lecslides-1

8/17/2019 LecSlides-1

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Nucleophile [ Y /Nu ]► electron pair donating reagent

► brings an electron pair to the substrate

► uses this pair to form the new bond

► anions or neutral species but not cations

► all nucleophiles are Lewis bases

Leaving group [the nucleofuge, X]

► comes away with an electron pair

Nucleophilic aliphatic substitution

Electrophiles

► electron pair acceptors

► contain either a deficiency in the valence electron shell of one of the atoms or

► valence-saturated but contain an atom from which a bonding electron pair can be

removed as part of a leaving group

► cations or neutral compounds but not anions


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Nucleophilic substitution at an alkyl carbon is alkylation of the nucleophile.

Nucleophilic substitution at an acyl carbon is an acylation of the nucleophile.

When Y/ Nu is the solvent, the reaction is called solvolysis as in

Different charge types of nucleophilic substitution


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MECHANISMS

limiting mechanisms as defined by Hughes and Ingold

► Direct displacement mechanism (SN 2, substitution-nucleophilic-bimolecular)

ANDN is the IUPAC designation indicates that bond breaking is concurrent with

bond formation

► Ionization mechanism (SN 1, substitution-nucleophilic-unimolecular)

DN+AN or D‡

N+AN indicating former happens first and RDS

The IUPAC system is based on a very simple description of bond changes.

letter A represents formation of a bond (association)

letter D represents breaking of a bond (dissociation)

The basic description of a mechanism consists of these letters, with subscripts

to indicate where the electrons are going.subscript is N if a core atom is forming a bond to a nucleophile (AN) or breaking a

bond to a nucleofuge (DN).

The core atoms in any mechanism are defined as

the two atoms in a multiple bond that undergoes addition,

the two atoms that will be in a multiple bond after elimination

the single atom at which substitution takes place.


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The SN2 Mechanism

► In the TS the central carbon atom has changed hybridization from initial sp3 to sp2 ► One lobe of the p orbital overlaps with the nucleophile and the other with the leaving

group.

► three nonreacting substituents and the central carbon are approximately coplanar

► backside attack involves the maximum amount of overlap throughout the course of

the reaction.

► follow the second order rate expression► inversion of configuration at the reaction centre--Walden inversion

trans-tosylate A

gives exclusively

the cis-cyclohexyl

acetate B

A molecular orbital viewpoint

strongest initial interaction is between the filled orbital on the

nucleophile and the antibonding ∗ orbital of C-X

a front-side approach involve

both a bonding and an

antibonding interaction


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Evidence that the transition state in an SN2 reaction must be linear

Given reaction of a methyl(arenesulfonate) intermolecular or intramolecular??

Crossover Experiment to determine whether reactions take place intra- or intermolecularly

Two substrates differing from each other by a double substituent variation are reacted as a

mixture.


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Bent transition state enforcedLinear transition state possible

Reaction coordinate-intramolecularReaction coordinate-intermolecular

Intramolecular SubstitutionIntermolecular Substitution

Cyclic six-membered transition state is not favored here at all!!!!

In an SN2 reaction the approach path of the nucleophile must be collinear with the bond

between the attacked C atom and the leaving group


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Other evidences for SN2 Mechanism

► Reaction between optically active 2-octyl iodide and radioactive iodide ion

Rate of inversion was found to be identical with the rate of uptake of radioactive *I

If started with the pure R isomer, at first each exchange will produce an S isomer

Then with increasing concentration of S isomer, it will compete for I

At the end a racemic mixture is left.Rate of racemization, was measured which is twice the rate of inversion

► Unsuccessful reaction attempts at bridgeheads under SN 2 conditions

Difficulty in approach from the rear for the nucleophile

1-bromo-8,8-dimethylbicyclo [2.2.2]octane 1 - bromobicyclo- [3.3.1]nonan-9-one


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The effect of solvent /medium on SN 2 reaction

Depends on the charge type of the reaction

Solvent chosen for a given reaction has a strong influence on the course of that reaction.

Protic/aprotic solvents as well as polar /nonpolar solvents can have effects ranging from

solubility to solvent assisted ionization or stabilization of transition states.


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Polar Versus Nonpolar solvents

Only type II SN 2 reactions, where the both the reactants are uncharged, but the

transition state has developed a charge, is aided by polar solvents

In types I and IV, an initial charge is dispersed in the transition state, so the reaction is

hindered by polar solvents.

In type III, initial charges are decreased in the transition state, so that the reaction

is even more hindered by polar solvents.

Energy profile for SN2 reactions


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Some examples of polar aprotic solvents

dimethylformamide

(DMF)

dimethylacetamide

(DMAC)

dimethyl sulfoxide

(DMSO)

hexamethylphosphoramide

(HMPA)

propylene carbonate

acetone, nitromethane,

nitrobenzene, acetonitrile (CH3CN),

benzonitrile

N-methyl-2-pyrrolidone

(NMP)

Protic Versus Aprotic solvents in SN 2 reactions

For reactions of types I and III ,

where the nucleophile is anionic,

TS is more solvated in polar aprotic solvents than in protic ones,

whereas the charged nucleophile

is less solvated in aprotic solvents

Small anions are solvated best in protic solvents

large anions are solvated best in aprotic solvents

Protic solvents have highly developedstructures held together by hydrogen bonds

Aprotic solvents have much looser structures,

hence easier for a large anion to be fitted in

So the rate of attack by small anions is

most greatly increased by the change from

a protic to an aprotic solvent

Relative rates at 25oC for the reaction between MeI

and Cl are

MeOH - 1 (55.5) HCONH2 (protic but a weaker

acid)-12.5 (56.6) HCONHMe - 45.3

HCONMe2

- 1.2 106 (43.8)


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The SN1 Mechanism

substitution, nucleophilic, unimolecular

Ionization is always assisted by solvent

energy necessary to break the bond is largely

recovered by solvation of R+ and of X-

Ionization of t-BuCl to t-Bu+ and Cl

in the gas phase requires

150 kcal mol-1.

In water, this ionization

requires only 20 kcal mol-1

protic solvent pulls the leaving group away

from front side in limiting SN1


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Neutral substrates

Polar solvents increase the rate by stabilization of TS

When the substrate is positively charged, the charge is

more spread out in the TS than in the starting ion

Stabilization of T.S is less than for the more polar

reactant.

Polar solvents decrease the rate


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Relative Rates of Ionization of p-Methoxyneophyl Toluenesulfonate

Trifluoroacetic acid has even greater ionizing

power than any solvent listed in the tableIt has very low nucleophilicity and is an excellent

solvent for SN1 solvolyses

Other good solvents for this purpose are

1,1,1-trifluoroethanol CF3CH2OH,

1,1,1,3,3,3-hexafluoro-2-propanol, (F3C)2CHOH

list of solvents in order of ionizing power


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Aspects of kinetics of SN 1 reactions

Pure first-order kinetics may not be followed in SN 1 always!!

If the first step is reversible the X formed in this step competes with Y for the cation.

In the beginning of the reaction, when the concentration of X is very small,

k-1[X ] is negligible and rate equation reduces to

In the later stages of SN1 solvolyses, [X

-

] becomes large, rate should decrease according to theabove equation .

Solvolysis of diphenylmethyl halides in aqueous acetone follows the above complex kinetics

But tert-butyl halides follow for entire reaction


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► diphenylmethyl cations more stable than tert-butylcations

► tert-butylcations are less selective than diphenylmethy cation► more water available since it is the solvent

► halide ion is a much more powerful nucleophile than water

► less selective tert-butyl ion does not wait for a reactive but relatively rare halide

ion and combines with the solvent

► selective diphenylmethyl cation survives many collisions with solvent molecules

before combining with a reactive halide

diphenylmethyl halides Versus tert-butyl halides … What is different about the kinetics??

the rate for diphenylmethyl solvolysis decreases by the addition of halide ions

but not the rate for tert-butylhalides.

Common ion effect !!!

► retardation of rate by addition of X (leaving ion)

How will the rate be affected if some halide is added to the system??


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► How to tell a pseudo first order SN2 reaction from an an ordinary SN1 reaction?Common ion effect could be of help….in cases where it works.

Addition of a common ion will not markedly affect the rate of an S N2 reaction beyond the

effect caused by other ions.

Salt effect?

► increase in ionic strength of the solution usually increases the rate of an S N1 reaction

For SN1 reaction of charge type II, where both Y and RX are neutral the ionic

strength increases as the reaction proceeds and this increases the rate.

Fact that addition of outside ions increases the rate of most SN1 reactions makes the

common ion effect especially impressive.


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SN1 reactions at bridgehead positions??

Difficulty in assuming the planarity required for the cationic center

[2.2.1] (1-norbornyl) systems like this molecule gave no reaction even afterboiling for 48 hrs with aqueous ethanolic silver nitrate, or for 21 hrs with

30% KOH in 80% ethanol although analogous open-chain systems reacted

readily in these conditions

SN1 reactions should be possible with larger rings, if near-planar carbocations could

be formed

[2.2.2] bicyclic systems undergo SN1 reactions much faster than smaller bicyclic

systems, although the reaction is still slower than with open-chain systems.


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Ion Pairs in the SN1 Mechanism (Saul Winstein)

many first-order substitutions do give complete racemization—a planar carbocation

But many do not, and give 5 –20% inverted products.

intimate,

contact, or

tight ion pair

loose, or

solvent-separated

ion pair

dissociated ions

a diagram of all the

possibilities for solvolysis

reactions in a solvent SH

it is unlikely

that all these reactions

occur

in any particular case

In internal return the intimate ion pair recombines to give the original substrate


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Other evidences for the intervention of ion pairs

Solvolysis of 2-octyl brosylate labeled at the sulfone oxygen with 18O

unreacted brosylate recovered at various stages of solvolysis had considerable 18O scrambling

In an intimate ion pair, the three oxygens become equivalent

Solvolyzing unlabeled substrate in the presence of labeled HOSO2Ar, showed, though

there is some amount of intermolecular exchange(which cannot be explained by

return at intimate ion pair stage) not enough to account for the extent of scrambling

in the original experiment

The step leading to the scrambling of labeling could be happening at another stage ???


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Special salt effect

The addition of LiClO4 or LiBr in the acetolysis of certain tosylates produced an initial

steep rate acceleration and then decreased to the normal linear acceleration (caused by

the ordinary salt effect).

the ClO4 (or Br ) traps the solvent separated ion pair to give

Which is unstable and goes to product.

Hence, the amount of solvent-separated ion pair that would have returned to the starting

material is reduced, and the rate of the overall reaction is increased.

Other evidences for the intervention of ion pairs

Partial retention (20 –50%) of configuration in certain SN1 reactions !!!

Ion pairs have been invoked to explain some of these.

For example, phenolysis of optically active -phenylethyl chloride

Product ether is of net retained configuration.


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Cases that cannot be characterized easily into pure SN1 or SN2

some intermediate mechanism? a mechanistic ‘‘borderline’’ region?

or resulting from simultaneous SN1 and SN2 mechanisms??

i)a) intermediate-mechanism theory- neither ‘‘pure’’ SN1 nor ‘‘pure’’ SN2

A formulation by Sneen- Ion Pair Mechanism- applies to all nucleophilic substitutions

according to which

in SN1 formation of the ion pair (k1) is rate determining

In SN2 destruction of ion pair (k2) is rate determining

Borderline behavior when the rates of formation and destruction of the ion pair are of

the same order of magnitude.

Mixed SN1 and SN2 Mechanisms

b) SN2(intermediate) mechanism- Schleyer

Varying degrees of nucleophilic solvent assistance to ion-pair formation


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II) borderline behavior resulting from simultaneous SN1 and SN2 mechanisms

Hydrolysis of 4-methoxybenzyl chloride in 70% aqueous acetone

MeO CH2Cl MeO CH2OH70% aq.acetone

SN1 path

MeO CH2Cl

70% aq.acetone

azide ionsMeO CH2OH MeO CH2N3+

In presence of azide ions

Rate of ionization increases …….. the salt effect

Rate of hydrolysis decreases ………rate of formation of alcohol product decreases……..

…….. some azide must be formed by SN1 process

Rate of ionization was found to be less than the total rate of reaction

Some azide must also form by an SN2 mechanism


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Hydrolysis of optically active 2-octyl brosylate

in 75% aqueous dioxane, gave inverted 2-

octanol in 77% optical purity.

In presence of sodium azide, 2-octyl azide

and 2-octanol formed, 2-octanol 100%

inverted.

Was 2-octanol produced by two different processes??

an SN2 reaction leading to inverted product,and another process (SN1) with an intermediate that leads to partial racemization or

retention?

Did azide ions scavenge this intermediate, while the SN2 process went on to give inverted 2-

octanol?

Arguments against (SN1) process, simultaneously operating in this reaction….

For 2-octyl brosylate or 2-octyl methanesulfonate SN2 mechanism operates in more polarsolvents water or methanol

Solvolysis of 2-RBs in pure methanol gave methyl 2-octyl ether with 100% inversion of

configuration

Solvolysis of 2-RMs in pure water gave 2-octanol, 100% inversion of configuration

Hence unlikely that any SN1 process could occur in 75% aqueous dioxane.

A nucleophilic substitution reaction that seem to involve a ‘‘borderline’’ mechanism,

but do not


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Solvent

%

Dioxane

[NaN3 ],

M

2-

octanol,%

yield

Optical

Purity of 2-

octanol,%

(inverted)

75 --- 100 77

75 0.0126 73 76

75 0.03 35 100

75 0.06 22 100

50 --- 100 88

50 0.03 75 75

50 0.09 48 96

25 --- 100 95

25 0.03 83 9625 0.04 78 97

water --- --- 100

water 0.1 --- 98


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But the following scheme accomodates the inversion of configuration observed for

the azide product. An intimate ion pair is involved.

In absence of azide some part of reaction go by the dioxane attacking the ion pair,

which then goes on to give the alcohol with retention of configuration.


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A reaction that is reported to be proceeding by a simultaneous, independent SN 1 and SN 2

pathway

plots of the pseudo-first order rate constants, k obs Vs

concentrations of nucleophiles in non-solvolyzing solvent,

acetonitrile at 50oC

Conc. of (Z)-substituted

N,N-dimethyl anilines

Slope of the linear parts of these plots gave the second-

order rate constants, k 2.

k 2 increases with increasing nucleophilicity of Z-

substituted N,N-dimethylanilines as

in the order Z = p-Me > H > p-Br > m-NO2.

Menschutkin reaction of N,N-dimethylanilines

with benzyl bromides less activated than p-

methoxybenzyl bromide proceeds entirely by a second-orderprocess (SN2 reaction)

MeO CH2Br Me2N Z+ MeO CH2

N Z

Me

Me

Br

Menschutkin reaction of benzylic systems with aromatic tertiary amines

The kinetic equation can be seen as the sum of zero and

first-order terms in nucleophile concenteration


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Mechanism corresponding to these observations can be expressed by the scheme given below

Percentage (%) contribution of SN1 process is given by

• SN1 ratio increased for the weaker nucleophile• k 1 values are independent of the

nucleophilicity

• k 2 values, are dependent on nucleophilicity


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Nucleophilicity is the measure of the ability of the nucleophile to make an electron

pair available to the electrophile.

Factors that influence nucleophilicity

solvation energy of the nucleophile

strength of the bond being formed to carbon

electronegativity of the attacking atompolarizability of the attacking atom

steric bulk of the nucleophile

The relative nucleophilicity of a given nucleophile is a combination of effects of substrate,

solvent, leaving group, hence may be different towards different reactants.

No absolute scale of nucleophilicity.

Nucleophiles in SN reactions

Empirical measures of nucleophilicity obtained by


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Swain –Scott equation :

nucleophilic constant (n)

Empirical measures of nucleophilicity obtained by

comparing relative rates of reaction of a standard

reactant with various nucleophiles

methanolysis of methyl iodide as the

standard reaction

Trends in nucleophilicity

When attacking atom is same

nucleophilicity parallels basicity

decreases going across a row in theperiodic table.

determined by electro -

negativity and polarizability

increases going down the periodic table

Decrease in electro-

negativity

greater polarizability

weaker solvation


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Alpha effect (-effect )

Enhancement in nucleophilicity when an atom containing one or more unshared

pairs is adjacent to the attacking atom on the nucleophile.

Reason for -effect could be

• ground state of the nucleophile is destabilized by repulsion between the adjacent pairsof electrons

• the transition state is stabilized by the extra pair of electrons

• adjacent electron pair reduces solvation of the nucleophile

Evidence supporting the third explanation is that there was no alpha effect in the reaction

of HO2 with methyl formate in the gas phase HO2

shows a strong alpha effect in solution.


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Macrocyclic polyethers that specifically solvate cations such as Na

+

and K

+

andenhance solubility and reactivity.

The complexed cation as it is surrounded by the nonpolar crown ether, gains high

solubility in the nonpolar media.

To maintain electroneutrality the anion is also transported into the solvent.

When added to nonpolar solvents, the crown ethers increase the solubility of ionic

materials

In the absence of crown ether, potassium fluoride is insoluble in benzene and

unreactive toward alkyl halides.


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Relative Solvolysis Rates of 1-Phenylethyl Esters and Halides in 80% aqueous ethanol at

75o C

The reactivity of the leaving groups generally parallels their electron-accepting capacity.

Sulfonate esters are very useful reactants in nucleophilic substitution

reactions in synthesis. They have a high level of reactivity and can be prepared from

alcohols

The Effect of the Leaving Group


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the limiting SN 1 and SN 2 mechanisms differ in their sensitivity to the nature of the

leaving group.

SN 1 mechanism should exhibit a greater dependence on leaving-group ability because it

requires cleavage of the bond to the leaving group without assistance by thenucleophile.

Tosylate/Bromide Rate Ratios for Solvolysis of RX in 80% Ethanol


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Relative Reactivity of Leaving Groups in SN2 Substitution ReactionsBimolecular rate constants at 25 oC

Leaving-group effects are diminished in SN 2 reactions, because the nucleophile

assists in bond breaking

In the aprotic dipolar solvent DMF, the leaving-group order is I− >Br− >−O3SCH3 for both

azide and thiocyanate anions.


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Distortion of halide leaving group order in reaction of 4-tert -butylbenzyl (4-t-BuBn) halides

with macrocyclic amine 1


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binding pocket in macrocycle 1 accelerates the reaction and distorts the halide

leaving group order

Increased transition-state stabilization due to hydrogen bonding in the

macrocyclic pocket

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