Nucleophilic Reactions In the 1930’s, Hughes and Ingold …biewerm/12-nucleophilic.pdf · 2016-06-20 · Nucleophilic Reactions! In the 1930’s, Hughes and Ingold experimentally

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 CH3

H3C Br

H3C CH3

CH3Br

CH3OH

H3C CH3

H3C OCH3

In a second step, the carbocation reacts with a nucleophile to generate a substituted product

k1

k2 k3

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 SN1 reactions) 288


A full kinetic expression for the reaction, however, shows other details

H3C CH3

H3C Br

H3C CH3

CH3Br

CH3OH

H3C CH3

H3C OCH3k1

k2 k3

d[R+]/dt = k1[R-Br] – k2[R+][Br-] – k3[R+][CH3OH] = 0

Apply steady-state approximations on reactive carbocation:

[R+] = k1[R-Br]

k2[Br-] + k3[CH3OH]

-d[R-Br]/dt = k1[R-Br]k3[CH3OH] k2[Br-] + k3[CH3OH]

Insert in rate expression for disappearance of SM (or appearance of Product)

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


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

RLG

RRRR

R

<R-C-R = 109.5˚ <R-C-R = 120˚

The transition state has less sterics than the starting material due to

hybridization change

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 SN1 reaction) 290


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

Reaction Coordinate

CH3O H3C Cl

H

HH

H3CO Cl

CH3OCH3 Cl

Bond is forming Bond is breaking

H

HH

Transition state in a SN2 reaction resembles a sp2 hybridized carbon

NUC LG

Unlike a SN1 reaction, however, the NUC and LG are also present

291


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]

*(characteristic of all SN2 reactions)

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

HHNUC LG

SN2 transition state Pentacoordinate carbon,

high sterics

R

RR

SN1 transition state Trigonal (sp2) carbon,

lower sterics

292


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

R-Y Bond Formation

With this diagram, a SN2 mechanism would correspond to a diagonal line with a transition state in the middle of the box

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

Y R

RThese two

mechanisms represent limiting cases, there are

actually an infinite number of

possibilities

293


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 CH3

CH3

H3C CH3

H3C XX

H3C CH3

H3C OCH3

H3C

CH3

CH2

CH3OHSN1

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


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

H3C CH3

H3C Br

H3C CH3

CH3Br

H3C CH3

CH3Br

Ion Pair Separated Ions (limiting SN1 case)

Solvent

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


The addition of salts to nucleophilic reactions also indicated situations beyond the limiting mechanisms, remember the example discussed earlier concerning common ion salts

H3C CH3

H3C Br

H3C CH3

CH3Br

CH3OH

H3C CH3

H3C OCH3k1

k2 k3

When a steady-state approximation was applied:

-d[R-Br]/dt = k1[R-Br]k3[CH3OH] k2[Br-] + k3[CH3OH]

-d[R-Br]/dt = k1k3’

k2[Br-] + k3’

If the solvent is used in excess, a pseudo first order approximation can be applied:

[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


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


-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

[R-Br] (1/[X-] + b)

Common ion rate depression

If k3’ >> k2[X-]:

-d[R-Br]/dt = [R-Br] k1(1 + b[salt])

Non common ion rate enhancement

To know whether a rate will increase or decrease depends upon the k2 versus k3 rate constants 298


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

Time

Cl

Time

Cl

RCl

RCl + LiCl

RCl + LiBr

RCl

RCl + LiCl

Common ion rate, non common ion rate

Both common and non common ion rate

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


OBs

H3CO

Winstein observed some curious results when studying chiral brosylates

BsOAcO

OAc

H3CO

OAc

H3CO BsOH

Ion Pair Separated Ions

Racemic

[LiClO4]

k

kα

kt

Winstein could measure either the loss of optical activity (kα) or the formation of BsOH product (kt)

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”

S. Winstein, G.C. Robinson, J. Am. Chem. Soc., 1958, 80, 169-181

OCH3BsO OCH3

300


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

H3C CH3

H3C BrH3C CH3

CH3Br

H3C CH3

CH3Br

H3C CH3

CH3 Br

Intimate Ion Pair Solvent Separated Ion Pair Free Ions

R X R X R X// R X+

Any of these species could be where the nucleophilic reaction occurs from and each would result in different properties of the reaction

Limiting SN2

SN1, but with high inversion

SN1, but stereochemistry can change

Limiting SN1

301


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 Benzene

CCl4

THF

Acetic acid Phenol

tButanol

Acetone DMF

DMSO HMPA

Water Methanol Ethanol

302


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

N I IN !+

!-

SN2 Transition state

SN1

H3C CH3

H3C Br

H3C CH3

H3CBr

!+

!- Reaction is faster in polar solvents as the transition state will be stabilized

more than the starting material 303


2) Hydrogen Bonding

Important consideration for protic solvents

Occurs when structures have atoms with lone pairs of electrons

OH

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


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

R X Y Y R X!- !-Transition state Effect of increasing polarity

Small decrease with increasing polarity, SM stabilized more than TS

R X Y!+Y R X

!-Large increase with increasing

polarity, TS stabilized more than SM

R X Y Y R X!+!-

Large decrease with increasing polarity, SM stabilized more than TS

R X Y Y R X!+!+

Small decrease with increasing polarity, SM stabilized more than TS

305


SN1

R X

Transition state

R X!+ !-

Effect of increasing polarity

Large increase with increasing polarity, TS is stabilized much more than the SM for this type of reaction

R X R X!+ !+

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


Consider specific reactions:

OHH3C

S CH3

CH3CH3OH H3C

SCH3

krel

CH3OH

H2O

N H3CS CH3

CH3N H3C

SCH3

krel

CH3OH

H2O 307


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" Cl CH3Cl" I

Krel*

Methanol (Protic solvent) 1

Formamide (HCONH2)

(Protic solvent, but weaker acid)

Dimethylformamide (DMF, HCON(CH3)2)

(Aprotic solvent)

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


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 R CN NaX

Alkyl halide has low solubility in aqueous solvents, but high solubility in organic solvents

Sodium cyanide has high solubility in aqueous solvents,

but low solubility in organic solvents

How do we bring these two starting materials together to react if they are not soluble in the

same solvent system?

309


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

RN

R R

RX XQ

When added to a biphasic system, quarternary ammonium salts can cross the phase boundary

R X

NaCN"Aqueous phase

Organic phase

XQ

XQ

CNQ

CNQ R CN

NaX"

When crossing the boundary layer, they bring the counterion with them which allows the SN2 reaction to occur

Alkyl halide and nitrile

cannot react

310


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

18-crown-6

K

O O

O

O

O

O

K

Can be used to solubilize inorganic solids in organic solvents

CH3

CH3

KMnO4

KMnO4

No Reaction

18-crown-6

O

OH311

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

NUC NUC CH3

The reference reaction was determined to be a nucleophile reacting with methyl bromide in water solvent

CH3Br 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

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)

PhS- 9.92 6.5

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" I

Krel*

Methanol (Protic solvent)

Formamide (HCONH2)

(Protic solvent, but weaker acid)

Dimethylformamide (DMF, HCON(CH3)2)

(Aprotic solvent)

* A.J. Parker, Chem. Rev., 1969, 69, 1-32

N3 CH3N3

315

Nucleophilicity

2) Polarizability (when comparing atoms down a column of the periodic table, larger atoms are more polarizable and also more nucleophilic)

O S Se

N P

η (CH3I) 5.75 9.9 10.7

η (CH3I) 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 N<

triethylamine Quinuclidine

NN

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 HO O

NH3 H2N NH2

η (CH3I)

η (CH3I)

6.29 7.8

5.50 6.61

As seen in these examples, the α effect causes a rate enhancement of over an order of magnitude

so the effect can be dramatic

HO NH2

6.60

See a similar effect with hydroxyamine

(used to form oximes) compared to ammonia

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-

Tosylate (OTs)

Triflate (OTf)

H3C SO3

CF3SO3

319

Structural Effects on Substrate

R3R1R2

X

Y!-

!-

SN2: a major concern with the substrate is the sterics at the electrophilic carbon between the nucleophile and the alkyl substituents

R1 R2 R3 krel

H H H

CH3 H H

CH3 CH3 H

CH3 CH3 CH3

C(CH3)3 H H

HH

X

Y!-

!-

CH3

CH3CH3

CH3H3CH3C

X

Y!-

!-A 3˚ alkyl halide has

essentially no rate for a SN2 because another

mechanism would occur (usually E2)

320


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

HH

H

HH

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)

H3C CH3

LG RRH3C

H3C

R=CH3, krel = 1 R=CH3CH2, krel = 1.67

321


Another way to stabilize a carbocation in a SN1 reaction is through resonance

Cl O Cl O Cl

SN1 krel:

322

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Nucleophilic Reactions In the 1930’s, Hughes and Ingold …biewerm/12-nucleophilic.pdf · 2016-06-20 · Nucleophilic Reactions! In the 1930’s, Hughes and Ingold experimentally