Recative Intermediates

8/6/2019 Recative Intermediates

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Reactive intermediates

A chemical reaction may take place in a single step or it may involve a number of

steps.When a reaction takes place in a single step, it is known as a concerted reaction,

and goes through a transition state. An example is a SN2 reaction

Energy diagram for SN2 reaction

Transition states occur at energy maxima and has only a fleeting existence, and

cannot be isolated.


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On the other hand, in a majority of reactions a number of steps

are involved .

Each of these steps (other than the last step) results in the

formation of one or more relatively unstable chemical species

known as intermediates or reactive intermediates .

(The term reactive intermediate would seem to be a pleonasm

in that, all intermediates are reactive).

The reactive intermediates are usually very short lived and

undergo further reaction, until eventually , in the last step a stable

product is formed.


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SN1 reaction is an example of a two step reaction.

An energy diagram for the SN1

reaction

Reactive intermediate is at aenergy minimum.

The term reactive is a relative term. Normally one understands by the term

reactive intermediates those classes of compounds that are sufficiently unstableunder normal conditions so as to make their isolation extremely difficult.

However, some intermediates are more stable than others and some fairly stable

examples have been prepared.


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There are basically three classes of reactive intermediates some molecules fall

into more than one class:

[1] Charged species Charged species are inherently unstable. This is true evenin the case of inorganic salts such as sodium chloride, which are only stable

because of either interaction with themselves (in crystals) or by interaction with

solvents (solvation).

[2] Electron deficient species These are unstable because they have vacant

orbitals available for bonding purposes, and most environments abound innucleophiles. Bond formation will almost always result in the formation of a more

stable system, and the energy of activation for this process is often very low.

[3] Highly strained species Such species can be simple molecules that comply

with the accepted laws of chemical bonding, but only at considerable cost inenergy terms. The imposition of geometric constraints on bond angles or bond

lengths is one of these.

The most frequently encountered of these reactive species are those in classes [1]

and [2]. Some of these fall into both categories.


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The reactivity of a reactive intermediate is such that their life time in a reaction,

even one that takes place under mild conditions can be so short, and their

steady state concentrations so low, that establishing their existence can prove tobe difficult.

Usually this is done indirectly by trapping techniques.

Sometimes their existence can only be inferred rather than be proved.

With the advances of modern chemical techniques, especially spectroscopy,

establishing their existence and even determining their structures have been

considerably simplified.

Often once evidence for their existence is established and the reasons for theirinstability understood, it may prove possible to predict how the lifetimes of

these species may be increased by the introduction of carefully chosen

substituents, so that they may be isolated and studied further.


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There are four types of reactive intermediates in which carbon has a

valence of only 2 or 3.

1. Carbocations 2. Free radicals

3. Carbanions 4. CarbenesOf the four only carbanions have a complete octet of electrons

around the carbon.

CarbocationsThe most common type of carbocation is a molecule in which one of

the carbon atoms bears a positive charge and has six electrons in its

outter shell (i.e., it is both charged and electron deficient).

tert-butyl cation methyl cation

The simplest carbocation is CH3+.


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For many years this type of carbocations were called carbonium

ions although it was thought this usage was inappropriate because

onium refers to a covalency higher than that of the neutral atom

(e.g., Ammonium ion).

Until recently the use of the term carbonium ion caused no

problems.

However, George Olah and co-workers found evidence for anothertype of intermediate with a +ve charge at a carbon atom with a

formal covalence of the carbon atom 5 rather than 3 (e.g., +CH5).

CH4 + H+ CH5

+ +C

H

H

H

H

H

C

H

H

HH

H

+

Such a species in which carbon atom appears to be bonded to more

than 4 atoms is known as a hypercoordinated carbon compound.


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Carbocations

Trivalent-tricoordinated

Carbenium ions

classical ions CH3+

Hypercoordinated

Carbonium ions

nonclassical ions CH5+

A species such as CR3+ can be formally considered as the addition

product of carbene and a proton (Note: they are not generated this

way). So it should be more properly termed a carbenium ion.

More often, however, the more general term carbocation is used

instead of carbenium ion.

Olah proposed that the term carbonium should be reserved for the

penta-coordinated +ve ions of carbon and the trivalent cation

should be named carbenium ions.


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Structure

Name tert-butyl cation isopropyl cation ethyl cation methyl cation

(type) (a 3 carbocation) (a 2 carbocation) (a 1 carbocation)

Relative

stabilitymost stable

next-to-most

stable

next-to-least

stableleast stable

Methyl carbocations are very unstable as both electron deficiency and the charge

are concentrated or localized at a point. Dispersal of either (preferably both)over other parts of the ion increases the stability.

Many examples are known of rearrangements of primary or secondary

carbocations to tertiary, both in solution and in gas phase.

Alkyl groups are weakly electron donating relative to H and stabilize the

carbocation due to their inductive effect. Thus 30 carbocations are more stable

than 20 carbocations which in turn are more stable than 10 carbocations.

However, hyperconjugation provides a better explanation for the stabilization of

carbocations due to the attached alkyl groups.


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Hyperconjugation

In molecular orbital terms, hyperconjugation is the overlap of the filled sigma orbitals of

the C-H bonds adjacent to the carbocation with the empty "p" orbital on the positively

charged carbon atom. This electronic "spillover" helps delocalize the positive charge onto

more than one atom. The more alkyl substituents, the more sigma bonds for

hyperconjugation.

The sigma bonds one atom removed from the positively charged carbon atom are the

bonds that help to stabilize it. These bonds can rotate into an "eclipsed" conformation

with the empty "p" orbital, and can thus interact with it.

Another way of viewing the effect of hyperconjugation is via Lewis formulas, using "no-

bond resonance".


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Simple alkyl carbocations are not stable in ordinary acid solutions

(e.g., in H2SO4).

However, many of them could be kept indefinitely in mixtures of

fluorosulfuric acid and antimony pentafluoride. FSO3H-SbF5 usually

dissolved in SO2 or SO2ClF are among the strongest acid solutions

known and are called super acids.

The original experiments involved the addition of alkyl fluorides to

SbF5:

RF + SbF5 R+

SbF6-

Subsequently, it was found that the same cation could also begenerated from alcohols in super acid in SO2 at -60

0C, and from

alkenes by the addition of a proton from super acid or HF-SbF5 in

SO2 or SO2ClF at low temperature.


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Even alkanes give carbocations in super acid by the loss of H-

, for

example, isobutane or n-butane in super acid gives the t-butyl

cation.

Me3CH Me3C+ SbF5FSO3

-+ H2

(To date no primary carbocation has survived long enough for

detection).

The most stable of all alkyl cations is the t-butyl cation. Even the

relatively stable t-pentyl and t-hexyl cations fragment at higher

temperatures to produce the t-butyl cation, as do all other alkylcations with four or more carbons so far studied.

FSO3H SbF5


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Carbocations stabilized by resonance effects:

Besides the simple alkyl carbocations, another class ofcarbocations are those that are stabilized by resonance.

This usually occurs in one of two ways:

1) By conjugation with adjacent pi bondingelectrons;

2) By conjugation with lone pairs (non-bonding

electrons) on adjacent heteroatoms.


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1)Carbocations conjugated to pi bonds:

The prototypical members of this class are the allylic andthe benzylic carbocations:


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Despite what might seem to be a greater degree of delocalization in

the "benzyl" carbocation than in the "allyl" system, each of these

ions is about as stable as the other. In fact, they are each about as

stable as an ordinary 2 alkyl carbocation. Further alkyl substitutionon the allylic or benzylic carbon atoms will further increase the

stability.

Triphenylmethyl cation

One of the earliest evidence for the existence of carbocation

intermediates was the observation that triphenylmethyl chloride

(trityl chloride) gave conducting solutions when dissolved in liquid

SO2, a polar non-nucleophilic solvent.

Ph3CCl Ph3C+ + Cl-

Trityl chloride also reacts with Lewis acids (AlCl3, BF3 etc.) to give

coloured salt like solids. Some are available commercially.


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The presence of triphenylmethyl cation in a solid has been

confirmed by X-ray crystallography of triphenylmethyl perchlorate.

C

The central sp2hybridized carbon is planar,but the three phenyl rings are at an angle of

540 to the plane of the trigonal carbon, giving

it a propeller-like shape. NMR studies

indicate it has the same structure in solution.

The triarylmethyl cations are particularly stable because of the

conjugation with aryl groups, which delocalizes the positive charge.

Arylmethyl cations are further stabilized if they have electron-

donationg substituents at ortho- orpara- positions.

The twisting of aromatic rings with respect to each other is

evidently the result of van der Waals repulsions between the ortho-

hydrogens .


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Since carbocations are sp2 -hybridized and planar, they are difficult

or impossible to form at certain bridgehead atoms especially in

small rings for example in [2.2.1] systems.

1-chlorocamphane is resistant to both SN1 (cannot form planar C+)

and SN2 (due to steric reasons) reactions.

Cl

X

However, in larger systems, it becomes easier to form carbocations

at the bridgehead. For example, adamantyl cation has been

synthesized as the SbF6- salt.

Adamantyl cation


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Stabilization due to electron delocalization can be considerably

enhanced if as a result of such delocalization aromatic stability is

gained.

The best known example of this are the cyclopropenyl and tropylium

cations . These ions are aromatic according to Huckels rule, with

cyclopropenium ion having two T electrons and tropylium ion having

sixT

electrons.

Cyclopropenyl cation

tropylium cation


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2) Carbocations conjugated to adjacent lone pairs

Carbocations form very readily on carbon atoms that

have an attached heteroatom ("X"), especially when X =oxygen or nitrogen:

Carbocations stabilized in this way, i.e., by the (partial)

"conversion" of non-bonding electrons into bonding

electrons, are remarkably stable. For example, thecompound MeOCH2

+SbF6- can be isolated as a stable

solid!

R

R

C O Me

R

R

C O Me


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Hydride abstraction from neutral precursors

R 3C H + Lewis-Acid R 3C H =

HH

H

R S

R S

H

H

R 2N

R 2N

H

Hetc.

Lewis-Acid: P h3C BF 4, BF 3, PCl5

Rem oval of an energy-poor anion f rom a neutra l precursor v ia Lewis Acids

R 3C X + LA LAX LA: Ag , AlCl3 , SnCl4 , SbCl5, SbF5 , BF 3 , FeCl3 , ZnCl2, PCl3, PCl5 , POCl3 .. .X: F, Cl, Br, I, OR

Acidic dehydratization of secondary and tert iary alcohols

R 3C O H- H 2O R: Aryl + other charge stabilizing substituents

X: SO 42- , ClO 4

-, FSO 3-, C F3S O 3

-

From neutral precurso rs via heterolytic dissociation (solvolysis) - First step in S N1 or E 1 react ions

solventAbility of X to function as a leaving group:

-N 2+ > - OS O 2R' > -OPO(OR')2 > - I -Br > Cl > OH 2

+ .. .

Carboca t ion G enerat ion

R 3C

R 3C +

+ R 3C +H X X

R 3C X R 3C + X

Addit ion of electrophiles to -systems

R

R

R

R

H R

R

R

R

H R RH R

H

R

H

Methods of formation


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Once formed carbocations follow one of two main pathways to give stable

products:

(1) It combines with a species possessing an electron pair (i.e., a Lewis acid-base

reaction). The nucleophile may be OH-, halide ion, or any other negative ion,

or it may be a neutral species with a lone pair to donate (in which case the

immediate product must bear a positive charge)

(2) The carbocation may lose a proton (or much less often, another positive ion)

from the adjacent atom to give a unsaturated compound.

Carbocations can also adopt two other pathways that lead not to stable products,

but to other carbocations which will undergo further reaction:

(3) Rearrangement an alkyl or an aryl group or a hydrogen migrates with its

electron pair to the positive centre, leaving another positive centre behind.

(For example: 1,2-shifts that result in the rearrangement of primary andsecondary carbocations to more stable tertiary carbocations and Pinacol

Rearrangement )

(4) Addition A carbocation may add to a double bond , generating a positive

charge at a new position.


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The pinacol Rearrangement

H3

H H

H3 H3

H3 H3

H3

H3

H3

Pinacol Pinacolone

H2SO4

This is a general reaction. When I,2-diols are treated with acid they

rearrange to ketones or aldehydes.

R4

O

C

O

C

R R2

R1R4

R

C C

R1O

R2

1,2- iol keto e or al ehy e

H2 4R = H, lkyl or aryl

Mechanism?

Which group migrates depends on a number of factors including

stability of the initially formed carbocation, migratory aptitude of

the migrating group, stereochemistry (especially in cyclic

systems), reaction conditions.


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O O

H2 4

Ph

O O

Ph 3

3

H2 4

Ph

O O

3 Ph

3

H2 4

What are the product of the following rearrangements?

The migratory aptitude of an aryl group is much greater than that of alkyl or

hydrogen. Amongst aryl groups migratory aptitude increases as the aromatic

nucleus is made increasingly electron rich.


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Special Types of Carbocations - The 2-norbornyl cation

In the early 1950s Saul Winstein showed that when chiral 2-exo-

norbonyl brosylate was solvolysed in acetic acid, racemic 2-exo-norbonyl acetate was formed. No endo-product was formed.

OBsOAc AcO

AcOH

+

1

35

6

7

A B

The exo isomer solvolysed 350 times faster than the endo isomer.

On solvolysis the endo isomer also gives a mixture of A and B but

the mixture contains a small excess of A over B.

OBs


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Winstein interpreted the rate enhancement is due to the nighbouring group

participation (anchimeric assistance) by 1,6 W-bond assisting the departure of the

brosylate.

The resulting non-classical carbocation C has an equal probability of being

attacked at two sites carbon 1 or 2. Attack at 1 gives the enantiomer B while

attack at 2 gives the enantiomer A, resulting in a racemic mixture.

Attack at both carbons takes place only from exo-direction.

OBs

OAc

Ac H

16

HOAc

HOAc

- H+

- H+

AcOAcO

A

B

C


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He suggested that the reaction of the endo-isomer was slower

because it was not possible for the 1,6-bond to assist the departure

of the brosylate (i.e., it is not in a favorable position for backside

attack). Consequently solvolysis of the endo isomer takes place at a

normal rate.

D

He further stated that, the solvolysis of the endo

isomer led initially to a classical cation, D, which

then isomerised to the more stable non-classical

one.

Evidence for this interpretation is that the product from the endo

isomer is not entirely racemic, but contains somewhat more of the

enantiomer A, suggesting that when D is formed, some of it reacts

to give a small amount of A, before it transforms to the non-

classical cation C.


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H.C. Brown disagreed with Winsteins interpretation. He believed

instead of a non-classical carbocation the intermediate was made

up of two rapidly equilibrating classical cations.

The initially formed carbocation underwent extremely rapid and

reversible rearrangement to another classical carbocation. The 1,2-shifts which interconvert the two carbocations resembled the

action of a windscreen wiper. This rapid interchange accounted for

the isolation of the racemic product. The rapid movement of 1,2-

shifts also accounted for preferential approach of the nucleophile

from the exo direction.

He attributed the lower rate of reaction of the endo isomer to steric

hindrance to the departure of the brosylate.


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In other words, Brown considered Winsteins non-classical cation to

be the transition state between two classical species and therefore

represented an energy maximum.

Winstein believed it to be an energy minimum, of lower energy

than either of Browns classical species.

No -classical carbocatio

Today Winsteins interpretation is widely accepted due to support

from spectroscopic studies.


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These are also known as bridged carbocations.

In a classical carbocation the positive charge is localized on one

carbon atom or delocalized by resonance involving an unshared pair

of electrons or double or triple bond in the allylic position.

In a non-classical carbocation the positive charge is delocalized by adouble or triple bond that is not in the allylic position or by a single

bond.

Another example:

Non-classical carbocations

H H

HH

7-Norbor e yl catio


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Furthermore, it may be possible to generate a particular non-

classical carbocation in more than one way if the proper substrates

are chosen.

For example the norbornyl cation can be generated via the

following two routes:

X

X

W-route T-route

The argument against the existence of non-classical carbocations isessentially that the canonical forms that contribute to the non-

classsical carbocation are real structures and there is rapid

equilibration among them.


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To explain these observations, it has been proposed that perhaps a

non-classical carbocation intermediate (Z) is involved.

CH X

X

X

Z

The common intermediate could be obtained by three routes

H2C

H2C

CH CH2

H2C

H2C

CH

CH2

H2C

CH2

CH

CH2

Structure of the non-classical carbocation intermediate Z


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Much work has been done on these systems and it is apparent that matters are

not that simple. There is much that is not completely understood.

However, it is generally accepted that the cyclopropylmethyl cation is initially

formed as an intermediate and it is surprisingly stable (more stable than benzyl

cation). The initially formed cyclopropylmethyl cation appears to have a

symmetrical structure with the vacant 2p orbital of the side-chain carbon parallel

to 3,4- C-C bond, a geometry known as the bisect configuration.

This cation is symmetrically stabilized byhyperconjugative interactions with both 2,3 and 2,4

bonds of the ring. The C-C bonds in cyclopropane have

only about 17% s character and this enhances the

hyperconjugative interactions.

Thus the cyclopropylmethyl cation can be represented as shown below.

CH2 CH2CH2

1

2

3 4


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Once formed this classical cation undergoes stereospecific rearrangement to form

two other identical classical cyclopropylmethyl cations.

CH2

H2C

H2C

1

2

3

4

11

22

33

44

Note: These are not

resonance forms

It is this rearrangement that leads to the scrambling of the carbons that isobserved.

This interconversion is believed to proceed via the non-planar cyclobutyl cation.

The cyclopropylmethyl cation has been generated in super-acid solution at lowtemperature, where 13C NMR spectra has shown that it consists of a mixture of

the cyclobutonium ion (Z) and the bisected cyclopropylmethyl cation in

equilibrium. Each form was present in equal amounts, indicating that they are of

approximately equal energy, and both represent energy minima.

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Recative Intermediates

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