Significance of the Sy2 rate equation

This equation is useful for two reasons. Firstly, it gives us a test for the S_2 mechanism. Let's
illustrate this with another example: the reaction between NaSMe
(an ionic solid-the nucleo-
phile will be the anion MeS) and Mel to give Me2S, dimethyl sulfide.

SN2?
Mes Me MeS-Me +1

To study the rate equation, first, we keep the concentration of NaSMe constant and in a
rate series of experiments vary that of Mel and see what happens to the rate. Then in another set
of experiments we keep the concentration of Mel constant and vary that of MeSNa and see
what happened to the rate. If the reaction is indeed SN2 we should get a linear relationship in
slope 1 both cases: the graphs in the margin show a typical set of results.
[Mel The first graph tells us that the rate is proportional to [Mel, that is, rate = k,[Mel] and the

rate second graph that it is proportional to [MeSNal, that is, rate =k,|MeSNal. But why are the
slopes different? If you look at the rate equation for the reaction, you will see that we have
siope 2 incorporated a constant concentration of one of the reagents into what appears to be the rate
constant for the reaction. The true rate equation is

NaSMe]
rate = k2[MeSNa] [Mel

If [MeSNa] is constant, the equation becomes

rate = k,[Mel}, where k, = k,[MeSNa]

If [Mell is constant, the equation becomes

rate k,[MeSNa], where k, = k>[Mel]

you examine the grapBhs you will see that the slopes are different because

slope I = k, = k2|MeSNal, but slope 2 = k, = k;l[Mel]

We can
easily measure the true rate constant k, from these slopes because we know the co
stant values for
[MeSNal in the first experiment and for (Mell in the second. The vaiuof k
 MECHANISMS FOR NUCLEOPHILIC SUBSTITUTION
331

from both experiments should be the same. The mechanism for this reaction is indeed S2:
the nucleophile MeS attacks as the leaving group I leaves.
The second reason that the SNz rate equation is useful is that it confirms that the perfor-
mance of an Sy2 reaction depends both on the nucleophile and on the carbon electrophile.
We can therefore make a reaction go better (speed it up or improve its yield) by changing
either. For example, if we want to displace I from Mel using an oxygen nucleophile we might
consider using any of those in the table below.

Oxygen nucleophiles in the Sh2 reaction

Oxygen nucleophile pK, of conjugate acid Rate in Sy2 reaction

HO 15.7 (H,0) fast
RCO about 5 (RCO,H) moderate
H,0 -1.7 (H,0) Slow S e e Chapter 8 for discussion
RSO,0 0 (RSO,OH) slow of pK, values.

The same reasons that made hydroxide ion basic (chiefly that it is unstable as an anion and
therefore reactive) make it a good nucleophile. Basicity can be viewed as nucleophilicity You saw in Chapter 10 that
towards a proton, and nucleophilicity towards carbon must be related. So if we want a fast nucleophilicity towards the car-
reaction, we should use NaOH rather than, say, Na,s0, to provide the nucleophile. Even at the bonyl group is closely related to
same concentration, the rate constant k, with HO as the nucleophile is much greater than the basicity. The same is not quite so
k with SO; as the nucleophile. true for nucleophilic attack on
But that is not our only option. The reactivity and hence the structure of the carbon elec- the saturated carbon atom, as we
shall see, but there is a relation-
trophile matter too. If we want reaction at a methyl group we can't change the carbon skele-
ship nonetheless.
ton, but we can change the leaving group. The table below shows what happens if we use the
various methyl halides in reaction with NaOH. The best choice for a fast reaction (greatest
value of k) will be to use Mel and NaOH to give methanol. We shall discuss
nucleophilicity and leaving
group ability in more detail
SN2
Ho MeL rate k2 [NaOH] [Mel] later.

Halide leaving groups in the Sy2 reaction

Halide X in MeX of conjugate acid HX Rate of reaction with NaOH

pk,
F +3 very slow indeed
moderate
CI -/

Br -9 fast
-10 very fast

The rate of an S,2 reaction depends on:

the nucleophile
the carbon skeleton
the leaving group
solvent.
along with the usual factors of temperature and

Significance of the Sn1 rate equation

bromide with a substitution of t-butyl bromide, we get
it we replace the substitution of n-butyl this reaction is first order: its HO
turns out that, kinetically,
the reaction shown in the margin. It matter how much
tert-BuBr-it doesn't hydroxide Br
rate depends only on the concentration of OH
you add: the rate equation is simply
 SUBSTITUTION AT SATURATED CARBON
NUCLEOPHILIC
332 CHAPTER 15

rate k,[t-BuBr]

S: first the bromie

reaction happens in two steps:
The reason for this is that the bromide leaves,
ion move in to attack to
generate a carbocation, and only
then does the hydroxide attack, forming
the
alcohol.

ion
mechanism: reaction of t-BuBr with hydroxide
the Sy1
Siow OH fast

Br
carbocation
stage 2: reaction of the carbocation OH
formation of the
stage 1:
In the Syl mechanism, the formation of the cation is the rate-determining step. Thic.makes
so it will be formed slowly from
sense: a carbocation
is an unstable species and a
stable a

good ha fast,
molecule. But once formed, being very reactive, all its reactions will
neutral organic
regardless of the nucleophile. The rate of disappearance of t-Bubr is theretore simply the rate sot
is not involved in this step and therefore doess not
the slow first step: the hydroxide nucleophile
r

and hence cannot affect the rate. If

this is not clear to you, think ta af
appear in the rate equation
crowd of people trying to leave a railway station or a football match through some turnstiles, t
doesn't matter how fast they walk, run, or are driven away in taxis afterwards, it is only the rate
of struggling through the turnstiles that determines how fast the station or stadium empties.
Once again, this rate equation is useful because we can determine whether a reaction is S.1
rate or Sn2. We can plot the same graphs as we plotted before. If the reaction is Sy2, the graphs look
like those we have just seen. But if it is Sy1, the graphs in the margin show what happens when
we vary [t-BuBr] at constant [NaOH] and then vary [NaOH] at constant [t-BuBr].
slope The slope of the first graph is simply the first-order rate constant because rate = kj[t-BuBr).

But the slope of the second graph is zero. The rate-determiningstep does not involve NaOH so
[+BuBr)
rate adding more of it does not speed upthe reaction. The reaction shows first-order kinetics (the
slope = 0
rate is proportional to one concentration only) and the mechanism is called Sy1, that is,

Substitution, Nucleophilic, ist order.

same rate at any [NaOH] This observation is very significant. The fact that the nucleophile does not appear in the rae
equation means that not only does its concentration not matter-its reactivity doesn't matter
[NaOH]
either! We are wasting our time opening a tub of NaOH to add to this reaction-water will do
just as wel. All the oxygen nucleophiles in the table above react at the same rate with E-bubr
although they react at very different rates with Mel. Indeed, Syl substitution reactions are

generally best done with weaker, non-basic nucleophiles to avoid the competing eliminatiou
reactions discussed in Chapter 17.

The rate of an S1 reaction depends on:

the carbon skeleton

the leaving group

along with the usual factors of temperature and solvent.

But NOT the
nucleophile.

How can we decide which mechanism

apply to (1 or S2) Wi
given organic compound?
a
So, Substitution reactions
with

at saturated C go via
a one of two alternative mechani
very different
dependence on the nature of the
nucleophile. It's importane
predict which mechanism is inetic

experiments to likely to apply to any reaction, and rather than the

find out, we can
give you a few simple
o* operate

pointers to predict w
S1 or S2?
choice of S1 or Sy2 mechanism
Simple structures and
R R
R
H
Me-X H H R
Structure
methyl primary secondary tertiary
type
S1 reaction? no no moderate excellent
moderate no
S2 reaction? good good
attack
unhindered H
fome attack hindered p
Nu carbocei R
reluctantiy Nuo
readily forms
carbocation
CHAPTER 15 NUCLEOPHILIC SUBSTITUTION AT SATURATED CARBON

transition state
transition state

intermediate

BrO

HO

reactants

H20
Br
products

Br
HO
OH

reaction coordinatetor s N

as an intermediate-a species with a finite (if short) lifetime for

The carbocation is shown
And because we know that the first step, the formation of
reasons we shall describe shortly.
transition state. The
the carbocation, is slow, that be the step with the higher energy
must

transition state, which determines

the overall rate of the reaction, is closely
energy of that the most
intermediate, and it is for this reason that
linked to the stability of the carbocation
otherwise
of an Syl reaction is the stability or
important factor in determining the efficiency
formed intermediate.
of any carbocation that might be as an

and stability of carbocations

Shape
a mathyl cation in Chanter 4 (p. 103), and the tert-butyl
CHAPTER 15 NUCLEOPHILIC SUBSTITUTION AT SATURATED CARBON

Rates of
indicate SN'
solvolysis of alkyl chlorides in 50% aqueous ethanol at 44.6°C

Compound Relative rate Comments

CI 0.07 primary chloride: probably all S2

0.12 secondary chloride: can do

c S1 but not very well

2100 tertiary chloride: very good at Sy

c 1.0 primary but allylic: S 1 all right

91 allylic cation is secondary at one end

130000 allylic cation is tertiary at one end: compare with 2100 for
C simple tertiary
Ph CI 7700 primary but allylic and benzylic
 phile affects the rate of the reaction. Suength and concentration of the P
nucleo-
The transition state for an Sy2 reaction

We introduced the terms Ahather wav to put this would be to say that the
all
nucleophile, the methyl group,
and the leav.
transition state and intermediate ino orouD are
present in the transition state TOr the
reaction. The
in Chapter 12. est energy point on the reaction transition state is the high.
pathway. In the case of an S_2 reaction
it will be the noint
where the new bond from the nucleophile is
partly formed while the old bond to
the leavino
group is not yet completely broken. It will look something like this: ing

starting materials transition state:

highest energy state
on reaction pathway
products

Nu H
Nu-
x
H H
transition state
H
reaction coordinate

The dashed bonds in the

transition state indicate partial bonds (the C-Nu bond is partly
formed and the C-X bond partly broken) and the
charges in brackets indicate substantial
partial charges (about half a minus charge each in this case). Transition states are often shown
Interactive mechanism for in square brackets and marked with the
¢. symbol
simple Sh2 Another way to look at this situation is to
consider the orbitals. The nucleophile must have
lone-pair electrons, which will interact with the o' orbital of the C-X bond.
empty o* orbital
H of C-X bond
new o bond H
Nu
Nu- NuC
filled orbital H H
of nucleophile HAH H
new o bond p orbital old o bond
being formed on C atom being broken
 The benzyl group acts in much the Same way using the t system of the benzene ring for
Jgation with the p orbital in the transition state. Benzyl bromide reacts very well with
ethers.
alkoxides to make benzyl
Among the fastest of all Sy2 reactions are those where the leaving group is adjacent to a car-
ar-
honvl group. With o-bromo carbonyl compounds, two neighbouring carbon atoms are both
nowerfully electrophilic sites. Each has a low-energy empty orbital-r* from C-O and o* from
CBr (this is what makes thenm electrophilic)-and these can combine to form a new LUMo
(4O)lower in energy than either. Nucleophilic attack will occur easily where this new
orbital has its largest coefficient, shown in orange on the diagram.

two low-energy new molecular LUMO

orbitals of empty orbitals
Br Tt of the
o of the Tt + Br
C=O bond
C-Br bond Combine
O-
O:

nucleophilic attack
Occurs easily here

The effect of this interaction between antibonding orbitals is that each group becomes more
the C-Br bond
electrophilic because of the presence of the other-the C=O group makes
more reactive and the Br makes the C=O group more fact, it may well be that the
reactive. In
whereas displacement
nucleophile will attack the carbonyl group, but this will be reversible
of bromide is irreversible.
with amines go well and the
nere are
many examples of this type of reaction. Reactions
aminoketone products are widely used in the synthesis of drugs.
 Quantifying structural effects
on S2 reactions chlorides with Kl in acetane
of of the following alkyl
reaction
e at
Some actual data may help at this point.The rates
analysed. These are
relative rates with resnae
bect
reactivity we have just
S0 °C broadly illustrate the patterns
of Sy2
notice of precise figures
but rather tron
observe thetrends
should not take too much
n-BuCl as a 'typical primary halide'. You of ten.
full from 0.02 to 100,000 is eight powers
large-the range
and notice that the variations are quite

SN2 +

the iodide ion

Relative rates of substitution
reactions of alkyl chlorides with

Alkyl chloride Relative rate Comments

200 least hindered alkyl chloride
Me-CI

0.02 secondary alkyl chloride; slow because of steric hindrance

CI
chloride accelerated by t conjugation in transition
79 allyl
c state

Cl benzyl chloride a bit more reactive than allyl: benzene ring

200
slightly better at t conjugation than isolated double bond

conjugation with oxygen lone pair accelerates reaction (this

Me- C 920 is an S! reaction)

conjugation with carbonyl group much more effective than

CI 100,000 with simple alkene or benzene ring; these a-halo carbony!
Compounds are tiie most reactive of all

Contrasts between S1 and Sy2

You have now met the key features of both
important mechanisms for substitution. 1o
should at this stage in the chapter have a ates
grasp of the kinetics, the nature of the intermeu
and transition states, and the
simple steric and electronic factors that control reactivity Sy
and Sy2 reaction
pathways.
We are now
going to look in more detail at some other aspects where there are sig a r e significant

se
contrasts between the
mechanisms, either because they lead to different outcomes orDe
they lead to a
change in reactivity towards one or the other of the two pathways.
You may hear it said that tert-
alkyl compounds do not react by
the Sy2 mechanism because the
steric hindrance would be too
great. In fact t-alkyl compounds
react so fast by the S 1 mecha
nism that the Sy2 mechanism
wouldn't geta chance evenifit
went as fast as it goes with
methyl compounds. You can see
the figures that show this in the
box on p. 338. Some tertiary alkyl
Compounds will react by slow
Sh2 it, for example, S1 is prev-
ented by an adjacent electron-
withdrawing carbonyl group.
Likewise, primary alkyl halides
that experience steric hindrance
for other reasons react neither
by S1 (because they are pri-
mary) nor Sy2 (because they are
hindered)-a notorious example
is the unreactivity of
neopentyl
halides'

Br
CI

neopentyl tertiary and

chloride adjacent to C-O
no SN1; V. slow SNI
slow S2
due to hindrance reacts slowly
by SN2
Quantifying the rates of Sy1 and Sn2 reactions
holow illustrate the effect of structure
the rates of
on
S1 and
hC the rates (k,) of an S1 reaction: the conversion of alkyl bromides to Si2 reactions. The green curve on the qraph
Cormic acid is a polar solvent and a weak nucleophile:
alkyl formate esters in formic acid
°C at 100
perfect
for an S1 reaction. The red curve shows the rates of
enlarement of Br- by radioactive 8Br in acetone at 25 °C. Acetone solvent and
the good nucleophile Br- favour
The rates (k) are multiplied by 10° to bring both curves onto the same graph. S2.

O
SN1
S2
R-Br
HCOH R-o H
+ HBr 82p,6
92pro. ,L
acetone solvent
82Br-R

Both curves are plotted on a log scale, the log10 of the actual rate being used on the y-axis. The x-axis has no real
it just shows the four points signifi-
cance; corresponding to the four basic structures: MeBr, MeCH,Br, Me,CHBr, and Me CBr.
Rates of Sy1 and Sn2 rates for simple alkyl bromides
+8
SN1 log k
SN2 5 +log

+4

4
MeBr EtBr -PrBr +BuBr
H Me Me Me
H Br H- Br H Br Me Br
H H Me Me
 CHAPTER 15 NUCLEOPHILIC SUBSTITUTION AT SATURATED CARBON
346

The values are also summarized in the table below, which gives the relative rates compared with that o
pared
with that of the
halide, i-PrBr, set at 1.0 for each reaction. secondary
Rates of Sw1 and Sy2 reactions of simple alkyl bromides

Br CH,CH,Br (CH,),CHBr
alkyl bromide type methy! primary secondary (CH,),CBr
tertiary
0.6 1.0 26
10
105k,(M- dm s-') 13,000 170
0.0003
relative K 2x 10-2 4x 10-2 4x 106
relative k 6x1103 30 5x 10-5

Although the reactions were chosen to give as much S1 reaction as p0Ssible in one case and as much S.2 eact 1on
possible in the other, of course you will understand that we cannot prevent the molecules doing the 'wrong reaction!as
The values for the 'S,1 reaction of MeBr and MeCH, Br are actually the low rates of Sy2 displacement ofthe bror
ion by the weak nucleophile HC0,H, while the "Sn2' rate for t-8uBr may be the very small rate of ionization of :u
acetone.

A closer look at electronic effects

We mentioned above that adjacent t systems increase the rate of the Sy2 reaction by stabiliz.
ing the transition state, and likewise increase the rate of Syl reactions by stabilizing the carbo-
cation. The effect on the S^2 reaction applies to both C=C (electron-rich) and C=o
(electron-deficient) t systems, but only C=C t systems increase the rate of Syl reactions.
Adjacent C=O groups in fact significantly decrease the reactivity of alkyl halides towards Sl
reactions because the electron-withdrawing effect of the carbonyl group greatly destabilizes
the carbocation.
Electron-withdrawing or -dornating groups can also tip finely balanced cases from one
mechanism to another. For exanmple, benzylic compounds react well by either Syl or Sy2, and
a change of solvent, as just discussed, might switch them from one mechanism to another.
Alternatively, a benzylic compound that has a well-placed electron-donating group able to
stabilize the cation will also favour the Sh1 mechanism. Thus 4-methoxybenzyl chloride
reacts by Sy1 for this reason: here we show the
diate
methoxy group stabilizing the cation interme
by assisting departure of the chloride.

electron donation favours the SN1 mechanism

NU
Meo
MeO MeO
On the other
hand, an electrorn-withdrawing
group, such as a nitro group, witnin e benzylic
compound will decrease the rate of the
S1 reaction and allow the S2 mechanism to take over.
Rate measurements for
benzylic electron withdrawal
chlorides illustrate the import disfavours the SN1 mechanism
ance of this effect. We can force
them all to react by S1 by using CI
methanol as the solvent (metha-
nol is a poor nucleophile and a OO, no S1
polar solvent: both disfavour electron-withdrawing nitro group
Would destabilize cationic
Sy2). Comparing with the rate of the same
substitution of benzyl chloride benzylic chloride instead reacts by the Sn2 mechanism
intermediate

itself, PhCH,C, 4-methoxybenzyl Nu

chloride reacts with methanol
about 2500 times faster and the SN2
4-nitrobenzyl chloride about
3000 times more
slowly. transifionstate
stabilized by adjacent
electron-deficient system O
 THE LEAVING GROUP IN S1 AND S,2 REACTIONS
347

Summary of structural variations and nucleophilic substitution

We are now in aposition to summarize the structural effects on both mechanisms we
lists have been discussing over the last few
nages. The table the structural types and rates each
reaction qualitatively.
R X R X X
Electrophile Me-X
H R
HH R R
methyl primary secondary tertiary 'neopenty

SN1 mechanism? bad bad poor excellent bad

SN2 mechanism? excellent poor bad bad

Ar RO X
Electrophile x R R
/
allylic benzylic -alkoxy
(adj. lone pair)
-carbonyl -carbony!
and tertiary

Sy1 mechanism? good good good bad bad

okay but S1 better excellent possible

SN2 mechanism? good good

We nave considered the important effects of the basic carbon skeleton and of solvent on the
cours Or SNl and S2 reactions and we shall now look at two final structural factors: the

leaving group first because it plays an

Opnile and the leaving group. We shall tackle the
important T
The T.S. (15a) will thus be at a much higher energy level,
AG* (n 208
lower.
will be larger and the reaction rate correspondingly
The effect of structure on relative reactiVity may be seen particulatlu

clearly when a halogen atom is located at the bridgehead of a bicve

system. Thus the following rates were observed lor solvolysis in 80

aqueous ethanol at
25°:
Br Br Br

(8) (16) (17)

1 106 10-14

All are tertiary halides so that attack by the Sy2 mode would not be
expected to occur on (16) or (17) any more than it did on (8|(cf. p. 82).
Sy2 attack from the back' on the carbon atom carrying Br would in
any case be prevented in (16) and (17) both sterically by their cage.
like structure, and also by the impossibility of forcing their fairly rigid
framework through transition states with the required planar distribu.
tion of bonds to the bridgehead carbon atom (cf. p. 84). Solvolysis via
rate-limiting formation of the ion pair (S, 1), as happens with (8) is

also inhibited because the resultant carbocations from (16) and (17)
would be unable, because of their rigid frameworks, to stabilise
themselves by collapsing to the stable planar state. These carboca-
tion intermediates are thus of very much higher energy level than
usual, and therefore are formed only slowly and with reluctance.
The very greatly reduced solvolysis rate of (17) compared with (16)
refiects the greater rigidity about the bridgehead (cationic) carbon
with a one-carbon (17), than with a two-carbon (16), bridge.
This rigidity is carried even furiher in 1-bromotriptycene (19),

Br
Ph
Ph
Ph

(18) (19) )
1 10-23

in which the bromine atom is found to be virtually inert to nucleophiles.

Despite the formal resemblance in the environment of the bromine
atom in (19) to that in (18), they are found to differ in their rate of
reaction under parallel conditions by a factor of 10723:1! This is
because stabilisation of the carbocation from (18) can occur by
delocalisation of its charge through the T orbital systems of the
three benzene rings; whereas the extremely rigid structure of (19)
will hold the cation's empty orbital (from loss of Br°) all but at right
angles to these 7 orbital systems, thus preventing such delocalisa-
tion.
In nucleophilic substitution the attacking reagent (the nucleophile) brings an electron pair
to the substrate, using this pair to form the new bond, and the leaving group (the nucleofuge)
comes away with an electron pair:

RSX+Y - R-Y +X
This equation says nothing about charges. Y may be neutral or negatively charged; RX may
be neutral or positively charged; so there are four charge types, examples of which are

Type I R-I+OH > R-OH +I

Type II R-I+ NMe3 >R-NMey + I
Type III R-NMe + OH R-OH+NMe3
Type IV R-NMe, + HS R-SH2 + NMe3
In all cases, Y must have an unshared pair of electrons, so that all nucleophiles are Lewis
bases. When Y is the solvent, the reaction is called solvolysis. Nucleophilic substitution at
an aromatic carbon is considered in Chapter 13.
Nucleophilic substitution at an alkyl carbon is said to alkylate the nucleophile. For ex-
ample, the above reaction between RI and NMes is an alkylation of trimethylamine. Sim-
ilarly, nucleophilic substitution at an acyl carbon is an acylation of the nucleophile.

MECHANISMS
Several distinct mechanisms are possible for
al1phatic nucleophilic substitution reactions,
depending on the substrate, nucleophile, leaving group, and reaction conditions. In all of
them, however, the attacking reagent carries the electron pair with it, so that the similarities
aregreater than the differences. Mechan1sms that occur at a saturated carbon atom are
considered first.' By far the most common are the SNI and SN2 mechanisms.
 At this point it is desirable for us to see
just how it was
originally proved that a given
substitution reaction proceeds with inversion of configuration, even before the mechanism
was known. Walden presented a number of examples" in which inversion must have taken
place. Forexample. (+)>malic acid could be converted to (+)-chlorosuccinic acid by thionyl
chloride and to (-)-chlorosuccinic acid by phosphorus pentachloride:

ÇOOH COOH ÇOOH

(+CHCI SOch (+HOH -CHCI
H,COOH CH,COOH CH,COOH
One of these must be an inversion and the other a retention of configuration, but the question
is which is which? The signs of rotation are of no help in answering this question since, as
we have seen (p. 108), rotation need not be related to configuration. Another example
discovered by Walden is

COOH COOH COOH

KOH
Ag,O
(+CHOH H,O
(+)CHCI CHOH
H,COOH CH,COOH CHCOOH

but which?4 It may älso be

Once again, one reaction and only one must be an inversion,
acid and treatment of the
noticed lillustrated by the use of thionyl chloride on (+ )-malic
into its
to convert an optically active compound
product with KOH] that it is possible
enantiomer." takes
attle the matter of exactly where inversion
CHAFI
MECHANISMS 301

C SbF Br
8 9 10
oso,CF,
11

be planar or nearly planar, then it is no surprise that

bridgehead 1-norbornyl carbon atoms,
which cannot assume planarity, do not become the seat of carbocations. As an
example, 8,
boiled 21 hr with 30% KOH in 80% ethanol or 48 hr with aqueous ethanolic silver nitrate,
gave no reaction in either case,20 though analogous open-chain systems reacted readily.
According to this theory, SN1 reactions should be possible with larger rings, since near-
planar carbocations might be expected there. This turns out to be the case. For example,
2.2.2] bicyclic systems undergo SNi reactions much faster than smaller bicyclic systems,
though the reaction is still slower than with open-chain systems,27 Proceeding to a still larger
solution in
system, the bridgehead [3.2.2] cation 9 is actually stable enough to be kept in
Other small bridgehead
SDF-SO,CIF at temperatures below -50°C2 (see also p. 345).
systems that undergo SN1reactions are the [3.1.1] (e.g., 10)" and the cubyl (e.g., 11)
it cannot be planar,
ystems. Ab initio calculations show that the cubyl cation, though
quires less energy to form than the 1-norbornyl cation. can take
substitution reactions that normally involve carbocations
ertain nucleophilic carbocations are actually
bridgeheads32 (though it is not certain that
Cat norbornyl used is of the type that cannot
function as a

ved in all cases) if the leaving grouphas

EOphile (and thus come back) once
it gone, e.g.
lon Pairs in the Sn1 Mechanism

Like the kinetic evidence, the stereochemical evidence for the Snl mechanism is
less clear.
cut than it is for the Sn2 mechanism. If there is a free
carbocation, it is planar (p. 172), and
the nucleophile should attack with equal facility from either side of the
plane, resulting in
complete racemization. Although many first-order substitutions do give complete racemi
zation, many others do not. Typically there is 5 to 20% inversion, though in a few cases, a
small amount of retention of configuration has been found. These and other results have
led to the conclusion that in many SNl reactions at least some of the products are not formed
from free carbocations but rather from ion pairs. According to this concept,56 SNi reactions
proceed in this manner:
R-X=R'X
R'X = R X R +X
12 13 14

where 12 is an intimate, contact, or tight ion pair, 13 a loose, or solvent-separated ion pair,
and 14 the dissociated ions (each surrounded by molecules of solvent).37 The reaction in
which the intimate ion pair recombines to give the original substrate is referred to as internal
return. The reaction products can result from attack by the nucleophile at any stage. In the
intimate ion pair 12, R* does not behave like the free cation of 14. There is probably
significant bonding between R* and X and asymmetry may well be maintained.8 X
solvates" the cation on the side from which it departed, while solvent molecules near 12
can only solvate it from the opposite side. Nucleophilic attack by a
solvent molecule on 12
thus leads to inversion.
a solvent SH (ignoring
A complete picture of the possibilities for solvolysis reactions in
17 and 18) is the following,
the possibilities of elimination or rearrangement-see Chapters
it is unlikely that all these reactions
occur:
though in any particular case
CHAPTER10

MECHANISMS 323
tahilize a
positive charge."C nmr data
show that
enzene ring of 54 cause the ion
to become
less electron-withdrawing groups on the
enhance the classical nature of the ion. 157 classical, while electron-donating groups
h The cyclopropylmethyl system. Apart from the
amount of effort
amo
in the search for C-C 2-norbornyl system, the greatest
nwlmethyl system. It has participation
long been known that
has been devoted to the cyclopro0
with abnormally high rates and that the
products
cyclopropylmethyl
often
substrates solvolyze
include not only unrearranged
cyclopropylmethyl but also
cyclobutyl and homoallylic compounds. An example is
OH
CH,CI EtON-H,0 -CH,OH +
+CH=CHCH,CH,OH
48% ~47% ~5%
Cyclobutyl subsiuätes also solvolyze abnormally rapidly and give similar
more, when the reactions are carried out with labeled products. Further-
substrates, considerable, though not
complete, scrambling is observed. For these reasons it has been suggested that a common
intermediate (some kind of nonclassical intermediate,
e.g., 23, p. 313) is present in these
cases. This common intermediate could then be
obtained by three routes:

bent a route 23
CH-X route

route

CH=CH-CH-CH-X
In recent years much work has been devoted the study of these
to systems, and it is apparent
that matters are not so simple. Though there is much that is still not completely understood,
Some conclusions can be drawn.
i. In solvolysis of simple primary cyclopropylmethyl systems the rate is enhanced because
of
participation by the o bonds of the ring.The ion that forms initially is an unrearranged
cyclopropylmethyl cation6l that is symmetrically stabilized, that is, both the 2,3 and 2,4 o
bonds help stabilize the positive charge. We have already seen (p. 169) that a cyclopropyl
group stabilizes an adjacent positive charge even beter than a phenyl group. One way of
representing the structure of this catión is as shown in 55. Among the evidence that 55 is a

55

Symmetrical ion is that substitution of one or more methyl groups in the 3 and 4 positions
Increases the rate of solvolysis of cyclopropylcarbinyl 3,5-dinitrobenzoates by approximately

157k 10 00 SK92. Do.

CHAPTER 10 MECHANISMS 327

SN' me chavism
rest of the leaving group in the process. The IUPAC designation is Dy +
itself from the
AD The first step is the same as the very first step of the Sn1 mechanism-dissociation
into an intimate ion pair. But in the second step part of the leaving group attacks,
in retention of
necessarily from the front since it is unable to get to the rear. This results
configuration:

Step 1 R-OSOCI R
S=O

Step 2
S=O R-a
R-Cl +
s=OI

of this mechanism yet discovered, since the

Theexample shown is the most important case
halides usually proceeds in this way,
reaction of alcohols with thionyl chloride to give alkyl
ROSOCI (these alkyl chlorosulfites
with the first step in this case being ROH + SOCh
can be isolated).
the addition of pyridine to the mixture of
Evidence for this mechanism is as follows:
dicohol and thionyl chloride results in the formation
of alkyl halide with inverted configu-

reacts with ROSOCI to give ROSOÑC;Hs

On.Inversion results because the pyridine freed in this process nowattacks from the
The Cl
eOre anything further can take place. chloride is second order, which is predicted
ar.The reaction between alcohols and thionyl of ROSOCI is first order.176
by simple heating
S mechanism, but the decomposition Another example is the decomposition of ROCOCI
mechanism is relatively rare.
SNI
(alkyl chloroformates) into RC
and CO2.177

Rearrangements
leophilic Substitution at an Allylic Carbon. Allylic
substitution reactions especially rapidly
(see p. 341),
lylic substrat
ates undergo nucleophilic certain
but we discuss them because they usually accompanied by
are
a

kind Cuss them in separate

a
section
substrates
allylic are
of rearrar known as an allylic rearrangement.78 When
treatoearrangement
two nreducts are usually obtained: the
 The Effect of Substrate Structure

The effect on the reactivity of a change in substrate structure depends on the mechanism.

1. Branching at the a and B carbons. For the SN2 mechanism, branching at either the
a or the B carbon decreases the rate. Tertiary systems seldom24 react by the SN2 mechanism
and neopentyl systems react so slowly as to make such reactions, in general, synthetically
useless.248Table 10.3 shows average relative rates for some alkyl substrates. The reason
for these low rates is almost certainly steric.230 The transition state 1 is more crowued when
larger groups are close to the central carbon.

TABLE 10.3 Average relative SN2 rates for some alkyl substrates249

Relative rate R Relative rate

Methyl 30 Isobutyl 0.03

10-5
Ethyl 1 Neopentyl
0.4 Allyl 40
Propyl
0.4 Benzyl 120
Butyl
Isopropyl 0.025
342 ALIPHATIC NUCLEOPHILIC SUBSTITUTION

TABLE 10.5 Relative rates for

the Sn1 reaction between ROTs
and ethanol at 25°C261

Group Relative rate

Et 0.26
iso-Pr 0.69
CH-CHCH, 8.6
100
PhCH
PhCH 10
1010
Ph,C

hilized bu
 358 ALIPHATIC NUCLEOPHILIC SUBSTITUTION

TABLE 10.11 Transition states

for SN1 reactions of charged and uncharged substrates, and for SN2
reactions of the four charge types366

Charge in the
transition state How an increase
relative to in solvent polarity
Reactants and transition states starting materials affects the rate
TypeI RX + Y R.X
Type II RX+
Dispersed Small decrease
Y+R Increased Large increase
SN2 Type III RX* + Yo R X8+ Decreased Large decrease
Type IV RX* +1 Y*RX+ Dispersed Small decrease
SN1 RX R X- Increased Large increase
RX- R Xo
Dispersed Small decrease

a greater solvent polarity slows the reaction. Even for solvents with about the same
there is a difference between polarity,
protic and aprotic solvents. 367 SN1 reactions of un-ionized
substrates are more rapid in protic solvents, which can form hydrogen bonds with the leaving
group. Examples of protic solvents are water, alcohols, and carboxylic acids, while some
polar aprotic solvents are dimethylformamide (DMF), dimethyl
acetone, sulfur dioxide, and hexamethylphosphoramide [(MezN),PO], sulfoxide,3o acetonitrile,
For SN2
HMPA.
reactions, the effect of the solvent
depends on which of the four charge types
 2. All negatively charged nucleophiles must of course have a positive counterion. If this
ion is Ag (or some other ion that specifically helps in removing the leaving group,
rather than the usual Na* p. 359),
more or K*, then the transition state is more SN1-like. Therefore
the use of Ag promotes attack at the more electronegative atom. For example, alkyi halides
treated with NaCN generally give mostly RCN, but the use of AgCN increases the yield of
isocyanides RNC.431
3. Inmany cases the solvent infiuences the position of attack. The freer the nucleophile