Orientation and Reactivity - Lesson 2 - Addition to Carbon–Carbon Multiple Bonds - Introduction - March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition (2013)

March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition (2013)

Part II. Introduction

Chapter 15. Addition to Carbon–Carbon Multiple Bonds

15.B. Orientation and Reactivity

15.B.i. Reactivity

As with electrophilic aromatic substitution (Chapter 11), electron-donating groups increase the reactivity of a double bond toward electrophilic addition and electron-withdrawing groups decrease it. This is illustrated in Tables 15.1and 15.2.69 As a further illustration, the reactivity toward electrophilic addition of a group of alkenes increased in the order CCl3CH=CH2 < Cl2CHCH=CH2 < ClCH2CH=CH2 < CH3CH2=CH2.70 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=CF271 and (NC)2C=C(CN)2.72 The effect of substituents is so great that it is possible 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.73 There are some reagents that attack only as nucleophiles (e.g., 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 (NimgC)2C=CHCimgN with initial attack by Cl74 and that HF adds to F2C=CClF with initial attack by F.75 Compounds that have a double bond conjugated with a Z group (as defined in Sec. 15.A.ii) nearly always react by a nucleophilic mechanism.76 These are actually 1,4-additions, also discussed in Section 15.A.ii. A number of studies have been made of the relative activating abilities of various Z groups.77 On the basis of these studies, the following order of decreasing activating ability has been suggested: Z = NO2, COAr, CHO, COR, SO2Ar, CN, CO2R, SOAr, CONH2, and CONHR.78

Table 15.1 Relative Reactivity of Some Alkenes Toward Bromine in Acetic Acid at 24 °Ca.

Alkene

Relative Rate

PhCH=CH2

Very fast

PhCH=CHPh

18

CH2=CHCH2Cl

1.6

CH2=CHCH2Br

1.0

PhCH=CHBr

0.11

CH2=CHBr

0.0011

Reproduced from de la Mare, P.B.D. Q. Rev. Chem. Soc. 1949, 3, 126 with permission from the Royal Society of Chemistry.

a. See Ref. 69.

Table 15.2 Relative Reactivity of Some Alkenes Toward Bromine in Methanola.

Alkene

Relative Rate

CH2=CH2

3.0 × 101

CH3CH2CH=CH2

2/9 × 103

cis-CH3CH2CH=CHCH3

1.3 × 105

(CH3)2C=C(CH3)2

2.8 × 107

[Reprinted with permission from Dubois, J.E. Mouvier, G. Tetrahedron Lett. 1963, 1325, Copyright © 1963, with permission from Elsevier Science].

a. See Ref. 69.

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,79 so the reaction is possible in some cases. This is probably true, and yet similar reasoning does not always apply to a comparison between double and triple bonds.80 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 site and more subject to nucleophilic attack than double bonds.81 This statement 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.82 In fact, all reagents that form bridged intermediates like 2 react faster with double than with triple bonds. On the other hand, addition of electrophilic H+ (acid-catalyzed hydration, Reaction 15-3; addition of hydrogen halides, Reaction 15-2) takes place at about the same rates for alkenes as for corresponding alkynes.83 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 PhCimgCH, the addition of a second phenyl group (PhCH=CHPh versus PhCimgCPh) lowered the rate ratio to ~250.84 In the case of trans-MeOOCCH=CHCOOMe versus MeOOCCimgCCOOMe, the triple-bond compound was actually brominated faster.85

As mentioned earlier, it is true that in general triple bonds are more susceptible to nucleophilic and less prone to reaction at an electrophilic site than double bonds, in spite of their higher electron density. One explanation is that the electrons in the triple bond are held more tightly because of the smaller carbon–carbon distance. Thus it is harder to donate an electron pair to an electrophile. There is evidence from far-UV spectra to support this conclusion.86Another possible explanation has to do with the availability of the unfilled orbital in the alkyne. It has been shown that a π∗ orbital of bent alkynes (e.g., cyclooctyne) has a lower energy than the π orbital of alkenes, and it has been suggested87 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.88 As might be expected, triple bonds connected to a Z group (CimgC–Z) undergo nucleophilic addition especially well.89

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Although alkyl groups in general increase the rates of electrophilic addition, as mentioned in Section 15.A.i, category 1, 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.90 Where the second step is rate determining [e.g., oxymercuration Reaction (15-3), hydroboration Reaction (15-17)], steric effects are important.89

Free radical additions can occur with any type of substrate. The determining factor is the presence of a reactive free radical 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 (Sec. 14.A.ii) 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.91 However, nucleophilic radicals react with alkynes more slowly than with the corresponding alkenes,92 which is contrary to what might have been expected.93

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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.94 A similarly inactive compound is tetra-tert-butylallene (t-Bu)2C=C=C(t-Bu)2, which is inert to Br2, Cl2, O3, and catalytic hydrogenation.95

15.B.ii. Orientation

When 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? In other words, what is the regioselectivity of the reaction? Regioselectivity is defined as one direction of bond making or breaking that occurs preferentially over all other possible directions. The terms side and face are arbitrary, and a simple guide is shown to help understand

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the arguments used here. For reaction with an electrophile, the traditional answer is given by Markovnikov's rule: The positive portion of the reagent goes to the side of the double or triple bond that has more hydrogen atoms.96Mechanistically, regioselectivity is predicted by attack of the π bond on Y+, forming a bond to the carbon that will give the more stable carbocation. For example, secondary carbocations are more stable than primary:

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This mechanism is supported by evidence from core electron spectroscopy and by theoretical analysis.97 The Hammond postulate is invoked to say that the lower energy carbocation is preceded by the lower energy transition state. Markovnikov's rule also applies for halogen substituents, and the mechanistic rationale is that the halogen stabilizes the carbocation by resonance, so the intermediate with the positive charge on the Cl bearing carbon is more stable.

Markovnikov's rule is also followed where bromonium ions or other three-membered rings are intermediates formed in protic solvents (e.g., methanol).98 In such a medium, attack by the nucleophile W on the three-membered ring must resemble the SN1 (see Sec. 10.A.ii) rather than the SN2 mechanism (and see Sec. 10.G.viii), although the overall stereospecific anti addition in these reactions means that the nucleophilic substitution step is taking place with inversion of configuration. This result suggests a tight ion pair rather than a free carbocation.

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Alkenes containing strong electron-withdrawing groups may violate Markovnikov's rule, but formation of the more stable carbocation still controls the reaction. For example, attack at the Markovnikov position of Me3N+–CH=CH2would 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 shown99 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. Molecular electrostatic potentials for the π-region of substituted alkenes were studied, with electron donating and withdrawing substituents (based on the increase or decrease in the negative character of Vmin - most negative-valued point), and plots of Vmin shows a good linear correlation with the Hammett σρ constants, suggesting similar substituent electronic effects for substituted ethylenes and substituted benzenes.100

In free radical addition101 the main effect seems to be steric.102 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, which generates Br in situ via hydrogen-atom exchange, 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 more stable secondary intermediate.

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In intramolecular additions (radical cyclization, see Reaction 15-30) of radicals containing a 5,6 double bond,53 both five- and six-membered rings can be formed, but in most cases103 the five-membered rings are greatly preferred kinetically, even (as in the case shown) where five-membered ring closure means generating a primary radical and six-membered ring closure a secondary radical. This phenomenon may be caused by more favorable entropy factors leading to a five-membered ring, as well as by stereoelectronic factors, but other explanations have also been offered.104 Similar behavior is found when the double bond is in other positions (from the 3,4 to the 7,8 position). In each case, the smaller ring (exo-trig addition) is preferred to the larger (endo-trig addition)105 (see Baldwin rules, Sec. 6.E). However, when a radical that is unsaturated in the 5,6 position contains an alkyl group in the 5 position, formation of the six-membered ring is generally favored, presumably due to unfavorable steric interactions.106

For conjugated dienes, attack at a positive ion, by a negative ion, or reaction with 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. The compound 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 that places the proton at an end of the conjugated system.

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When allenes attack electrophilic reagents,107 Markovnikov's rule would predict that formation of the new bond should be at the end of the system, since there are no hydrogen atoms in the middle. 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.108 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 (Sec. 4.C, category 5). Probably because of this, reaction of the unsubstituted CH2=C=CH2 is most often at the end carbon, to give a vinylic cation, although reaction at the center carbon has also been reported. However, as alkyl or aryl groups are substituted on the allene carbons, reaction 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 react most often at the end, but RCH=C=CHR′ usually gives reaction at the center carbon.109Free radicals110 react with allenes most often at the end,111 although reaction at the middle carbon has also been reported.112 As with reactions that proceed via electrophilic intermediates 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, the presence of alkyl groups increases the extent of reaction by a radical at the middle carbon.113

15.B.iii. Stereochemical Orientation

It 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 compounds steric orientation must be considered. 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, although not always, from the less-hindered face. For example, epoxidation of 4-methylcyclopentene gave 76% addition from the less-hindered and 24% from the more-hindered face.114

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In anti addition to a cyclic substrate, the initial reaction with the electrophile is also from the less-hindered face. However, many (although not all) electrophilic additions to norbornene and similar strained bicycloalkenes are syn additions.115 In these cases reaction is always from the exo side, as in formation of 23,116 unless the exo

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side is blocked by substituents in the 7 position, in which case endo attack may predominate [e.g., 7,7-dimethylnorbornene undergoes syn–endo epoxidation (Reaction 15-50) and hydroboration117 (Reaction 15-16)]. However, addition of DCl and F3CCO2D to, and oxymercuration (Reaction 15-2) of, 7,7-dimethylnorbornene proceeds syn–exo in spite of the methyl groups in the 7 position.118 Similarly, free radical additions to norbornene and similar molecules are often syn–exo, although anti additions and endo attacks are also known.119

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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, dibromocarbene reactions (15-64), and hydroboration (15-16) all take place predominantly from the face that is syn to the electron-withdrawing fluorine.120 In the case shown, about twice as much 25 was formed, compared to 26. Similar results have been obtained on other substrates:121 groups that are electron withdrawing by the field effect (−I) direct attack from the syn face; +I groups from the anti face, for both electrophilic and nucleophilic attack. These results are attributed122 to hyperconjugation (Sec. 2.M): For the adamantane case, there is overlap between the σ orbital of the newly forming bond (between the attacking species and C-2 in 24) and the filled σ orbitals of the Cα–Cβ bonds on the opposite side. This is called the Cieplak effect. The LiAlH4 reduction of 2-axial methyl or methoxy cyclohexanones supports Cieplak's proposal.123 In addition reactions of methanol to norbornanones, however, little evidence was found to support the Cieplak effect.124 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.125 This is so because diaxial opening of the three-membered ring preserves a maximum coplanarity of the participating centers in the transition state; indeed, on opening, epoxides also give diaxial products.126 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. In free radical additions to cyclohexenes in which cyclic intermediates are not involved, the initial reaction with the radical is also usually from the axial direction,127 resulting in a diaxial initial product if the overall addition is anti. The direction from which unsymmetrical radicals react has also been studied.128 For example, when the radical (27) adds to a double bond it preferentially does so anti to the OH group, leading to a diaxial trans product.126

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15.B.iv. Addition to Cyclopropane Rings129

Section 4.Q.iv showed that cyclopropane rings resemble double bonds in some aspects of their reactivity.130 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, as in the two examples shown, where Reactions 15-2 and 15-47 describe the reaction to alkene chemistry.

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Reaction 15-2

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Reaction 15-47

Ref. 131

Other examples are discussed at Reaction 15-3, 15-15, and 15-63.

Additions to cyclopropanes can take place by any of the four mechanisms already discussed in this chapter, but the most important type involves attack on an electrophile.132 For substituted cyclopropanes, these reactions usually follow Markovnikov's rule, although exceptions are known and 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.133 The rule predicts that the electrophile (in this case H+) goes to the

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carbon with the most hydrogen atoms and the nucleophile goes to the carbon that can best stabilize a positive charge (in this case the tertiary rather than the secondary carbon). The stereochemistry of the reaction can be investigated at two positions: the one that becomes connected to the electrophile and 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,134 100% inversion,135 and with mixtures of retention and inversion.136 At the carbon that becomes connected to the nucleophile, the result is usually inversion, although retention has also been found,137 and 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 reaction with HX, but analogous mechanisms can be written for other electrophiles).

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Mechanism a involves a corner-protonated cyclopropane138 (28). Examples of such ions were seen in the 2-norbornyl and 7-norbornenyl cations (Sec. 10.C.i). Mechanism b involves an edge-protonated cyclopropane (29). Mechanism c consists of a one-step SE2 type attack on H+ to give the classical cation 30, which then reacts with the nucleophile. Although the three mechanisms as drawn 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+139; and for mechanism a with D+ and Hg2+.140 Ab 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 29.141 There is some evidence against mechanism c.142

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.143 A mechanism that accounts for this behavior is144

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In some cases, conjugate addition has been performed on systems where a double bond is “conjugated” with a cyclopropyl ring. An example is the formation of 31.145

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