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CHAPTER 13 Aromatic Nucleophilic Substitution

It must pointed out that nucleophilic substitutions proceed so slowly at an aromatic carbon that the reactions of Chapter 8 are not feasible for aromatic substrates. There are, however, exceptions to this statement, and it is these exceptions that form the subject of this chapter.

Reactions that are successful at an aromatic substrate are largely of four kinds:1. reactions activated by electron-withdrawing groups ortho and para to the leaving group; 2. reactions catalyzed by very strong bases and proceeding through aryne intermediates; 3. reactions initiated by electron donors; 4. reactions in which the nitrogen of a diazonium salt is replaced by a nucleophile.

MECHANISMSThere are four principal mechanisms for aromatic nucleophilic substitution.1. The SNAr Mechanism 2. The SN1 Mechanism 3. The Benzyne Mechanism 4. The SRN1 Mechanism

It is noted that solvent effects can be important

1. The SNAr Mechanism

Evidence for The SNAr MechanismThere is a great deal of evidence for the mechanism, we shall discuss only some of it. e.g.:

have been isolatedIntermediates of this type are stable salts, called Meisenheimer or Meisenheimer–Jackson salts and many more have been isolated. The structures of several of these intermediates have been proved by NMR and by X-ray crystallography.

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The break of the Ar-X was not the rate-determining stepThe following reaction indicated that Ar-X bond is not broken until after the rate-determining step.

Element effect of leaving groupAn increase in the electronegativity of X causes a decrease in the electron density at the site of attack attack, resulting in a faster attack by a nucleophile. When X=F, the relative rate was 3300 (compared with I=1). The very fact that fluoro is the best leaving group among the halogens in most romatic nucleophilic substitutions is good evidence that the mechanism is different from the SN1.

When X was Cl, Br, I, SOPh, SO2Ph, or p-nitrophenoxy, the rates differed only by a factor of 5. This behavior would not be expected in a reaction in which the Ar–X bond is broken in the rate-determining step. We do not expect the rates to be identical, because the nature of X affects the rate at which Y attacks.

The SN1 MechanismFor aryl halides and sulfonates, even active ones, a unimolecular SN1 mechanism is very rare; it has only been observed for aryl triflates in which both ortho positions contain bulky groups (tert-butyl or SiR3). It is in reactions with diazonium salts that this mechanism is important.

The evidence for the SN1 mechanismIn the following reaction, there are follwing evidence

1. The reaction rate is first order in diazonium salt and independent of the concentration of Y. 2. When high concentrations of halide salts are added, the product is an aryl halide but the rate is independent of the concentration of the added salts. 3. The effects of ring substituents on the rate are consistent with a unimolecular rate-determin

ing cleavage.

4. When reactions were run with substrate deuterated in the ortho position, isotope effects of~1.22 were obtained. It is difficult to account for such high secondary isotope effects in any other way except that an incipient phenyl cation is stabilized by hyperconjugation, which is reduced when hydrogen is replaced by deuterium.

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5. That the first step is reversible cleavage was demonstrated by the observation that when Ar15N≡N was the reaction species, recorvered starting material contained not only Ar15N≡N, but also ArN≡15N. This could arise only If the nitrogen breaks away from the ring and then returns. Additional evidence was obtained by treating PhN≡15N with unlabeled N2 at various pressures. At 300 atm, the recovered product had lost 3% of the labeled nitrogen, indicating that PhN2+ was exchanging with atmospheric N2.

There is kinetic and other evidence that step 1 is more complicated and involves two steps, both reversible:

Intermediate[Ar+N2], which is probably some kind of a tight ion–molecule pair, has been trapped with carbon monoxide.

The Benzyne MechanismThe incoming group does not always take the position acated by the leaving group (most interesting of all). Some aromatic nucleophilic substitutions are clearly ifferent in character from those that occur by the SNAr mechanism (or the SN1 mechanism). These substitutions occur on aryl halides that have no ctivating groups; Bases are required that are stronger than those normally used; 50% 50% e.g.: the reaction of 1-14C-chlorobenzene with potassium amide:

Mechanism

Other evidence1. If the aryl halide contains two ortho substituents, the reaction should not be able to occur. 2. It had been known many years earlier that aromatic nucleophilic substitution occasionally results in substitution at a different position.This is called cine substitution and can be illustrated by the conversion of o-bromoanisole to m-aminoanisole. In this particular case, only the meta isomer is formed.

3. The fact that the order of halide reactivity is Br> I> Cl> F (when the reaction is performed with KNH2 in liquid NH3) shows that the SNAr mechanism is not operating here.

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Fact:Me Me I Me NH2-

The SRN1 MechanismH2N Me Me Me+ H2N Me Me Me

Reaction condition: Strong base Result: 1. cine substitution along with normal substitution 2. The ratio of A and B was not the same 3. If Cl or Br replace I, the ratio of A and B was 1.46:1

ExplainingTo explain the iodo result, it has been proposed that besides the benzyne mechanism,this free-radical mechanism is also operating here:

A 0.63Me

:Me+ H2N

B 1Me Me

Me I Me Me

NH2

-

H2N

Me

Me

A 5.9

:

B 1

This mechanism is called the SRN1 mechanism. An electron donor is required to initiate the reaction. In the case above it was solvated electrons from KNH2 in NH3.

Problem: If benzyne Mechanism take place, the ratio of A and B should be the same because the same aryne intermediate would be formed in both cases.

E

vidence for SRN1 mechanism1. The addition of potassium metal (a good producer of solvated electrons in ammonia) completely suppressed the cine substitution. 2. addition of radical scavengers (which would suppress a free radical mechanism) led to A:B ratios much closer to 1.46:1. 3. In the case above, some 1,2,4-rimethylbenzene was found among the products.

REACTIVITY

The Effect of Substrate StructureIn the discussion of electrophilic aromatic substitution, equal attention was paid to the effect of substrate structure on reactivity (activation or eactivation) and on orientation. The question of orientation was important because in a typical substitution there are 4 or 5 hydrogens that could serve as leaving groups. This type of question is much less important for aromatic nucleophilic substitution, since in most cases, there is only one potential leaving group in a molecule. Attention is largely focused on the reactivity of one molecule compared with another and not on the comparison of the reactivity of different positions within the same molecule.

SNAr MechanismThe substitutions are accelerated by electron-withdrawing groups, especially in positions ortho and para to the leaving group. hindered by electron-attracting groups.

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Benzyne MechanismFactor A: The direction in which the aryne forms

But when a meta group is present, the aryne can form in two different ways:

In such cases, the more acidic hydrogen is removed. Acidity is related to the field effect of Z. An electron-attracting Z favors removal of the ortho hydrogen An electron-donating Z favors removal of the para hydrogen.

Factor B: the aryne, once formed, can be ttacked at two positions. The favored position for nucleophilic attack is the one that leads to the more stable carbanion intermediate, and this in turn also depends on the eld effect of Z. For -I groups, the more stable carbanion is the one in which the negative charge is closer to the substituent. These principles are illustrated by the reaction of the three dichlorobenzenes with alkali-metalamides to give the predicted products shown.

Main product

Main product

Main product

The Effect of the Leaving GroupThe common leaving groups in aliphatic nucleophilic substitution (halide, sulfate, sulfonate, NR3+, etc.) are also common leaving groups in aromatic nucleophilic substitutions. But the groups NO2, OR, OAr, SO2R and SR, which are not generally lost in aliphatic systems, are leaving groups when attached to aromatic rings. Surprisingly, NO2 is a particularly good leaving group. An approximate order of leaving-group ability is F> NO2> OTs> SOPh> Cl, Br, I> N3> NR3+>OAr, OR, SR, NH2. This depends greatly on the nature of the nucleophile.e,.g. C6Cl5OCH3 treated with NH2- gives mostly C6Cl5NH2; The leaving group is methoxy rather than chlorines.

The Effect of the Attacking NucleophileIt is not possible to construct an invariant nucleophilicity order because different substrates and different conditions lead

to different orders of nucleophilicity. But an overall approximate order is NH2> Ph3C> PhNH (aryne mechanism)>ArS> RO-> R2NH> ArO-> OH-> ArNH2> NH3> I-> Br-> Cl->H2O> ROH. As with aliphatic nucleophilic substitution, nucleophilicity is generally dependent on base strength: Nucleophilicity increases as the attacking atom moves down a column of the periodic table. But there are some surprising exceptions, for example, OH-, a stronger base than ArO-, is a poorer nucleophile.

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Examples of Reaction1. Hydroxylation of Aromatic Compounds

2. Alkali Fusion of Sulfonate Salts

3. Replacement by SH or SR Conditions: activating groups are present or exceedingly strenuous conditions are employed. For the conversion of aryl halides to phenols, a good method is the use of aryl Grignard reagents:

4. Replacement by NH2, NHR, or NR2

5. Replacement of a Hydroxy Group by an Amino Group (Bucherer reaction)

6. Homo-Coupling of Aryl Halides: The Ullmann Reaction

7. Aryl–Alkyne Coupling Reactions

8. Conversion of Aryl Substrates to Carboxylic Acids, Their Derivatives,Aldehydes, and Ketones

9. The von Richter Rearrangement

Chapter 14 Addition to Carbon–Carbon Multiple BondsThere are four fundamental ways in addition to a double or triple bond. Three of these are two-step processes: Initial attack by a nucleophile, or an electrophile or a free radical. The second step consists of combination of the resulting intermediate with Respectively, a positive species, a negative species, or a neutral entity. The fourth type of mechanism: Attack at the two carbon atoms of the double or triple bond is simultaneous (concerted).

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Which of the four mechanisms is operating in any given case is determined by: the nature of the substrate, the reagent, the reaction conditions. Some of the reactions in this chapter can take place by all four mechanistic types.

MECHANISMS

1. Electrophilic Addition

In many brominations it is fairly certain that 1, if formed at all, very rapidly cyclizes to a bromonium ion (2):

Slow 1

2 This intermediate is similar to those encountered in the neighboring-group mechanism of nucleophilic substitution. Step 2 is the same as the second step of the SN1 mechanism The attack of w on an intermediate like 2 is an SN2 step. Whether the intermediate is 1 or 2, the mechanism is called AdE2 (electrophilic addition, bimolecular).

There are three possibilities for Y-W addition to: 1. Both Y and W may enter from the same side of the the molecule plane, in which case the addition is stereospecific and syn; 2. Y and W may enter from opposite sides for stereospecific anti addition; 3. The reaction may be nonstereospecific. In order to determine which of these possibilities is occurring in a given reaction, the following type of experiment is often done: Y-W is added to the cis and trans isomers of an alkene of the form ABC=CBA.

Stereochemistry for the additon of molecule ABC=CBAA B A B

A B

B A

Cis isomer

trans isomer

We may use the cis

alkene as an example.

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If the addition is syn, the product will be the erythro dl pair, because each carbon has a 50% chance of being attacked by Y:

If the addition is anti, the threo dl pair will be formed:

Of course, the trans isomer will give the opposite results: the threo pair if the addition is syn and the erythro pair if it is anti. The threo and erythro isomers have different physical properties. In the special case, where Y=W (as in the addition of Br2), the ''erythro pair'' is a meso compound. In addition to triple-bond compounds of the type AC≡CA, syn addition results in a cis alkene and anti addition in a trans alkene.

Cyclic intermediateIt is easily seen that in reactions involving cyclic intermediates like 2, addition must be anti, since the second step is an SN2 step and must occur from the back side. Evidence: Treatment of maleic acid with bromine gave the dl pair of 2,3-dibromosuccinic acid, while fumaric acid (the trans isomer) gave the meso compound. If the two bromines approach the double bond from opposite sides, it is very unlikely that they could come from the same bromine molecule. Treatment of ethylene with bromine in the presence of chloride ions gives some 1-chloro-2-bromoethane along with the dibromoethane.

Open Carbocation IntermediatesIt is not so easy to predict the stereochemistry for reactions involving 1.

When the electrophile is a proton, a cyclic intermediate is not possible and the intermediate 1 is formed

Evidence: 1. The reaction is general-acid, not specific-acid-catalyzed, implying that proton transfer from the acid to the double bond is a rate determining step. 2. The existence of open carbocation intermediates is supported by the contrast in the pattern of alkyl substituent effects in brominations, where cyclic intermediates are involved. In bromination,substitution of alkyl groups on H2C=CH2 causes a cumulative rate acceleration until all four hydrogens have been replaced by alkyl groups, because each group helps to stabilize the positive charge. In addition of HX, the effect is not cumulative. Replacement of the two hydrogens on one carbon causes great rate increases but additional substitution on the other carbon produces little or no acceleration.

If 1 has a relatively long life, the addition should be nonstereospecific, since there will be free rotation about the single bond.

3. Open carbocations are prone to rearrange

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The stereochemistry of HX addition is varied. Examples are known of predominant syn, anti, and nonstereoselective addition. It was found that treatment of 1,2-dimethylcyclohexene (4) with HBr gave predominant anti addition, while addition of water to 4 gave equal amounts of the cis and trans alcohols:

4

On the other hand, there may be some factor that maintains the configuration, in which case W may come in from the same side or the opposite side, depending on the circumstances.

On the other hand, addition of DBr give predominant syn addition.

5

For example, the po

sitive charge might be stabilized by an attraction for Y that does not involve a full bond (see 3).

A circumstance that would favor syn addition would be the formation of an ion pair after the addition of Y:

The second group would then come in anti. Since W is already on the same side of the plane as Y, collapse of the ion pair leads to syn addition.

Stereochemistry of AdE3 mechanismAnother possibility is that anti addition might, at least in some cases, be caused by the operation of a mechanism in which attack by W and Y are essentially simultaneous but from opposite sides: In all these cases (except for the AdE3 mechanism), we assumed that formation of the intermediate (1, 2, or 3) is the slow step and attack by the nucleophile on the intermediate is rapid, and this is probably true in most cases. However, some additions have been found in which the second step is rate determining.

This mechanism is called the AdE3 mechanism. i.e. termolecular addition. Disadvantage: three molecules must come together in the transition state.

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Nucleophilic AdditionIn the first step of nucleophilic addition, a nucleophile brings its pair of electrons to one carbon atom of the double or triple bond, creating a carbanion. The second step is combination of this carbanion with a positive species:

In the special case of addition of HY to a substrate of the form–C=C-Z, where Z=CHO, COOR, CONH2, CN, NO2, SOR, SO2R, and so on, addition nearly always follows a nucleophilic mechanism,with Y- bonding with the carbon away from the Z group. e.g.

Enolate ion

Enol

When the alkene contains a good leaving group substitution is a side reaction.

Protonation of the enolate ion is chiefly at the oxygen, which is more negative than the carbon, but this produces the enol, which tautomerizes, So although the net result of the reaction is addition to a carbon–carbon double bond, the mechanism is 1,4-nucleophilic addition to the C=C-C=O (or similar) system and is thus very similar to the mechanism of addition to carbon–oxygen double and similar bonds

With any substrate, when Y is an ion of the type ZCR2 (Z is as defined above; R may be alkyl, aryl, hydrogen, or another Z), the reaction is called the Michael reaction, Systems of the type C=C-C=C-Z can give 1,2- 1,4- or 1,6-addition.

Enolate ion

Enol

When Z is CN or a C=O group, it is also possible for Y- to attack at this carbon, and this reaction sometimes competes. When it happens, it is called 1,2-addition. 1,4-Addition to these substrates is also known as conjugate addition. The Y- ion almost never attacks at the 3 position, since the resulting carbanion would have no resonance stabilization:

Michael-type reactions are reversible, and compounds of the type YCH2CH2Z can often be decomposed to YH and CH2=CHZ by heating,either with or without alkali.

For example, the (E) and (Z) forms of an alkene ABC=CDE would give 7 and 8. If the mechanism for nucleophilic addition is the simple carbanion mechanism outlined bel

ow, the addition should be nonstereospecific, although it might well be stereoselective.D

If the carbanion has even a short lifetime, 7 and 8 will assume the most favorable conformation before the attack of W. This is of course the same for both, and when W attacks, the same product will result from each.

E A B

YA

D Y B 7

E

E D A B

YA

E Y B 8

D

This will be one of two possible diastereomers, so the reaction will be stereoselective. but since the cis and trans isomers do not give rise to different isomers, it will not be stereospecific.

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This prediction has not been tested on open-chain alkenes. Except for Michael-type substrates, the stereochemistry of nucleophilic addition to double bonds has been studied only in cyclic systems, where only the cis isomer exists. In these cases the reaction has been shown to be stereoselective, with syn addition reported in some cases and anti addition in others. When the reaction is performed on a Michael-type substrate, C=C-Z, the hydrogen does not arrive at the carbon directly but only through a tautomeric equilibrium. The product naturally assumes the most thermodynamically stable configuration, without relation to the direction of original attack of Y. In one such case (the addition of EtOD and of Me3CSD to transMeCH=CHCOOEt), predominant anti addition was found; there is evidence that the stereoselectivity here results from the final protonation of the enolate, and not from the initial attack.

Nucleophilic Additions to triple bondsAdditions to triple bonds cannot be stereospecific. As with electrophilic additions, nucleophilic additions to triple bonds are usually stereoselective and anti, although syn addition and nonstereoselective addition have also been reported.

Free-Radical AdditionThe mechanism of free-radical addition50 follows the pattern discussed in Chapter 11. The method of principal component analysis has been used to analyze polar and enthalpic(焓的 ) effect in radical addition reactions. A radical is generated by the following reaction:

Propagation then occurs by the following reaction:

Step 1 9 Step 2

or

Step 2 is an abstraction (an atom transfer), so W is nearly always univalent, either hydrogen or halogen. Termination of the chain can occur in any of the ways discussed in Chapter 11.

If 9 adds to another alkene molecule, a dimer is formed. This can add to still another, and chains, long or short, may be built up. This is the mechanism of free-radical polymerization. Short polymeric molecules (called telomers), formed in this manner, are often troublesome side products in free-radical addition reactions.

When free radicals are added to 1,5- or 1,6-dienes, the initially formed radical (10) can add intramolecularly to the other bond, leading to a cyclic product (11). When the radical is generated from an precursor that gives vinyl radical 12, cyclization leads to 13, which is in equilibrium with cyclopropylcarbinyl radical(14) and 15

9Radicals of the type 10, genera

ted in other ways, also undergo these cyclizations. Both five- and six-membered rings can be formed in these reactions

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However,stereospecificity has been found only in a few cases. The free-radical addition mechanism just outlined predicts that the addition should be non-stereospecific, at least if 9 has any, but an extremely short lifetime. 9 However, the reactions may be stereoselective, for reasons similar to those discussed for nucleophilic addition. Not all free-radical additions have been found to be selective, but many are. For example, addition of HBr to 1-bromocyclohexene is regioselective in that it gave only cis-1,2-dibromocyclohexane and none of the trans isomer (anti addition), and propyne (at -78o to -60oC) gave only cis-1-bromopropene (anti addition), making it stereoselective.H C C

The most important case is probably addition of HBr to 2bromo-2-butene under free-radical conditions at -80oC. Under these conditions,the cis isomer gave 92% of the meso product, while the trans isomer gave mostly the dl pair.C C H C C C C H C C H HBr, 80oC radical addition Br Br Br meso product, 92%

C C

Br HBr, 80oC H C radical addition Br C

C C

H

Br

C+ H C Br

Br C C

H

dl pair

This stereospecificity disappeared at room temperature, where both alkenes gave the same mixture of products (78% of the dl pair and 22% of the meso compound), so the addition was still stereoselective but no longer stereospecific.

This stereospecificity disappeared at room temperature, where both alkenes gave the same mixture of products (78% of the dl pair and 22% of the meso compound), so the addition was still stereoselective but no longer stereospecific. The stereospecificity at low temperatures is probably caused by a stabilization of the intermediate radical through the formation of a bridged bromine radical, of the type mentioned previously.

The stereospecificity at low temperatures is probably caused by a stabilization of the intermediate radical through the formation of a bridged bromine radical, of the type mentioned previously

This species is similar to the bromonium ion that is responsible for stereospecific anti addition in the electrophilic mechanism. Further evidence for the existence of such bridged radicals was obtained by addition of Br to alkenes at 77 K. The ESR spectra of the resulting species were consistent with bridged structures.

Addition to Conjugated SystemsFor many radicals, step 1 (C=C+ Y C-C-Y) is reversible. In such cases, free radicals can cause cis trans isomerization of a double bond by the pathway: When electrophilic addition is carried out on a compound with two double bonds in conjugation, a 1,2-addition product (16) is often obtained, but in most cases there is also a 1,4-addition product (17), often in larger yield:

16

17

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If the diene is unsymmetrical, there may be two 1,2addition products. The competition between two types of addition product comes about because the carbocation resulting from attack on Y+ is a res

onance hybrid, with partial positive charges at the 2 and 4 positions:

In the case of electrophiles like Br+, which can form cyclic intermediates, both 1,2-and 1,4-addition products can be rationalized as stemming(起源 ) from an intermediate like 18.

18

Direct nucleophilic attack by W- would give the 1,2-product, while the 1,4-product could be formed by attack at the 4 position, by an SN2'-type mechanism W- may then attack either position. The original attack of Y+is always at the end of the conjugated system because an attack at a middle carbon would give a cation unstabilized by resonance. a cation unstabilized by resonance Intermediates like 19 have been postulated, but ruled out for Br and Cl by the observation that chlorination or bromination of butadiene gives trans 1,4products. If an ion like 19 were the intermediate, the 1,4-products would have to have the cis configuration.

19

In most cases, more 1,4- than 1,2-addition product is obtained. This may be a consequence of thermodynamic control of products, as against kinetic. In most cases, under the reaction conditions, 16 is converted to a mixture of 16 and 17 which is richer in 17. That is, either isomer gives the same mixture of both, which contains more 17. It was found that at low temperatures, butadiene and HCl gave only 20–25% 1,4adduct, while at high temperatures, where attainment of equilibrium is more likely, the mixture contained 75% 1,4product. 1,2-Addition predominated over 1,4- in the reaction between DCl and 1,3-pentadiene, where the intermediate was the symmetrical (except for the D label). H3CHC-CH-CHCH2D Ion pairs were invoked to explain this result, since a free ion would be expected to be attacked by Cl equally well at both positions, except for the very small isotope effect.

Addition to conjugated systems can also be accomplished by any of the other three mechanisms. In each case, there is competition between 1,2- and 1,4-addition. In the case of nucleophilic or free-radical attack, the intermediates are resonance hybrids and behave like the intermediate from electrophilic attack.

Dienes can give 1,4-addition by a cyclic mechanism in following way:

Other conjugated systems, including trienes, enynes, diynes, and so on, have been studied much less, but behave similarly. 1,4-Addition to enynes is an important way of making allenes:

ORIENTATION AND REACTIVITY

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ReactivityAs with electrophilic aromatic substitution, electron-donating groups increase the reactivity of a double bond toward electrophilic addition and electron-withdrawing groups decrease it. The reactivity toward electrophilic addition of a group of alkenes increased in the order: CCl3CH=CH2< Cl2CHCH=CH2<ClCH2CH=CH2< CH3CH2=CH2 For nucleophilic addition the situation is reversed.These reactions are best carried out on substrates containing three or four electron-withdrawing groups, two of the most common being F2C=CF2 and (NC)2C=C(CN)2. The effect of substituents is so great that it is possibl

e to make the statement that simple alkenes do not react by the nucleophilic mechanism, and polyhalo or polycyano alkenes do not generally react by the electrophilic mechanism.

There are some reagents that attack only as nucleophiles, for example, ammonia, and these add only to substrates susceptible to nucleophilic attack. Other reagents attack only as electrophiles, and, for example, F2C=CF2 does not react with these.

In still other cases, the same reagent reacts with a simple alkene by the electrophilic mechanism and with a polyhalo alkene by a nucleophilic mechanism. For example, Cl2 and HF are normally electrophilic reagents, but it has been shown that Cl2 adds to (NC)2C=CHCN with initial attack by Cl- and that HF adds to F2C=CClF with initial attack by F-.

Compounds that have a double bond conjugated with a Z group (as defined in section"Nucleophilic Addition") nearly always react by a nucleophilic mechanism. These are actually 1,4-additions, as discussed in section"Nucleophilic Addition". The following order of decreasing activating ability has been suggested: Z=NO2, COAr, CHO, COR, SO2Ar, CN, COOR, SOAr, CONH2, CONHR.

It seems obvious that electron-withdrawing groups enhance nucleophilic addition and inhibit electrophilic addition because they lower the electron density of the double bond. Addition of electrophilic radicals to electron rich alkenes has been reported. But similar reasoning does not always apply to a comparison between double and triple bonds. There is a higher concentration of electrons between the carbons of a triple bond than in a double bond, and yet triple bonds are less subject to attack at an electrophilic attack and more subject to nucleophilic attack than double bonds.

The statement that triple bonds are less subject to attack at an electrophilic attack and more subject to nucleophilic attack than double bonds is not universally true, but it does hold in most cases. In compounds containing both double and triple bonds (nonconjugated), bromine (an electrophilic reagent) always adds to the double bond. In fact, all reagents that form bridged intermediates like 2 react faster with double than with triple bonds.

Furthermore, the presence of electron-withdrawing groups lowers the alkene/alkyne rate ratio. For example, while styrene PhCH=CH2 was brominated 3000 times faster than PhC≡CH, the addition of a second phenyl group (PhCH=CHPh versus PhC≡CPh) lowered the rate ratio to about 250. In the case of trans-MeOOCC=CHCOOMe versus MeOOCC≡CCOOMe, the triple bond compound was actually brominated faster.

On the other hand, addition of electrophilic H+(acidcatalyzed hydration; addition of hydrogen halides) takes place at about the same rates for alkenes as for corresponding alkynes.

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As mentioned, it is true that in general triple bonds are more susceptible to nucleophilic and less to attack on an electrophilic site than double bonds, in spite of their higher electron density. One explanation is that the electr

ons in the triple bond are held more tightly because of the smaller carbon–carbon distance; it is thus harder for an attacking electrophile to pull out a pair. There is evidence from far-UV spectra to support this conclusion. Another possible explanation has to do with the availability of the unfilled orbital in the alkyne.

Another possible explanation has to do with the availability of the unfilled orbital in the alkyne. It has been shown that aπ* orbital of bent alkynes (e.g., cyclooctyne) has a lower energy than theπ* orbital of alkenes, and it has been suggested that linear alkynes can achieve a bent structure in their transition states when reacting with an electrophile. Where electrophilic addition involves bridged-ion intermediates, those arising from triple bonds (20) are more strained than the corresponding 21.

This may be a reason why electrophilic addition by such electrophiles as Br, I, SR, and so on, is slower for triple than for double bonds. As might be expected, triple bonds connected to a Z group (C≡C-Z) undergo nucleophilic addition especially well.

Although alkyl groups in general increase the rates of electrophilic addition, we have already mentioned that there is a different pattern depending on whether the intermediate is a bridged ion or an open carbocation. For brominations and other electrophilic additions in which the first step of the mechanism is rate determining, the rates for substituted alkenes correlate well with the ionization potentials of the alkenes, which means that steric effects are not important. Where the second step is rate determining[e.g., hydroboration steric effects are important

Free-radical additions can occur with any type of substrate. The determining factor is the presence of a free-radical attacking species. Some reagents (e.g., HBr, RSH) attack by ionic mechanisms if no initiator is present, but in the presence of a free-radical initiator, the mechanism changes and the addition is of the free-radical type. Nucleophilic radicals behave like nucleophiles in that the rate is increased by the presence of electron-withdrawing groups in the substrate. The reverse is true for electrophilic radicals. However, nucleophilic radicals react with alkynes more slowly than with the corresponding alkenes, which is contrary to what might have been expected.

Steric influences are important in some cases. In catalytic hydrogenation, where the substrate must be adsorbed onto the catalyst surface, the reaction becomes more difficult with increasing substitution. The hydrocarbon 22, in which the double bond is entombed between the benzene rings, does not react with Br2, H2SO4, O3, BH3,:CBr2, or other reagents that react with most double bonds.

OrientationWhen an unsymmetrical reagent is added to an unsymmetrical substrate, the question arises: Which side of the reagent goes to which side of the double or triple bond? The terms side and face are arbitrary, and a simple guide is shown to help understa

nd the arguments used here.face 1 side 1 side 2 face 2

A similarly inactive compound is tetra-tert-butylallene (tBu)2C=C=C(t-Bu)2, which is inert to Br2, Cl2, O3, and catalytic hydrogenation.

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For electrophilic attack, the answer is given byMarkovnikov's rule: The positive portion of the reagent goes to the side of the double or triple bond that has more hydrogens. A number of explanations have been suggested for this regioselectivity, but the most probable is that Y+ adds to that side that will give the more stable carbocation. This premise has been examined by core electron spectroscopy and by theoretical analysis. Thus, when an alkyl group is present, secondary carbocations are more stable than primary:

We may ask: Why does Y+ add to give the more stable carbocation? As in the similar case of electrophilic aromatic substitution, we invoke the Hammond postulate and say that the lower energy carbocation is preceded by the lower energy transition state. Markovnikov's rule also applies for halogen substituents because the halogen stabilizes the carbocation by resonance:

More stable

Markovnikov's rule is also usually followed where bromonium ions or other three-membered rings are intermediates. This means that in these cases attack by W must resemble the SN1 rather than the SN2 mechanism, although the overall stereospecific anti addition in these reactions means that the nucleophilic substitution step is taking place with inversion of configuration.

Alkenes containing strong electron-withdrawing groups may violate Markovnikov's rule. For example, attack at the Markovnikov position of Me3N+CH=CH2 would give an ion with positive charges on adjacent atoms. The compound CF3CH=CH2 has been reported to give electrophilic addition with acids in an anti-Markovnikov direction, but it has been shown that, when treated with acids, this compound does not give simple electrophilic addition at all; the apparently anti-Markovnikov products are formed by other pathways.

For nucleophilic additionThe direction of attack has been studied very little, except for Michael-type addition, with compounds of the type C=C-Z. Here the negative part of the reagent almost always attacks regioselectively at the carbon that does not carry the Z.

In free-radical additionThe main effect seems to be steric. All substrates CH2=CHX preferentially react at the CH2, regardless of the identity of X or of the radical. With a reagent such as HBr, this means that the addition is anti-Markovnikov.

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Thus the observed orientation in both kinds of HBr addition (Markovnikov electrophilic and anti-Markovnikov free radical) is caused by formation of the secondary intermediate. In the electrophilic case it forms because it is more stable than the primary; In the free-radical case because it is sterically preferred. The stability order of the free-radical intermediates is also usually in the same direction: 3o> 2o> 1o, but this factor is apparently less important than the steric facto

r.

For conjugated dienes, attack by a positive ion, a negative ion, or a free radical is almost always at the end of the conjugated system, since in each case this gives an intermediate stabilized by resonance. In the case of an unsymmetrical diene, the more stable ion is formed. For example, isoprene (CH2=CMeCH=CH2), treated with HCl gives only Me2CClCH=CH2 and Me2C=CHCH2Cl, with none of the product arising from attack at the other end. PhCH=CHCH=CH2 gives only PhCH=CHCHClCH3 since it is the only one of the eight possible products that has a double bond in conjugation with the ring and that results from attack by H+ at an end of the conjugated system.

When allenes attack electrophilic reagents, Markovnikov's rule would predict that the formation of the new bond should be at the end of the system, since there are no hydrogens in the middle.

Probably because of this, attack on the unsubstituted CH2=C=CH2 is most often at the end carbon, to give a vinylic cation, although center attack has also been reported. However, as alkyl or aryl groups are substituted on the allene carbons, attack at the middle carbon becomes more favorable because the resulting cation is stabilized by the alkyl or aryl groups (it is now a secondary, tertiary, or benzylic cation). For example, allenes of the form RCH=C=CH2 are still attacked most often at the end, but with RCH=C=CHR' center attack is more prevalent. Tetramethylallene is also attacked predominantly at the center carbon. Free radicals attack allenes most often at the end, although attack at the middle has also been reported. As with electrophilic attack and for the same reason, the stability of the allylic radical has no effect on the transition state of the reaction between a free radical and an allene. Again, as with electrophilic attack, the presence of alkyl groups increases the extent of attack by a radical at the middle carbon.

Reaction at the center gives a carbocation stabilized by resonance, but not immediately. In order for such stabilization to be in effect the three p orbitals must be parallel, and it requires a rotation about the C-C bond for this to happen.C C C

Therefore, the stability of the allylic cation has no effect on the transition state, which still has a geometry similar to that of the original allene.

Stereochemical OrientationIt has already been pointed out that some additions are syn, with both groups, approaching from the same side, and that others are anti, with the groups approaching from opposite sides of the double or triple bond. For cyclic considered. compounds steric orientation must be For example, epoxidation of 4-methylcyclopentene gave 76% addition from the less-hindered and 24% from the more-hindered face.

In syn addition to an unsymmetrical cyclic alkene, the two groups can come in from the more- or from the less-hindered face of the double bond. The rule is that syn addition is usually from the lesshindered face.

76%

24%

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In anti addition to a cyclic substra

te, the initial attack on the electrophile is also from the less-hindered face. However, many electrophilic additions to norbornene and similar strained bicycloalkenes are syn additions. In these cases reaction is always from the exo side, as in formation of 23

Electronic effects can also play a part in determining which face reacts preferentially with the electrophilic species. In the adamantane derivative 24, steric effects are about the same for each face of the double bond. Yet epoxidation predominantly take place from the face that is syn to the electron-withdrawing fluorine. About twice as much 25 was formed, compared to 26.

When the exo side is blocked by substituents in the 7 position, the endo attack may predominate; For example, 7,7-dimethylnorbornene undergoes syn– endo epoxidation and hydroboration. Similarly, free-radical additions to norbornene and similar molecules are often syn–exo.

Similar results have been obtained on other substrates: When Groups are electron withdrawing by the field effect (-I) the attack take place from the syn face;+I groups from the anti face, for both electrophilic and nucleophilic attack.These results are attributed to hyperconjugation: For the adamantane case, there is overlap between theσ* orbital of the newly forming bond (between the attacking species and C-2 in 24) and the filledσ orbitals of the Cα-Cβ bonds on the opposite side. The four possible bonds are C-3–C-4 and C-1–C-9 on the syn side and C-3–C-10 and C-1–C-8 on the anti side. The preferred pathway is the one where the incoming group has the more electron-rich bonds on the side opposite to it (these are the ones it overlaps with). Since the electron-withdrawing F has its greatest effect on the bonds closest to it, the C-1–C-8 and C-3– C-10 bonds are more electron rich, and the group comes in on the face syn to the F.

It has been mentioned that additions of Br2 and HOBr are often anti because of formation of bromonium ions and that free-radical addition of HBr is also anti. When the substrate in any of these additions is a cyclohexene, the addition is not only anti but the initially formed product is conformationally specific too, being mostly diaxial. This is so because diaxial opening of the three-membered ring preserves a maximum coplanarity (共面 ) of the participating centers in the transition state; indeed, on opening, epoxides also give diaxial products. However, the initial diaxial product may then pass over to the diequatorial conformer unless other groups on the ring render the latter less stable than the former.

Addition to Cyclopropane RingsWe have previously seen that in some respects, cyclopropane rings resemble double bonds. It is not surprising, therefore, that cyclopropanes undergo addition reactions analogous to those undergone by double-bond compounds, resulting in the opening of the three-membered rings.

Additions to cyclopropanes can take place by any of the four mechanisms already discus

sed in this chapter, but the most important type involves attack on an electrophile. For substituted cyclopropanes, these reactions usually follow Markovnikov's rule; The degree of regioselectivity is often small. The application of Markovnikov's rule to these substrates can be illustrated by the reaction of 1,1,2-trimethylcyclopropane with HX. The rule predicts that the electrophile (in this case H+) goes to the carbon with the most hydrogens and the nucleophile goes to the carbon that can best stabilize a positive charge (in this case the tertiary rather than the secondary carbon).

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The stereochemistry of the reaction can be investigated at two positions: the one that becomes connected to the electrophile the one that becomes connected to the nucleophile The results at the former position are mixed. Additions have been found to take place with 100% retention, 100% inversion, and with mixtures of retention and inversion. At the carbon that becomes connected to the nucleophile the result is usually inversion, although retention has also been found. Elimination, rearrangement, and racemization processes often compete, indicating that in many cases a positively charged carbon is generated at this position.

At least three mechanisms have been proposed for electrophilic addition (these mechanisms are shown for attack by HX, but analogous mechanisms can be written for other electrophiles).R R' R R' H+ R R' H28

Mechanism a

R R'

X-

R R' H

R R' X

Mechanism b

Mechanism c

28 is a corner-protonated cyclopropane, 29 is an edge-protonated cyclopropane, 30 is a classical cation caused by a one-step SE2-type attack on H+

Although the three mechanisms as we have drawn them show retention of configuration at the carbon that becomes attached to the proton, mechanisms a and c at least can also result in inversion at this carbon. Unfortunately, the evidence on hand at present does not allow us unequivocally to select any of these as the exclusive mechanism in all cases. Matters are complicated by the possibility that more than one edge-protonated cyclopropane is involved, at least in some cases. There is strong evidence for mechanism b with the electrophiles Br+ and Cl+; and for mechanism a with D+ and Hg2+. An initio studies show that the corner-protonated 28 is slightly more stable (1.4 kcal mol-1, 6 kJ mol-1) than the edge-protonated 29. There is some evidence against mechanism c.

Free-radical additions to cyclopropanes have been studied much less, but it is known that Br2 and Cl2 add to cyclopropanes by a free-radical mechanism in the presence of UV light. The addition follows Markovnikov's rule, with the initial radical reacting at the least-substituted carbon and the second group going to the most-substituted position. Several investigations have shown that the reaction is stereospecific at one carbon, taking place with inversion there, but nonstereospecific at the other carbon. A mechanism that accounts for this behavior is:

In some cases, conj

ugate addition has been performed on systems where a double bond is ''conjugated'' with a cyclopropyl ring. An example is the formation of 31.

REACTIONS

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REACTIONS IN WHICH HYDROGEN ADDS TO ONE SIDEA. Halogen on the Other SideAddition of Hydrogen Halides

The addition of hydrogen halides to simple alkenes, in the absence of peroxides, takes place by an electrophilic mechanism, and the orientation is in accord with Markovnikov's rule. When peroxides are added, the addition of HBr occurs by a free-radical mechanism and the orientation is anti-Markovnikov. It must be emphasized that this is true only for HBr. Free-radical addition of HF and HI has never been observed, even in the presence of peroxides, and of HCl only rarely. In the rare cases where free-radical addition of HCl was noted, the orientation was still Markovnikov, presumably because the more stable product was formed. Free-radical addition of HF, HI, and HCl is energetically unfavorable. It has often been found that anti-Markovnikov addition of HBr takes place even when peroxides have not been added. This happens because the substrate alkenes absorb oxygen from the air, forming small amounts of peroxides.

HI, HBr, and HF add at room temperature. The addition of HCl is more difficult and usually requires heat, although HCl adds easily in the presence of silica gel. A convenient method for the addition of HF involves the use of a polyhydrogen fluoride-pyridine solution. When the substrate is mixed with this solution in a solvent, such as THF at 0oC, alkyl fluorides are obtained in moderate-to-high yields.

Markovnikov addition can be ensured by rigorous purification of the substrate, but in practice this is not easy to achieve, and it is more common to add inhibitors, for example, phenols or quinones, which suppress the free-radical pathway. The presence of free-radical precursors, such as peroxides does not inhibit the ionic mechanism, but the radical reaction, being a chain process, is much more rapid than the electrophilic reaction. In most cases, it is possible to control the mechanism (and hence the orientation) by adding peroxides to achieve complete free radical addition, or inhibitors to achieve complete electrophilic addition, although there are some cases where the ionic mechanism is fast enough to compete with the free-radical mechanism and complete control cannot be attained. Markovnikov addition of HBr, HCl, and HI has also been accomplished, in high yields, by the use of phase-transfer catalysis.

It is also possible to add 1 or 2 equivalents of any of the four hydrogen halides to triple bonds. Markovnikov's rule ensures that gem-dihalides and not vicdihalides are the products of the addition of two equivalents.

This type of mechanism also occurs with Michael-type substrates C=C-Z. There the orientation is always such that the halogen goes to the carbon that does not bear the Z, so the product is of the form X-C-CH-Z, even in the presence of free-radical initiators.

B

. Oxygen on the Other SideHydrogen iodine adds 1,4 to conjugated dienes in the gas phase by a pericyclic mechanism: Hydration of Double bonds

HX can be added to ketenes182 to give acyl halides:

An acid is needed as a catalyst. The most common catalyst is sulfuric acid, but other acids that have relatively non-nucleophilic counterions, such as nitric or perchloric can also be used.

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The mechanism is electrophilic and begins with attack of theπ-bond on an acidic proton. The resulting carbocation is then attacked by negative species, such as HSO4- to give the initial product 32, then 32is hydrolyzed to the alcohol.

Another method for Markovnikov addition of water consists of simultaneously adding an oxidizing agent (O2) and a reducing agent (either Et3SiH or a secondary alcohol, e.g., 2-propanol) to the alkene in the presence of a cobaltcomplex catalyst. No rearrangement is observed with this method. The corresponding alkane and ketone are usually side products.

However, the conjugate base of the acid is not the only possible species that attacks the initial carbocation. The attack can also be by water to form 33.

Alkenes can be hydrated quickly under mild conditions in high yields without rearrangement products by the use of oxymercuration (addition of oxygen and mercury) followed by in situ treatment with sodium borohydride. For example, 2-methyl-1-butene treated with mercuric acetate,188 followed by NaBH4, gave 2-methyl-2-butanol.

Hydration of Triple Bonds

Catalysts: mercuric ion salts (often the sulfate or acetate) Mercuric oxide in the presence of an acid is also a common reagent. The addition follows Markovnikov's rule. Only acetylene gives an aldehyde. All other triple-bond compounds give ketones With alkynes of the form RC≡CH, methyl ketones are formed almost exclusively, but with RC≡CR' both possible products are usually obtained.

This method, which is applicable to mono-, di-, tri-, and tetraalkyl as well as phenyl-substituted alkenes, gives almost complete Markovnikov addition. Hydroxy, methoxy, acetoxy, halo, and other groups may be present in the substrate without, in general, causing difficulties.

The reaction can be conveniently carried out with a catalyst prepared by impregnating mercuric oxide onto Nafion-H (a super acidic perfluorinated resin sulfonic acid). Terminal alkynes react with water at 200oC with microwave irradiation to give the corresponding methyl ketone. Hydration of terminal alkynes can proceed with antiMarkovnikov addition. When 1-octyne was heated with water, isopropanol and a ruthenium catalyst, for example, the product was octanal. The presence of certain functionality can influence the regioselectivity of hydration. 1-Seleno alkynes, such as PhSe-C≡C-Ph, react with tosic acid in dichloromethane to give a seleno ester PhSeC(=O)SH2Ph after treatment with water.

The first step of the mechanism is formation of a complex (35) (ions like Hg2+ form complexes with alkynes). Water then attacks in an SN

2-type process to give the intermediate 36, which loses a proton to give 37. Hydrolysis of 37 gives the enol, which tautomerizes to the product.