Why Is Anti-Markovnikov HydroborationâOxidation of Alkenes Not

Research: Science and Education

Polar Addition to C=C Group: Why Is Anti-Markovnikov Hydroboration–Oxidation of Alkenes Not “Anti-“? Predrag-Peter Ilich,* Lucas S. Rickertsen, and Erienne Becker Division of Molecular and Life Sciences, Loras College, Dubuque, Iowa 52001; *[email protected]

Naming organic reactions, reagents, or even mechanisms after their purported discoverers has been a time-honored practice in organic chemistry education and research. There is a good reason for this in education as the names often provide a mnemonic for not one but a number of different reactions, substrates, and reagents. For example, an alcohol can lose the equivalent of a water molecule in the Zaytsev fashion, or the elimination of the same group of atoms can follow the Hofmann regioselectivity, to yield a different isomer of the alkene product. The Markovnikov rule seems to present another such case: instructors introduce it to explain why, for example, propene and hydrogen chloride will give 2chloropropane and not 1-chloropropane:

The usefulness of this name becomes apparent when students realize that the same “rule” applies to reactions as seemingly different as oxymercuration–demercuration of 1-methylcyclohexene and deuterobromination of cholesterol. However, teaching (and learning) the numerous electrophilic addition reactions to doubly and triply bonded carbon atoms becomes a rather daunting task when compounded with the concepts of carbocation rearrangement, reaction stereoselectivity, and product chirality. At the stage when most students begin to grasp the meaning of two concepts, Markovnikov regioselectivity and anti-stereochemistry, the instructor “breaks” the rule by introducing hydroboration–oxidative hydroxylation, a reaction that proceeds with syn-stereochemistry to give an anti-Markovnikov product. Eventually, however, these reactions, the rules, and the exceptions to the rules have been learned and memorized but the term Markovnikov will be never again mentioned in the course. One may wonder

whether assigning 2-propanol as “Markovnikov” and 1-propanol as “anti-Markovnikov” is the best way to introduce and explain the nature of an electrophilic addition to multiplybonded carbon atoms. Some three decades ago Jones hailed the Markovnikov rule as “an excellent pedagogic example” suitable for correlation with “general theory” (1). Subsequently, Isenberg and Grdinic, in the analysis of the “peroxide effect” (2), cite the “gradually modified” rule, in the form reprinted in contemporary sophomore organic chemistry textbooks: “In [the] addition of the molecule X–Y … the more positive part of the attacking molecule goes to that carbon of the double bond that is less substituted,…” (3). Recently, Hessley, on the basis of the AM1 (4) enthalpies of selected reactants and products, suggested a “logical extension” of the rule for the case of hydroboration–oxidation reactions (5). Gooch, on the other hand, citing qualitative chemical and pedagogic arguments, calls for an outright abandonment of the Markovnikov term (6). So we decided to take another look at the thermodynamics of electrophilic addition reactions to alkenes. We have used an electronic structure method, G3MP3 (7), to calculate Gibbs energies (energy) and electron density distributions (8) (charge) of selected alkenes and their intermediates and products. In particular, we have focused our analysis on two parameters: (i) the charge distribution in alkene and (ii) the energy difference between reactants and intermediates. The intermediates in some of the reactions we have studied are positively charged, and often very unstable, species; in the case of hydroboration–oxidative hydroxylation of alkenes the intermediates are neutral, stable molecules. However, as we show in our analysis, it is the way an intermediate forms, not its chemical nature, that determines the overall reaction. Results and Discussion

Figure 1. Addition of HCl to propene, the G3MP3 energies and the reactant charges.

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Hydrogenchlorination of Propene This reaction begins with a proton transfer from H⫺Cl to the vinyl group to form a carbocation intermediate, followed by the addition of chloride anion to yield the product. If a proton with a positive charge of +0.24 ends up on ⫽CH2, the negatively charged vinyl carbon (ρ = ᎑0.39), 2propenium cation will form; this intermediate will yield 2chloropropane as the final product. If in the first reaction step the proton “chooses” the less negatively charged vinylidine carbon, ρ = ᎑0.15, the more “expensive” (by 84 kJ兾mol) 1-propenium cation will form. In the absence of rearrangement, the 1-propenium cation will lead to the less stable 1-chloropropane product, (Figure 1). The observed product is the more stable 2-chloropropane. It appears that the best charge match in the first reaction step results in a more stable intermediate; this intermediate subsequently determines the form of the final product. This reaction course

Vol. 83 No. 11 November 2006

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Figure 2. Addition of BH3 to propene and conversion to propanol, the G3MP3 energies and the reactant charges.

is not peculiar to the addition of a proton: the same charge– energy pattern obtains for the electrophilic addition of, for example, sulfonium cation, a species considerably larger and more complex than a proton (see Table 1).

Hydroboration–Oxidation of Propene This reaction is presented as a simple sequence of the reactants propene and BH3, the intermediates 1-propaneborane and 2-propaneborane, and the products 1-propanol and 2propanol (Figure 2). As in the previous case, the first reaction step occurs between the doubly bonded carbon atoms of the alkene substrate and the positively charged center of the reagent. But in BH3 the hydrogen role is “reversed”, and it is the boron atom that is the positive center in the molecule. In the first reaction step, if boron binds to the more negative vinyl carbon a more stable 1-boranepropane will form, if boron binds to the less negative vinylidene carbon the (slightly) less stable 2-boranepropane will form. Unlike the propene carbocations, the boranealkanes are stable molecules. In a subsequent reaction of a boranealkane, initially reported by Jonhson and Van Campen (9) and subsequently developed

by Brown and Rao (10), the BH2 group will be “washed off “ through a nucleophilic attack by a peroxide anion (basic medium) and replaced by OH. The more stable 1-boranepropane will thus yield 1-propanol, which, though less stable than the 2-isomer, is the major reaction product. In a situation when a more stable intermediate yields a less stable final product we say that the energy levels cross in the course of the reaction. The energy level crossing in Figure 2 also tells us that in this reaction the major product is determined—or we may say “locked”—by the form of the most stable intermediate, not by the stability of the product isomers. Level crossing is not a necessary feature of hydroboration–oxidative hydroxylation reaction of alkenes. For example, 1-methyl-1cyclopentene will react with BH3 to form the 6 kJ兾mol more stable 1-methy-2-boranecyclopentane, which upon oxidative hydroxylation yields the 17 kJ兾mol more stable 2-methyl-1cyclopentanol, the major product (see Table 1). In both hydroboration–oxidative hydroxylation reactions presented here, the one involving level crossing and the one without level crossing, the form of the final product is determined by the structure of the reaction intermediate created through a best charge matching between the electron-rich substrate and the electrophilic reagent.

Addition of Iodoazide to 1,1-Dimethoxy-2-methyl-1-propene Perhaps as a complement to Markovnikov’s initial observation (11) a rule of thumb has been developed stating that, in the initial reaction step, the hydrogen (proton) in the electrophile will “join” the more hydrogenated alkene carbon. This seemingly intuitive rule goes a long way to explain the regioselectivity of the addition of H⫺X (X = Cl, Br, I, OH2) to unequally substituted alkenes. More importantly, this rule works well in cases where hydrogen is replaced by I+, HO3S+, H2B+, and other positive centers. Unfortunately, this rule is of no use in cases where no hydrogen atom is present on either alkene carbon center, as in the case of the addition of iodoazide to 1,1-dimethoxy-2-methyl-1-propene (dimethylketene dimethyl acetal) (Figure 3). Our calcula-

Figure 3. Addition of IN3 to 1,1-dimethoxy-2dimethylpropene, the G3MP3 energies and the reactant charges.

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tions1,2 suggest the formation of only one intermediate, best described as 2-iodo-1,1-dimethoxy-2-methylpropenium cation (we estimate that 1-iodo-1,1-dimethoxy-2-methylpropene cation would be 3–8 kJ兾mol less stable). If the more stable intermediate should determine the form of the final product then the expected product, 1-azido2-iodo-1,1-dimethoxy-2-methylpropane, will be 12 kJ兾mol less stable than the most stable product, 2-azido-1-iodo-1,1dimethoxy-2-methylpro-pane, another example of energy level crossing. But the first reaction step closely follows the pattern observed in the previous reactions: the binding of the electrophilic positive center to a more negative alkene carbon atom yields a more stable intermediate. The experimental reports on a similar compound, 1chloro-2-nitrosyl-1,1-dimethyoxy-2-methylpropane (12), and the reactions of iodoazide with some cyclic alkenes (13) support our regioselectivity but the overall evidence is hardly unequivocal. The problem with applying the “hydrogen goes with hydrogens” rule to the previous reaction is expected; however, the fact that the same rule fails to predict the regioselectivity of an electrophilic addition to an unequally hydrogenated alkene is not expected. We demonstrate the latter case with the addition of one equivalent of DCl to 1-methylene-3methyl-2,4-cyclopentadiene (Scheme I, 1). A textbook application of the Markovnikov rule would suggest 1-chloro1-deuteromethyl-3-methyl-2,4-cyclopentadiene (Scheme I, 2), as the major kinetically controlled product and 1-chloro-3deutero-methyl-1-methyl-2,4-cyclopentadiene (Scheme I, 3), as the major thermodynamically controlled product of the reaction. Our analysis of the six possible carbocation intermediates and thirty-one possible reaction products of this reaction suggests a very different picture (see Table 1).

Summary We summarize the results of our calculations in Table 1 and as follows: (i)

In the first reaction, the addition of hydrogen chloride to propene is predicted and observed to give the more stable 2-chloropropane and not the less stable 1-isomer.

(ii)

A 2-chloropropane isomer (2-chloro-1-sulfonylpropane) is predicted and observed to be the major product in the second reaction as well.

(iii)

In the third example, the major product of the addition of one equivalent of deuterium chloride to 1-methylene-3-methyl-2,4-cyclopentadiene is predicted to be neither the expected major kinetically controlled product 1-chloro-1-deuteromethyl-3-methyl-2,4-cyclopentadiene nor the expected major thermodynamically controlled product 1-chloro-3-deuteromethyl-1-methyl-2,4-cyclopentadiene (Scheme I,) but 1-chloro-2-deutero-1-methyl-3-methylene4-cyclopropene.

(iv)

The fourth reaction, hydroboration–oxidative hydroxylation of propene, is predicted, and observed, to yield the less stable 1-propanol and not the more stable 2-propanol.

(v) Contrary to it, hydroboration–oxidative hydroxylation of 1-methyl-1-cyclopentene is predicted, and observed, to give the more stable 2-methyl-1-cyclopentanol but not the less stable 1-methyl-1-cyclopentanol. (vi)

Finally, the addition of iodoazide (or another mixed halogen–pseudohalogenide, nitrosylchloride) to the hydrogenless 1,1-dimethoxy-2-methyl-1-propene is predicted, and in some cases observed, to give the less stable 1-iodo-2-azido (or 2-chloro-1- nitrosyl) but not the more stable 2-iodo-1azide (or more stable 1-chloro-2-nitrosyl) product.

Table 1. Summary of Six Polar Additions to Alkenes Reactants

Intermediatea

Productb

(i)

(ii)

(iii)

(iv)

(v)

(vi)

Scheme I. Expected addition of one equivalent of DCl to 1-methylene-3-methyl- 2,4-cyclopentadiene

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a Best charge match and minimum energy. b All products, except for product vi, were determined by the intermediate. Product vi had no unique path; different products were formed.


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The major product in the first, second, and fifth reactions is the most stable final product. In the fourth and sixth reactions the major product has been predicted, and observed, to be the less stable final product. In the third reaction the major product is ranked fourth on the energy scale of possible products. The popular form of the Markovnikov rule stating that “hydrogen goes with hydrogens” is satisfied in the first reaction, and if extended beyond Markovnikov’s original statement (11), to equate the binding proton with “a positively charged electrophilic center”, the rule applies to the second, fourth, and fifth reactions. The rule, either in the standard or the extended form, is useless in the case of addition reactions to fully substituted alkenes, given by the sixth example. Finally, the rule, applied either in the original or extended form, fails to predict the form of the cation intermediate and the final product in the third reaction. So what is common to these six addition reactions? Clearly, it is not the size or structure of the electrophilic agent or the number of hydrogen atoms on the alkene carbon centers, nor is it the structure or the lowest energy of the final product of the reaction. There is, however, a clear common thread in these reactions and we state it in the following way: An electrophilic addition reaction to an alkene is determined by the charge distribution in the alkene and the most stable reaction intermediate.

In each reaction presented in Table 1 the most stable intermediate forms when an electrophile binds to the most negatively charged alkene carbon atom in the substrate molecule. The form of this intermediate will determine the major final product of the addition reaction. We call the confluence of these two events the charge–energy, or C–E, match. It may seem that our C–E argument reaffirms the spirit of the Markovnikov rule; in fact we completely redefine this reaction type by using the tools and knowledge not available 137 years ago. First, we shift the focus of the analysis from the final reaction product to the reaction intermediate. Second, we characterize the alkene substrate in terms of electron density distribution rather than describe it by the number and distribution of hydrogen atoms. Third, we postulate that the type of electrophilic agent is largely irrelevant in the first reaction step. If the C–E match in the first reaction step is indeed interpreted as the essence of the Markovnikov regioselectivity then the rule should be restated in the following way: Every true electrophilic addition to an alkene is a Markovnikov-type reaction.

We should also remind ourselves that a number of addition reactions to alkenes do not meet these conditions. For example, the additions of amines, amides, and alkoxides to alkenes proceed with difficulty, lack of regioselectivity, or do not occur at all. Typically, these reactions have to be assisted either through strong and specific “neighboring group” or solvent participation, catalysis by a transition element, or catalysis by an enzyme. Although products of many such reactions are labeled as Markovnikov (or, more often, anti-Markovnikov) a simple analysis, as presented above, suggests that these reactions may not be determined by a firststep intermediate, characteristic to electrophilic addition reactions. In this sense they should not even be considered Markovnikov-type addition reactions; we may choose to call 1684


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them “non-Markovnikov” or, alternatively, we may drop the name altogether. Our conclusions are based on first-principles, thermodynamic calculations known to be comparable to or better than experimental thermochemical data (8). Though the method we have used is computationally fairly intensive we have obtained all the results reported here in a relatively short time, running relatively inexpensive software on a desktop PC. Computer programs of comparable quality and capabilities are also available free of charge.3 The molecular energies and atomic charges that have been reported on the pages of this Journal exhibit similar trends to our results and were obtained using simpler software and in a fraction of time (5). While the use of computational tools will benefit the study of organic chemistry, we are not suggesting that an analysis of the type presented above, even in a simpler form, would be suitable for the majority of sophomore organic chemistry students. We do think, however, that the nature of electrophilic addition reactions to alkenes should be explained correctly, using the qualitative arguments summarized in Table 1. The concepts we have used, energy difference and electron density, are not new to students. Organic chemistry instructors use them to explain much of the course material, from dipole moments to cis–trans isomers, to carbocation rearrangements, to heats of combustion, to zwitterionic forms of amino acids. Most of the electrophilic addition reactions to alkenes given in sophomore organic chemistry textbooks can be explained correctly using only qualitative arguments, for example, the higher stability of branched carbocations, or the position of boron on the electronegativity scale. For the more complicated cases the instructor should supply the actual atomic charges, easily obtained using one of the “molecular modeling” programs. Students will benefit from this approach in two ways: first, by learning the essence of electrophilic addition reactions to alkenes using simple, robust and highly portable concepts and, second, by not having to memorize names and terms of limited use. Finally, an instructor of organic chemistry resorting more often to modern, easily accessible and very powerful computational methods, is likely to acquire new insight into old, seemingly familiar things. Acknowledgments PPI would like to thank Una Ilich, The Ohio State University, Columbus, Ohio, for editorial help; William Kirk, Mayo Foundation, Rochester, Minnesota, for help with bibliography; the Department of Chemistry and Biochemistry, Loras College, Dubuque, Iowa, for a desktop microcomputer; and the Iowa Science Foundation (Grant # ISF 04-13) for a quantum chemistry software package. Notes 1. Effective-core-potential, ECP, methods were used to calculate Gibbs energies and atomic charges for compounds with elements beyond third-row, where the G3MP3 method is not applicable (reaction given in Figure 3, for example). The ECP calculations were carried out using the Los Alamos National Laboratory Double Zeta, or LANL2DZ, basis set and the hybrid Becke’s 3-parameter, Lee, Yang, and Parr’s functional (B3LYP). All calcula-


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Research: Science and Education tions were carried out using the GAUSSIAN-03 program, see: Frisch, Æ.; Frisch, M. Gaussian 03 User’s Reference; Gaussian, Inc.; Pittsburgh, PA, 2003. 2. Natural Bond Order, NBO, electron densities (e.g., Foster, J. P.; Weinhold, F. J. Am. Chem. Soc. 1980, 102, 7211–7218) were calculated using the B3LYP hybrid functionals (e.g., Frisch, Æ.; Frisch, M. Gaussian 03 User’s Reference; Gaussian, Inc.; Pittsburgh, PA, 2003, and references therein) with the LANL2DZ (reaction iii) basis sets. The electron densities, the charges throughout the text, (natural or Mullikan) are given as electron charge fraction per cubic Bohr radius [qe 兾a03]; 1 qe = 1.6 × 10᎑19 C and 1 a0 = 52.9 pm. 3. General Atomic and Molecular Electronic Structure System (GAMESS). http://www.msg.ameslab.gov/GAMESS/ GAMESS.html (accessed Jul 2006).

Literature Cited 1. Jones, G. J. Chem. Educ. 1961, 38, 296–300. 2. Kharasch, M. S.; Mayo, F. R. J. Am. Chem. Soc. 1933, 55, 2468–2496. 3. Isenberg, N.; Grdinic, M. J. Chem. Educ. 1969, 46, 601–605. 4. Dewar, J. J. S.; Zoebisch, E. G.; Healy, E. F. J. Am. Chem. Soc. 1985, 107, 3902–3909.

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5. Hessley, R. K. J. Chem. Educ. 2000, 77, 794–797. 6. Gooch, E. E. J. Chem. Educ. 2001, 78, 1358–1359. 7. Curtiss, L. A.; Redfern, P. C.; Raghavachari, K.; Rassolov, V.; Pople, J. A. J. Chem. Phys. 1999, 110, 4703–4709. 8. Hehre, W. J.; Radom, L.; Schleyer, P. von R.; Pople, J. A. Ab Initio Molecular Orbital Theory; Wiley-Intersicence: New York, 1986; Chapter 2.8. 9. Johnson, J. R.; van Campen, M. G., Jr. J. Am. Chem. Soc. 1938, 60, 121–124. 10. Brown, H. C.; Rao, B. C. S. J. Am. Chem. Soc. 1956, 78, 5694–5695. 11. Markovnikoff, W. Ann. Chem. Pharm. 1870, 153, 228–259, to cite: “…wenn ein unsymmetrisch constituirter Kohlenwasserstoff sich mit einer Haloïdwasserstofsäure verbindet, so addirt sich das Haloid an das weniger hydrogenisirte Kohlenwasserstoffatom, …” — “… when an asymmetric hydrocarbon reacts with (binds to) a hydrogen halide (acid) the halogen adds to the less hydrogenated carbon atom, … .” 12. Oglobin, K. A.; Kunovskaya, D. M. Zh. Obsch. Khim. 1965, 1, 1713–1715. 13. (a) Crotti, P.; Chini, M.; Uccello-Baretta, G.; Macchia, F. J. Org. Chem. 1989, 54, 4525–4529. (b) Cambie, R. C.; Jurlina, J. L.; Rutledge, P. S.; Woodgate, P. D. J. C. S. Perkin 1, 1982, 315–325.


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Why Is Anti-Markovnikov HydroborationâOxidation of Alkenes Not

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