X bonds in a anti coplanar
conformation. The substituents on the same side of the conformation will be
cis to each other in the product.

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 Note that the requirement for an anti-coplanar arrangement for the C-H and C-X
bonds can result in Zaitsev's rule not being followed. This occurs most
commonly in cyclohexyl halides.
For elimination to occur, the C-H and C-X must be anti. In a chair
conformation, this can only occur if they are both axial.
Consider, cis-1-chloro-2-isopropylcyclohexane. When treated with
methoxide, the major product is 1-isopropylcyclohexene. If we draw the chair
conformation, we can see that the favored conformation has the isopropyl
equatorial and the Cl axial. There is an axial H on the isopropyl carbon, so the
more substituted alkene is formed.
If we consider the trans isomer, the favored conformation has both the Cl and
isopropyl group equatorial. No elimination can occur. Only the less stable
ring flipped conformation has the Cl axial. Elimination occurs to give 3-

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isopropylcyclohexene because there the H on the isopropyl carbon is not axial.

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o The E2 and SN2 reactions are favored under similar conditions

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Nucleophile/base:

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It is more important to have a strong base, usually hydroxide or alkoxide, for the
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E2 reaction. The SN2 reaction will be preferred on primary and secondary alkyl
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halides with weakly basic nucleophiles like halides, cyanide, azide, etc. The E2
reaction will be favored by strongly basic nucleophiles, particularly if they are
sterically hindered (i.e. tert-butoxide).
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A hindered base will be a poor nucleophile.

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Alkyl halide:
The E2 reaction is favored over SN2 with tertiary alkyl halides in all cases if a
basic nucleophile is used. Less basic nucleophiles will just give no reaction
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For secondary alkyl halides, the preferred path often depends on the
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base/nucleophile. We saw in chapter 8 that the strongly basic acetylide anion

gave elimination with secondary alkyl halides, but not primary. Generally
strongly basic nucleophiles (acetylides, amides (NR2), and alkoxides) will give
elimination with secondary alkyl halides
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Primary alkyl halides give substitution except when very hindered bases are used,
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such as tert-butoxide
o E1 and SN1 generally occur together. In most cases, SN1 is favored.
9.8: Summary of SN1, SN2, E1 and E2 reactions
o Primary alkyl halides
Only SN2 and E2 reactions are possible. E1 and SN1 will not occur, unless it is allylic
or benzylic. SN2 reactions will happen most commonly
E2 only favored with sterically hindered, strongly basic nucleophiles like tert-
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 o Secondary alkyl halides
All reaction mechanism are possible in this case
SN2 reactions will be favored with good nucleophiles that are not strongly basic
(cyanide, azide, thiolates, halide)
E2 reactions favored when strongly basic nucleophiles used (alkoxides and
acetylides)
SN1 reactions are possible with non-basic nucleophiles in protic solvents. More likely
if the position is also allylic or benzylic
E1 reactions can occur with weakly basic or acidic conditions in a protic solvent.
Again, more likely with allylic or benzylic positions
o Tertiary alkyl halides

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SN2 will not happen

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E2 will occur under basic conditions, even with weakly basic nucleophiles (-CN, N3,

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RO, acetylide, RS, etc)

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SN1 and E1 will occur with weakly basic nucleophiles in protic solvents under neutral

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or acidic conditions. Usually both products are formed.
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9.9: Analysis of reactions
o Review the examples here. Use substitution elimination flowchart to figure out which
reaction is most likely.
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