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Nucleophilic Reactions
In the 1930’s, Hughes and Ingold experimentally observed two limiting cases for nucleophilic reactions
One type was called a SN1 reaction
(substitution-nucleophilic-unimolecular)
In this reaction, a carbocation is formed in the rate determining step
H3C Br
H3C
CH3
k1
k2
CH3
H3C
CH3
CH3OH
Br
k3
H3C OCH3
H3 C
CH3
In a second step, the carbocation reacts with a nucleophile to generate a substituted product
Usually the rate equation for this reaction is written -d[tButylbromide]/dt = k1[tButylbromide]
Thus the reaction is first order with respect to the starting material [R-X] and not dependent on the nucleophile* *(a characteristic of all S 1 reactions)
N
288 Nucleophilic Reactions
A full kinetic expression for the reaction, however, shows other details
k1
H3C Br
H3C
CH3
k2
CH3
H3C
CH3OH
CH3
Br
k3
H3C OCH3
H3 C
CH3
Apply steady-state approximations on reactive carbocation:
d[R+]/dt = k1[R-Br] – k2[R+][Br-] – k3[R+][CH3OH] = 0
[R+] =
k1[R-Br]
k2[Br-] + k3[CH3OH]
Insert in rate expression for disappearance of SM (or appearance of Product)
-d[R-Br]/dt =
k1[R-Br]k3[CH3OH]
k2[Br-] + k3[CH3OH]
Thus initially in reaction (when [Br-] is zero), the expression simplifies to the traditional first
order kinetics expression, but as reaction proceeds the rate will decrease as [Br-] increases or
if extra [Br-] is added to the reaction (called common ion rate depression)
289 Nucleophilic Reactions
According to Hammond postulate, the structure and energy of the transition state for the rate determining step should resemble the carbocation intermediate
If the carbocation structure can thus be stabilized, then the transition state structure will also
be stabilized and the rate of the reaction will be faster
Rate of an SN1 reaction is thus increased by either stabilizing the carbocation or by destabilizing the starting material
LG
R
R
R
R
R
R
<R-C-R = 109.5˚
The transition state has less sterics
than the starting material due to
hybridization change
<R-C-R = 120˚
If reaction proceeds through a limiting SN1 mechanism, then any stereochemistry at reacting carbon will be lost and product will be racemic*
*(another characteristic of all S 1 reaction)
N
290 Nucleophilic Reactions
A second limiting case for a nucleophilic reaction is called a SN2 mechanism (substitution nucleophilic bimolecular)
In this mechanism, there is no intermediate but rather the nucleophile reacts directly with starting material to generate the product through a transition state structure
Bond is forming
Bond is breaking
H
H3CO
Cl
Transition state in a SN2 reaction
resembles a sp2 hybridized carbon
HH
H
NUC
CH3O
H3C
HH
LG
Unlike a SN1 reaction, however,
the NUC and LG are also present
Cl
CH3OCH3
Reaction Coordinate
Cl
291 Nucleophilic Reactions
The rate of the SN2 reaction is therefore dependent upon both the starting material and the nucleophile*
-d[R-X]/dt = k1[R-X][nucleophile]
Due to the nucleophile reacting in a backside attack to the electrophilic carbon (and 180˚ from the departing leaving group), SN2 reactions always occur with inversion of configuration*
H
NUC
HH
R
LG
SN2 transition state
Pentacoordinate carbon, high sterics
RR
SN1 transition state
Trigonal (sp2) carbon, lower sterics
*(characteristic of all SN2 reactions)
292 Nucleophilic Reactions
Often when nucleophilic reactions are first introduced in organic chemistry classes, it is implied that there are only two possible mechanisms (SN1 or SN2)
Instead consider a diagram for nucleophilic substitution, called a More O’Ferrall-Jencks diagram
Y R
With this diagram, a SN2 mechanism would
correspond to a diagonal
line with a transition state
in the middle of the box
R
These two
mechanisms
represent limiting
cases, there are
actually an infinite
number of
possibilities
a SN1 mechanism would
correspond to a vertical
line first with one
transition state, followed
by a horizontal line with
another transition state
R X
R-Y Bond Formation
293 Nucleophilic Reactions
Consider again an SN1 type reaction with a tButyl Halide, but instead of generating only the substitution product an elimination (E1) can also occur
H3C OCH3
CH3
H3 C X
H3C
CH3OH
CH3
H3C
CH3
H3 C
CH3
SN1
X
CH3
H3 C
CH2
E1
We know from both stereochemical and kinetic analysis that a SN2 reaction is not occurring,
but when the product ratio is determined the nature of X affects the products
X
%E1 (EtOH)
Cl
44.2
Br
36.0
I
32.3
If a free carbocation intermediate was formed, then
the nature of X should not change the rate of SN1/E1
Data indicates that reaction must not be occurring
through the limiting SN1 case
294 Nucleophilic Reactions
Data is interpreted as resulting from an “ion pair” intermediate
Ion pair refers to a state where the C-X bond is broken, but there remains tight binding between the two ions
CH3
H3C Br
H3C
CH3
H3C
Br
CH3
CH3
H3C
Br
CH3
Solvent
Ion Pair
Separated Ions
(limiting SN1 case)
In an ion pair mechanism, the nature of X would thus affect the following reactions as it is involved in the intermediate structure
Ion pair mechanism would also cause a preference for inversion of configuration due to X group blocking approach of nucleophile from the front face (a limiting SN1 case would require a racemic mixture to be formed)
295 Nucleophilic Reactions
The addition of salts to nucleophilic reactions also indicated situations beyond the limiting
mechanisms, remember the example discussed earlier concerning common ion salts
H3C Br
H3C
CH3
k1
k2
CH3
H3C
CH3OH
CH3
Br
k3
H3C OCH3
H3 C
CH3
When a steady-state approximation was applied:
-d[R-Br]/dt =
k1[R-Br]k3[CH3OH]
k2[Br-] + k3[CH3OH]
If the solvent is used in excess, a pseudo first order approximation can be applied:
-d[R-Br]/dt =
k1k3’
k2[Br-] + k3’
[R-Br]
Thus if [Br-] increases, overall rate decreases (common ion rate depression)
On the other hand, if the dielectric constant of a solution increases, the rate of a SN1 reaction
should also increase (due to more polar solvent stabilizing carbocation)
296 Nucleophilic Reactions
This effect of increasing the rate of a SN1 reaction by adding ions to solution is called a “non common ion effect”
The effect on the kinetic expression is that the forward k1 rate will be increased
ksalt = k1(1 + b[salt])
Therefore a common ion salt has two effects operating: 1)  the increase in the reverse rate due to [X-] (common ion rate depression), and 2) the increase in the overall rate due to increasing dielectric constant of the medium
(non common ion effect)
If we replace k1 with ksalt term:
-d[R-Br]/dt =
k3’k1(1 + b[salt])
k2[Br-] + k3’
[R-Br]
297 Nucleophilic Reactions
-d[R-Br]/dt =
k3’k1(1 + b[salt])
k2[Br-] + k3’
[R-Br]
If k2[X-] >> k3’:
-d[R-Br]/dt =
k3’k1
k2
(1/[X-] + b)
[R-Br]
Common ion rate depression
If k3’ >> k2[X-]:
-d[R-Br]/dt =
k1(1 + b[salt])
[R-Br]
Non common ion rate enhancement
To know whether a rate will increase or decrease depends upon the k2 versus k3 rate constants
298 Nucleophilic Reactions
The stability of carbocation generated thus affects the k2 versus k3 ratio
If a very unstable carbocation is generated, then reactive intermediate will react with any nucleophile present, therefore k2 ~ k3 and k2[X-] < k3[SOH] and leads to non common ion rate enhancement
As carbocation becomes more stable, then there is more selectivity between potential nucleophiles, in a solvolysis reaction the negatively charged halide would react faster than the solvent and
thus k2 >> k3 and hence k2[X-] > k3[SOH], leads to common ion rate depression
Cl
RCl + LiBr
RCl
RCl + LiCl
RCl + LiCl
RCl
Common ion  rate, non common ion  rate
Time
Cl
Both common and non
common ion  rate
Time
L.C. Bateman, E.D. Hughes, C.K. Ingold, J. Chem. Soc., 1940, 974-978 M.G. Church, E.D. Hughes, C.K. Ingold, J. Chem. Soc., 1940, 966-970
299 Nucleophilic Reactions
Winstein observed some curious results when studying chiral brosylates
H3CO
H3CO
BsO
OCH3
OCH3
AcO
BsO
OAc
H3CO
OBs
Ion Pair
BsOH
Separated Ions
kα
Winstein could measure either the loss of optical
activity (kα) or the formation of BsOH product (kt)
k
kt
OAc
Racemic
When a nonnucleophilic salt was added (LiClO4) two effects
are noticed, kα is larger than kt and also the increase in kt at
low [LiClO4] but kα not affected
Winstein proposed a new type of ion pair, called solvent separated
ion pair and this type of salt effect called “special salt effect”
[LiClO4]
S. Winstein, G.C. Robinson, J. Am. Chem. Soc., 1958, 80, 169-181
300 Nucleophilic Reactions
Because the rate of product formation increases faster than the rate of loss of optical activity,
Winstein proposed that the nonnucleophilic ion must replace the leaving group, but this
cannot occur with the intimate ion pair nor would it matter if it occurred with the free ions
R X
R
CH3
Limiting
SN2
R
H3C
Br
CH3
// X
CH3
CH3
H3C Br
H3C
X
H3C
R
CH3
Br
CH3
+
X
H3C
Br
CH3
Intimate Ion Pair
Solvent Separated Ion Pair
Free Ions
SN1, but with high inversion
SN1, but stereochemistry
can change
Limiting
SN1
Any of these species could be where the nucleophilic reaction occurs from and each would result in different properties of the reaction
301 Nucleophilic Reactions
In addition to understanding what species the nucleophilic reaction occurs from, the choice of solvent is also critically important to understand the nucleophilic reaction
Solvents are categorized by two broad classes:
1)  Whether the solvent is protic or aprotic (protic solvents contain mobile hydrogens [lower pKa], therefore typically hydrogens attached to O, N)
2) Polarity of solvent (polar solvents have a high dielectic constant ≥ 15)
Solvents can thus be considered with four different classifications:
Nonpolar/aprotic
Nonpolar/protic
Polar/aprotic
Polar/protic
Hexane
Acetic acid
Acetone
Water
Benzene
Phenol
DMF
Methanol
CCl4
tButanol
DMSO
Ethanol
THF
HMPA
302 Nucleophilic Reactions
How can solvent affect reaction rates?
1) Polarity change
The solvent can interact, and stabilize, the starting materials and transition state for the rate determining step depending upon the polarity of the solvent
Remember this is a relative question, does the solvent stabilize the transition state more or less relative to how it stabilizes the starting material
SN2
Transition state
N !+
N
I !-
I
SN1
H3C Br
H3C
CH3
H3 C
Br !-
H3C !+ CH3
Reaction is faster in polar solvents as
the transition state will be stabilized
more than the starting material
303 Nucleophilic Reactions
2) Hydrogen Bonding
Important consideration for protic solvents
Occurs when structures have atoms with lone pairs of electrons
H
O
H
O
O
Protic solvents can thus stabilize negatively charged species more than neutral species due to hydrogen bonding between the protic solvent and the lone pair When running a nucleophilic reaction therefore need to consider whether a protic solvent
would stabilize the starting material or the transition state more through hydrogen bonding
304 Nucleophilic Reactions
One solvent therefore is not ideal for every type of nucleophilic reaction, need to consider the starting material and transition state for the specific reaction
SN2
Transition state
R X
R X
R X
R X
Y
!Y
Y
!+
Y
Y
!Y
Y
!+
Y
R
!X
R
!X
R
!+
X
R
!+
X
Effect of increasing polarity
Small decrease with increasing
polarity, SM stabilized more than TS
Large increase with increasing
polarity, TS stabilized more than SM
Large decrease with increasing
polarity, SM stabilized more than TS
Small decrease with increasing
polarity, SM stabilized more than TS
305 Nucleophilic Reactions
SN1
Transition state
R X
!+
R
!X
R X
!+
R
!+
X
Effect of increasing polarity
Large increase with increasing
polarity, TS is stabilized much more
than the SM for this type of reaction
Small decrease with increasing
polarity, SM is stabilized more than
the TS for this type of reaction
* Even with a given SN2 or SN1 reaction, the rate does not change uniformly with a given
change in solvent polarity, some reactions increase in rate while some decrease, not to
mention that the degree of change is dependent upon the amount of charge in SM and TS
Always need to know what the structures are for the starting materials and transition state to predict which solvent would be best for the reaction
306 Nucleophilic Reactions
Consider specific reactions:
OH
CH3
S
H3 C
CH3
CH3OH
H3C
S
CH3
krel
CH3OH
H2O
N
CH3
S
H3 C
CH3
N
H3C
S
CH3
krel
CH3OH
H2O
307 Nucleophilic Reactions
Also need to consider protic/aprotic solvents, protic solvents solvate negative charge better than positive charge
Therefore negatively charged species are solvated better (thus have lower energy) in protic solvents
CH3I"
CH3Cl"
Cl
I
Krel*
(Protic solvent)
Methanol
(Protic solvent, but weaker acid)
Formamide
(HCONH2)
(Aprotic solvent)
1
Dimethylformamide
(DMF, HCON(CH3)2)
Also small anions are affected more by change in solvation for protic solvents than large anions
* A.J.
Parker, Chem. Rev., 1969, 69, 1-32
308 Nucleophilic Reactions
At the most basic level, however, the purpose of the solvent is to dissolve the reactants and
allow them to collide with enough thermal energy to allow a bimolecular reaction to occur
If the electrophile and the nucleophile do not collide, then the reaction will never occur
Charged molecules, for example, often will have low solubility, especially in nonpolar solvents
Consider a common reaction between an alkyl halide and a nitrile
R X
NaCN
Alkyl halide has
Sodium cyanide has
low solubility in
high solubility in
aqueous solvents,
aqueous solvents,
but high solubility but low solubility in
in organic solvents
organic solvents
R CN
NaX
How do we bring these two starting materials
together to react if they are not soluble in the
same solvent system?
309 Nucleophilic Reactions
Can use principle of phase transfer catalysis (PTC)
A PTC is a substance that can have solubility in two different phases
Typical examples are tetralkylammonium salts
R R
X
N
R
R
Q
X
When added to a biphasic system, quarternary ammonium salts can cross the phase boundary
Organic phase
Q
CN
Aqueous phase
Q
CN
R X
NaX"
R CN
NaCN"
Q
X
Q
X
Alkyl halide
and nitrile
cannot react
When crossing the boundary layer, they bring the counterion with them which allows the SN2 reaction to occur
310 Nucleophilic Reactions
The PTC concept can also be used for solid/liquid interfaces
Crown ethers have been studied due to their ability to coordinate to cations
O
O
O
O
O
O
K
O
K
O
O
O
O
O
18-crown-6
Can be used to solubilize inorganic solids in organic solvents
CH3
KMnO4
No Reaction
O
CH3
KMnO4
18-crown-6
OH
311 Nucleophilicity
Want to quantify how reactive a nucleophile is in a nucleophilic reaction
Empirically it was found that when comparing reactions involving a nucleophilic attack at a
carbon atom a good correlation existed, therefore if a given nucleophile had a strong
nucleophilic rate with a given substrate, it also had a strong rate with a different substrate
A linear free energy relationship was then established to determine the nucleophilicity
(called a Swain-Scott equation)
log k/ko = η • S
η (eta) = nucleophilicity constant S = substrate sensitivity
The reference reaction was determined to be a nucleophile reacting with methyl bromide in water solvent
CH3Br
NUC
NUC CH3
Br
312 Nucleophilicity
Different nucleophilicity values will appear in databases, it is important to recognize how the values were obtained
The original Swain-Scott nucleophilicity constant (η) was determined with a LFER using methyl bromide in water solvent
There are many widely reported η values which were determined with methyl iodide
substrate in methanol solvent (the values will be different with different substrates)
nucleophile
η (CH3Br)a
η (CH3I)b
Cl-
2.70
4.37
Br-
3.53
5.79
I-
5.04
7.42
CH3CO2-
2.72
4.3
PhO-
3.5
5.75
HO-
4.2
6.29
a) P.R. Wells, Chem. Rev., 1963, 63, 171-219
b) R.G. Pearson, H. Sobel, J. Songstad, J. Am. Chem. Soc., 1968, 90, 319-326
313 Nucleophilicity
Some correlations exist when predicting nucleophilicity values
When the charge is on the same atom, nucleophilicity correlates strongly with basicity
nucleophile
η (CH3I)
pKa
CH3CO2-
4.3
4.7
PhO-
5.75
9.9
CH3O-
6.29
15.7
PhS-
9.92
6.5
Best base is also the best nucleophile
Not a good correlation, however, when charge is on different atoms (as seen with acidities, different trends occur depending on placement of charge)
Basicity – measure of affinity of a species for a proton
Nucleophilicity – measure of affinity of a species for CH3I
(when using η (CH3I) values)
314 Nucleophilicity
Factors affecting nucleophilicity:
1) Solvation
Solvated nucleophiles are usually less reactive nucleophiles (if the nucleophile is solvated, it cannot be as reactive toward the electrophilic carbon)
In practice with negatively charged nucleophiles, reactivity increases when using polar/aprotic solvents
CH3I"
N3
CH3N3
I
Krel*
(Protic solvent)
Methanol
(Protic solvent, but weaker acid)
Formamide
(HCONH2)
(Aprotic solvent)
Dimethylformamide
(DMF, HCON(CH3)2)
* A.J.
Parker, Chem. Rev., 1969, 69, 1-32
315 Nucleophilicity
2) Polarizability (when comparing atoms down a column of the periodic table, larger atoms are more polarizable and also more nucleophilic)
S
O
η (CH3I)
η (CH3I)
5.75
Se
9.9
10.7
N
P
6.66
8.72
316 Nucleophilicity
3) Steric Hindrance As the sterics increase around the nucleophilic atom, the reactivity decreases
O
>
O
Due to the steric bulk of the tert-butyl substituent, the t-Butoxide reacts much slower than methoxide in a SN2 reaction (the t-Butoxide would prefer an E2 mechanism with a 1˚, 2˚ or 3˚ alkyl halide)
N
triethylamine
<
N
Quinuclidine
N
N
DABCO
(diazabicyclooctane)
Quinuclidine is more reactive than triethylamine (~50 times) due to less steric hindrance of the alkyl substituents
Quinuclidine is structurally similar to a common base called DABCO
317 Nucleophilicity
4) α effect on nucleophilicity
Another effect on nucleophilicity is called the “α effect”, refers to whenever there is a lone pair of electrons on the atom α to the nucleophilic atom
HO
η (CH3I)
6.29
NH3
η (CH3I)
5.50
HO O
7.8
H2N NH2
6.61
See a similar effect with
hydroxyamine (used to form oximes)
compared to ammonia
HO NH2
6.60
As seen in these examples, the α effect causes a rate enhancement of over an order of magnitude so the effect can be dramatic
318 Leaving Group Ability
In addition to the rate changing with a change in nucleophile, a change in the leaving group can also have a dramatic effect on the rate
The leaving group will gain excess electron density as reaction proceeds, thus the atom needs to be stable with extra negative charge
In addition, however, the bond between the leaving group and the electrophilic carbon is being broken in the rate determining step so the atom needs to be polarizable
Leaving Group
krel
F-
Cl-
Br-
I-
H3C
SO3
CF3SO3
Tosylate (OTs)
Triflate (OTf)
319 Structural Effects on Substrate
SN2: a major concern with the substrate is the sterics at the electrophilic carbon between the nucleophile and the alkyl substituents
X
R1
R2
R3
H
H
H
CH3
H
H
CH3
CH3
H
CH3
CH3
CH3
C(CH3)3
H
H
krel
!-
R2
R1
R3
Y !-
X !-
X !-
A 3˚ alkyl halide has
essentially no rate for a
SN2 because another
mechanism would occur
(usually E2)
H3 C
H3 C
CH3
Y
!-
CH3
CH3
H
H
CH3
Y !320 Structural Effects on Substrate
SN1: a major concern with the substrate is how to stabilize the carbocation formed during the rate determining step
The more alkyl substituents present the more stable is the carbocation due to hyperconjugation effects
H
H
H
H
H
Can only donate electron density from
neighboring C-H bond if there is a
carbon attached, thus 3˚>2˚>1˚ cations
Bulky groups can destabilize the starting material in a SN1 reaction as the intermediate has less sterics at the electrophilic carbon (120˚ bond angle instead of 109.5˚ in SM)
LG R
H3 C
CH3
H3 C
H3 C
R=CH3, krel = 1
R=CH3CH2, krel = 1.67
R
321 Structural Effects on Substrate
Another way to stabilize a carbocation in a SN1 reaction is through resonance
Cl
O
Cl
O
Cl
SN1 krel:
322