Birch reduction
The Birch Reduction, Mechanistic and Historical Aspects
The Birch Reduction involves the reaction of an aromatic in liquid ammonia with an alcohol and sodium, lithium or potassium to afford an unconjugated 1,4-cyclohexadiene. The original reaction reported by Arthur Birch in 1944 utilized sodium and ethanol.[1] Subsequently A. L. Wilds noted that better yields result with lithium.[2] Also the use of t-butyl alcohol has become common. The reaction is one of the main organic reactions utilized in all types of syntheses.
The reduction of anisole is one of the simplest examples and is shown in Eqn. 1. Still another example is that of benzoic acid illustrated in Eqn. 2.
_Birch-Anisole.png)
_Birch-Benzoic.gif)
The solution of metal in ammonia provides electrons which are taken up by the aromatic ring to form the corresponding radical anion B in the first step of the reaction. This is followed by protonation by the alcohol to form a cyclohexadienyl radical C. Next a second electron is transferred to the radical to form a cyclohexadienyl carbanion D. In the last step a second proton leads the cyclohexadienyl carbanion to the unconjugated cyclohexadienyl product. These steps are outlined in Eqn 3 for the case of anisole.
_Birch_Basic-Mech.png)
The reaction is known to be third order – first order in aromatic, first order in the alkali metal, and first order in the alcohol [3]. This requires the rate-limiting step to be the conversion of radical anion B to the cyclohexadienyl radical C.
The mechanism of the Birch Reduction accounting for its regioselectivity. Birch’s rule for aromatics with electron donors such as methoxyl or alkyl is that the product will have the residual double bonds bearing the maximum number of substituents. For aromatics with electron withdrawing groups such as carboxyl, the substituent groups avoid the double bonds. In both cases, with electron donating and with withdrawing groups, the residual double bonds are unconjugated (vide infra). It has been a matter of intense interest to understand reaction mechanisms accounting for this regioselectivity.
The original Birch mechanism suggested that the initial radical anion protonation was meta to ring methoxy and alkyl groups and the last step, protonation of a cyclohexadienyl anion, was ortho.
Birch’s original mechanism was based on qualitative reasoning, namely that the radical anion’s electron density, resulting from the addition of an electron, would become highest meta to an electron donor (such as methoxy or methyl) due to avoiding the usual ortho-para high density in the neutral species. [Note Ref 1].
Using simple Hückel computations in 1961 it was shown that the Birch mechanism was incorrect. The correct mechanism M is depicted in Figure 1. [Note Ref[4], also Ref[5] ].
Figure 1. – The two a-priori alternative mechanisms O and M; Mechanism O is correct.
However, Birch did not accept this conclusion and continued publications suggesting meta protonation of the radical anion. He suggested at meta attack results from consideration of “opposition of the initial charge” [Ref 6].
[6] Birch, A. J.; Nasipuri, D. Tetrahedron 1959, 148-153.
Bothner-By in 1959 had given qualitative arguments favoring meta-protonation [Ref 3] as had been suggested previously by Birch.
Subsequently, Birch in a review article [Ref 7] noted that no experimental method at the time existed which would determine which was correct. But he did note that publication by Burnham [Ref 6] favored meta attack.
[7] Birch, A. J.; Subba , Rao, G. Adv. Org. Chem.1972, 8, 1-65 (and refs therein).
Burnham concluded that protonation is unlikely to occur predominantly at the ortho position and the reaction most probably occurs at the meta position but may occur at both sites at similar rates [Ref 8].
[8] Burnham, D. R., Tetrahedron, 1969 25, 897-904.
Thus there was a decade of controversy in the literature in which each of these two possible mechanisms was considered to be correct.
In 1980 publications Birch collaborated with Leo Radom and considered ortho and meta densities to be close with a slight ortho preference but with mixtures of ortho and para protonation occurring [Refs 9, 10]. In Refs 9 and 10 RHF/sto-3g and UHF/sto-3g computations were used. It was concluded that both ortho and meta substitutions would occur with a slight preference for ortho.
[9] Birch, A. J.; Hinde, A. L.;Radom, L. 1980, 102, 3370-3376.
[10] Birch, A. J.; Radom, L,, J. Amer. Chem. Soc., 1980, 102, 4074-4080.
Then in 1991 and 1993 [Refs 11, 12] a method was finally devised to experimentally assess whether the anisole and toluene radical anion protonated ortho or meta. The esoteric method began with the premise that the isotope selectivity in protonation in a protium-deuterium medium would be greater for the radical anion, of the first protonation step, than for the carbanion of the penultimate step. The reasoning was that carbanions are much more basic than the corresponding radical anions and thus will react more exothermically and less selectively in protonation. Experimentally it was determined that less deuterium at the ortho site than meta resulted (1:7) for a variety of methoxylated aromatics. This is a consequence of the greater selectivity of the radical anion protonation. Computations (e.g. ROHF/6-31g) of the electron densities concurred with the experimental observations. Also, it was ascertained that frontier orbital densities did not, and these had been used in some previous reports.
[11] "The Regioselectivity of the Birch Reduction", Zimmerman, H. E.; Wang, P. A., J. Am. Chem. Soc., 1990, 112, 1280-1281.
[12] "Regioselectivity of the Birch Reduction", Zimmerman, H. E.; Wang, P. A., J. Am. Chem. Soc., 1993, 115, 2205-2216.
Subsequently, in 1961 and 1962 Birch published twice still suggesting that meta protonation was preferred [Refs 13, 14]. This was a reversal of his earlier views as published with Leo Radom.
[13] Birch, A. J., Steroids, 1992, 57, 363-377. (showed mechanism w meta), note below:
[14] Birch, A. J., Pure & Appl. Chem., 1996, 68, (3), 553-556. (still suggests meta).
However, textbooks, publishing on the mechanism of the Birch Reduction, have noted that ortho protonation of the initial radical anion is preferred. [Ref 14].
[15] “Advanced Organic Chemistry: Reactions and synthesis”, Francis A. Carey, Richard J. Sundberg, pg 437.
In contrast to the examples with electron donating substituents, the case with withdrawing groups is more readily obvious. Thus, as depicted in Figure 2, the
Figure 2. Mechanism of Reduction of Benzoic Acids, Including Possible Alkylation
structure of the penultimate dianion D is characterized by its being subject to trapping by alkyl halides. This dianion results independent of whether alcohol is used in the reduction or not. Thus the initial protonation by t-butyl alcohol or ammonia is para rather than ipso as seen in the step from B to C.
[16] Bachi, J. W.; Epstein, Y.; Herzberg-Minzly, H.; Loewnenthal, J. E., J. Org. Chem., 1969, 34, 136-135.
[17] Taber, D. F.; Gunn, B.P; Ching Chiu, I, Organic Syntheses, Coll. Vol. 7, p.249 (1990); Vol. 61, p.59 (1983). Taber. D. F., 1976. 41, 2649-2650.
[18] Guo, Z.; Schultz, A. G., J. Org. Chem., 2001, 66, 2154-2157.
We turn now to the final step of the Birch Reduction affording unconjugated cyclohexadienes. This second step of the Birch Reduction posed interesting mechanistic questions as well. Thus as shown in Figure 3 there are three resonance structures B, C and D for the carbanion. Simple Hückel computations lead as noted in Table 1 to equal electron densities at the three atoms 1,3 and 5. However, in contrast to densities the Hückel computation is less naïve about bond orders [Refs 4, 19, 20] and bonds 2-3 and 5-6 will be shortened; note Table 1, entry 1. With bond orders modifying simple exchanges integrals in a Mulliken-Wheland-Mann computation it was shown (Table 1 again) that electron density at the central atom 1 become largest. More modern RHF computations lead to the same result [Refs 11,12].
Figure 3. Electron introduction to benzene and 3 resonance structures for the carbanion of the second step, and central protonation to give the unconjugated diene.
File:Fig 3 Cyclohexadienyl-Anion.gif
[19] Zimmerman, H. E., “Quantum Mechanics for Organic Chemists”, Academic Press, New York, 1975, 154-155.
[20] Zimmerman, H. E. in “Molecular Rearrangements”, De Mayo, P. Ed., Interscience, New York, 1963, p 350-352.
Table 1. The Pentadienyl Anion
| header 1 Approximation | Density Atom 1 | Density Atom 2 | Density Atom 3 | Bond Order 1-2 | Bond Order 2-3 |
|---|---|---|---|---|---|
| Huckel (1st Approx) | 0.333 | 0.00 | 0.333 | 0.788 | 0.578 |
| 2nd Approx | 0.317 | 0.00 | 0.365 | 0.802 | 0.564 |
| 3rd Approx | 0.316 | 0.00 | 0.368 | 0.802 | 0.562 |
Interestingly, central anion protonation had precedent [Refs 4,21]. Thus conjugated enolates as C=C-C=C-O- have been known for some time as kinetically protonating in the center of the enolate system to afford the β,γ-unsaturated carbonyl compound under conditions where the anion and not the enolate is the species protonated.
[21] Paufler, R. M. Ph.D. Thesis, Northwestern University, Evanston, IL. 1960.
References
- ^ (a) Birch, A. J., J. Chem. Soc. 1944, 430-436; (b) Birch, A. J., 1944, J. Chem. Soc., 430; 1945, 809; 1946, 593.
- ^ A. L. Wilds, A. L.; N. A. Nelson, N. A. J. Am. Chem. Soc. 1953, 75, 5360-5365.
- ^ Krapcho, A. P.; Bothner-By, A. A. J. Am. Chem. Soc. 1959, 81, 3658-3666.
- ^ "Orientation in Metal Ammonia Reductions," Zimmerman, H. E, Tetrahedron, 1961, 16, 169-176.
- ^ "Base-Catalyzed Rearrangements," Chapter 6 of "Molecular Rearrangements," Zimmerman, H. E., Ed. P. DeMayo, Interscience, 345-406, New York, 1963.
Howard E. Zimmerman 01:42, 29 March 2010 (UTC) Howard E. Zimmerman 02:25, 29 March 2010 (UTC) Howard E. Zimmerman 02:31, 29 March 2010 (UTC) Howard E. Zimmerman 02:09, 29 March 2010 (UTC 146.151.214.43 (talk) 12:25, 29 March 2010 (UTC) Howard E. Zimmerman 19:31, 29 March 2010 (UTC) Howard E. Zimmerman 19:33, 29 March 2010 (UTC) Howard E. Zimmerman 19:37, 29 March 2010 (UTC) Howard E. Zimmerman 20:55, 29 March 2010 (UTC) Howard E. Zimmerman 21:04, 29 March 2010 (UTC) Howard E. Zimmerman 21:30, 29 March 2010 (UTC) Howard E. Zimmerman 13:16, 30 March 2010 (UTC) Howard E. Zimmerman 13:21, 30 March 2010 (UTC)