Birch reduction

A solution of sodium in liquid ammonia consists of the intensely blue electride salt [Na(NH₃)_x]⁺ e⁻. The solvated electrons add to the aromatic ring to give a radical anion, which then abstracts a proton from the alcohol. The process then repeats at either the ortho or para position (depending on substituents) to give the final diene.{{JerryMarch}} The residual double bonds do not stabilize further radical additions.{{cite journal |author1=Rabideau, P. W. |author2=Marcinow, Z. |year=1992 |title=The Birch Reduction of Aromatic Compounds |journal=Org. React. |type=review |volume=42 |pages=1–334 |doi=10.1002/0471264180.or042.01 |isbn=0471264180}}{{cite journal |author=Mander, L. N. |year=1991 |title=Partial Reduction of Aromatic Rings by Dissolving Metals and by Other Methods |journal=Compr. Org. Synth. |type=review |volume=8 |pages=489–521 |doi=10.1016/B978-0-08-052349-1.00237-7 |isbn=978-0-08-052349-1}}

File:Birch reduction radical mechanism.svg, also available in animated form.|alt=Electron attacks a benzene ring, which then abstracts a proton from ROH; process then repeats in the para position.|thumb]]

The reaction is known to be third order – first order in the aromatic, first order in the alkali metal, and first order in the alcohol.{{cite journal |author1=Krapcho, A. P. |author2=Bothner-By, A. A. |year=1959 |title=Kinetics of the Metal-Ammonia-Alcohol Reductions of Benzene and Substituted Benzenes1 |journal=J. Am. Chem. Soc. |volume=81 |issue=14 |pages=3658–3666 |doi=10.1021/ja01523a042}} This requires that the rate-limiting step be the conversion of radical anion B to the cyclohexadienyl radical C.

File:Birch Basic-Mech.svg.]]

That step also determines the structure of the product. Although Arthur Birch originally argued that the protonation occurred at the meta position,{{sfn|Birch|1944}} subsequent investigation has revealed that protonation occurs at either the ortho or para position. Electron donors tend to induce ortho protonation, as shown in the reduction of anisole (1). Electron-withdrawing substituents tend to induce para protonation, as shown in the reduction of benzoic acid (2).{{Cite book |last1=Carey |first1=Francis A. |title=Advanced Organic Chemistry |last2=Sundberg |first2=Richard J. |publisher=Springer |year=2007 |isbn=978-0-387-44899-2 |edition=5th |volume=B: Reactions and Synthesis |location=New York |pages=437–439}}

File:Birch-Anisole.svg

File:Birch-Benzoic.svg

Solvated electrons will preferentially reduce sufficiently electronegative functional groups, such as ketones or nitro groups, but do not attack alcohols, carboxylic acids, or ethers.

The second reduction and protonation also poses mechanistic questions. Thus there are three resonance structures for the carbanion (labeled B, C and D in the picture). File:Cyclohexadienyl Anion1.svgSimple Hückel computations lead to equal electron densities at the three atoms 1, 3 and 5, but asymmetric bond orders. Modifying the exchange integrals to account for varying interatomic distances, produces maximum electron density at the central atom 1,{{cite journal |author=Zimmerman, H. E. |year=1961 |title=Orientation in Metal Ammonia Reductions |journal=Tetrahedron |volume=16 |issue=1–4 |pages=169–176 |doi=10.1016/0040-4020(61)80067-7}}{{cite book |last=Zimmerman |first=Howard E |url=https://archive.org/details/quantummechanics00zimm/page/154 |title=Quantum Mechanics for Organic Chemists |publisher=Academic Press |year=1975 |isbn=0-12-781650-X |location=New York |pages=[https://archive.org/details/quantummechanics00zimm/page/154 154–5] |url-access=registration}}{{cite book|last=Zimmerman|first=H. E.|title=Molecular Rearrangements|chapter=Base-Catalyzed Rearrangements|pages=350–352|editor-last=De Mayo|editor-first=P.|publisher=Interscience|location=New York|year=1963}} a result confirmed by more modern RHF computations.

• {{cite journal |author1=Zimmerman, H. E. |author2=Wang, P. A. |year=1990 |title=The Regioselectivity of the Birch Reduction |journal=J. Am. Chem. Soc. |volume=112 |issue=3 |pages=1280–1281 |doi=10.1021/ja00159a078}}
• {{cite journal |author1=Zimmerman, H. E. |author2=Wang, P. A. |year=1993 |title=Regioselectivity of the Birch Reduction |journal=J. Am. Chem. Soc. |volume=115 |issue=6 |pages=2205–2216 |doi=10.1021/ja00059a015}}

The result is analogous to conjugated enolates. When those anions (but not the enol tautomer) kinetically protonate, they do so at the center to afford the β,γ-unsaturated carbonyl.Paufler, R. M. (1960) Ph.D. Thesis, Northwestern University, Evanston, IL.

Traditional Birch reduction requires cryogenic temperatures to liquify ammonia and pyrophoric alkali-metal electron donors. Variants have developed to reduce either inconvenience.

Many amines serve as alternative solvents: for example, bis(methoxymethyl)amine in THF{{cite journal |author1=Ecsery, Zoltan |author2=Muller, Miklos |name-list-style=amp |year=1961 |title=Reduction vitamin D2 with alkaly metals |journal=Magyar Kémiai Folyóirat |volume=67 |pages=330–332}}{{cite journal |author1=Donohoe, Timothy J. |author2=House, David |name-list-style=amp |year=2002 |title=Ammonia Free Partial Reduction of Aromatic Compounds Using Lithium Di-tert-butylbiphenyl (LiDBB) |journal=Journal of Organic Chemistry |volume=67 |issue=14 |pages=5015–5018 |doi=10.1021/jo0257593 |pmid=12098328}} or mixed n-propylamine and ethylenediamine.{{cite journal |author=Garst, Michael E. |author2=Lloyd J. |author3=Shervin |author4=N. Andrew |author5=Natalie C. |author6=Alfred A. |display-authors=etal |year=2000 |title=Reductions with Lithium in Low Molecular Weight Amines and Ethylenediamine |journal=Journal of Organic Chemistry |volume=65 |issue=21 |pages=7098–7104 |doi=10.1021/jo0008136 |pmid=11031034}} Pure secondary and tertiary amines, however, fail to dissolve alkali metals.Audrieth & Kleinberg (1953), [https://archive.org/details/cftri.2662nonaqueoussolven0000ludw/page/114/ Non-aqueous solvents], pp. 117-118.

To avoid direct alkali, there are chemical alternatives, such as M-SG reducing agent. The reduction can also be powered by an external potential or sacrificial anode (magnesium or aluminum), but then alkali metal salts are necessary to colocate the reactants via complexation.{{cite journal |last1=Peters |first1=Byron K. |last2=Rodriguez |first2=Kevin X. |last3=Reisberg |first3=Solomon H. |last4=Beil |first4=Sebastian B. |last5=Hickey |first5=David P. |last6=Kawamata |first6=Yu |last7=Collins |first7=Michael |last8=Starr |first8=Jeremy |last9=Chen |first9=Longrui |last10=Udyavara |first10=Sagar |last11=Klunder |first11=Kevin |date=21 February 2019 |title=Scalable and safe synthetic organic electroreduction inspired by Li-ion battery chemistry |journal=Science |volume=363 |issue=6429 |pages=838–845 |bibcode=2019Sci...363..838P |doi=10.1126/science.aav5606 |pmc=7001862 |pmid=30792297 |last12=Gorey |first12=Timothy J. |last13=Anderson |first13=Scott L. |last14=Neurock |first14=Matthew |last15=Minteer |first15=Shelley D. |last16=Baran |first16=Phil S.}}

In Birch alkylation the anion formed in the Birch reduction is trapped by a suitable electrophile such as a haloalkane, for example:{{OrgSynth | author = Taber, D. F. | author2 = Gunn, B. P. | author3 = Ching Chiu, I. | year = 1983 | title = Alkylation of the anion from Birch reduction of o-Anisic acid: 2-Heptyl-2-cyclohexenone | collvol = 7 | collvolpages = 249 | prep = cv7p0249}}

:File:BirchAlkylationOrgSynth1990.svg

In substituted aromatics, an electron-withdrawing substituent, such as a carboxylic acid, will stabilize the carbanion to generate the least-substituted olefin;{{OrgSynth|author=Kuehne, M. E.|author2=Lambert, B. F.|year=1963|title=1,4-Dihydrobenzoic acid|collvol=5|collvolpages=400|prep=cv5p0400}} an electron-donating substituent has the opposite effect.{{OrgSynth|author=Paquette, L. A.|author2=Barrett, J. H.|year=1969|title=2,7-Dimethyloxepin|collvol=5|collvolpages=467|prep=cv5p0467}}

:File:BirchAlkylation.png to a Birch reduction of tert-butyl benzoate forms the 1,1-cyclohexadiene product.{{cite journal |author1=Clive, Derrick L. J. |author2=Sunasee, Rajesh |name-list-style=amp |year=2007 |title=Formation of Benzo-Fused Carbocycles by Formal Radical Cyclization onto an Aromatic Ring |journal=Organic Letters |volume=9 |issue=14 |pages=2677–2680 |doi=10.1021/ol070849l |pmid=17559217}}|alt=Birch alkylation|thumb]]

The Benkeser reduction is the hydrogenation of polycyclic aromatic hydrocarbons, especially naphthalenes using lithium or calcium metal in low molecular weight alkyl amines solvents. Unlike traditional Birch reduction, the reaction can be conducted at temperatures higher than the boiling point of ammonia (−33 °C).[https://web.archive.org/web/20080915221334/http://www.pmf.ukim.edu.mk/PMF/Chemistry/reactions/birch.htm Birch Reductions], Institute of Chemistry, Skopje, Macedonia{{OrgSynth | author = Vogel, E. | author2 = Klug, W. | author3 = Breuer, A. | year = 1974 | title = 1,6-Methano[10]annulene | collvol = 6 | colvolpages = 731 | prep = cv6p0731}}

For the reduction of naphthalene with lithium in a mixed ethylamine-dimethylamine solution, the principal products are bicyclo[3.3.0]dec-(1,9)-ene, bicyclo[3.3.0]dec-(1,2)-ene and bicyclo[3.3.0]decane. Edwin M. Kaiser and Robert A. Benkeser "Δ^9,10-Octalin" Org. Synth. 1970, vol. 50, p. 88ff. {{doi|10.15227/orgsyn.050.0088}}Merck Index, 13th Ed.

Image:Benkeser Reduction(corrected).png

File:BirchBenkeser small.png

The directing effects of naphthalene substituents remain relatively unstudied theoretically. Substituents adjacent to the bridge appear to direct reduction to the unsubstituted ring; β substituents (one bond further) tend to direct reduction to the substituted ring.

Arthur Birch, building on earlier (1937) work by Wooster and Godfrey who used water,{{Cite journal |last1=Wooster |first1=C. B. |last2=Godfrey |first2=K. L. |year=1937 |title=Mechanism of the Reduction of Unsaturated Compounds with Alkali Metals and Water |journal=Journal of the American Chemical Society |volume=59 |issue=3 |pages=596 |doi=10.1021/ja01282a504}} developed the reaction in the 1940s while working in the Dyson Perrins Laboratory at the University of Oxford.

• {{cite journal | last=Birch | first=A. J. | journal = J. Chem. Soc. | year = 1944 | pages = 430 | doi = 10.1039/JR9440000430 | title = Reduction by dissolving metals. Part I}}
• {{cite journal | last=Birch | first=A. J. | journal = J. Chem. Soc. | year = 1945 | pages = 809 | doi = 10.1039/jr9450000809 | title = Reduction by dissolving metals. Part II}}
• {{cite journal | last=Birch | first=A. J. | journal = J. Chem. Soc. | year = 1946 | pages = 593 | doi = 10.1039/jr9460000593 | title = Reduction by dissolving metals. Part III}}
• {{cite journal | journal = J. Chem. Soc. | year = 1947 | pages = 102 | doi = 10.1039/jr9470000102 | title = Reduction by dissolving metals. Part IV | author = Birch, A. J.}}
• {{cite journal | journal = J. Chem. Soc. | year = 1947 | pages = 1642 | doi = 10.1039/jr9470001642 | title = Reduction by dissolving metals. Part V | author = Birch, Arthur J.}}
• {{cite journal | author = Birch, A. J. | journal = J. Chem. Soc. | year = 1949 | pages = 2531 | doi = 10.1039/jr9490002531 | title = Reduction by dissolving metals. Part VI. Some applications in synthesis | last2 = Mukherji | first2 = S. M.}}

Birch's original procedure used sodium and ethanol,{{sfn|Birch|1944}}{{sfn|Birch|1945}}{{sfn|Birch|1946}} Alfred L. Wilds later discovered that lithium gives better yields.{{cite journal|author1=Wilds, A. L. |author2=Nelson, N. A. |journal=J. Am. Chem. Soc. |year=1953|volume= 75|pages= 5360–5365|doi=10.1021/ja01117a064|title=A Superior Method for Reducing Phenol Ethers to Dihydro Derivatives and Unsaturated Ketones|issue=21}}{{cite journal |author1=Birch, A. J. |author2=Smith, H. | journal = Quart. Rev. | year = 1958 | volume = 12 | issue = 1 | pages = 17 | type = review | doi = 10.1039/qr9581200017 | title = Reduction by metal–amine solutions: applications in synthesis and determination of structure}}

The reaction was difficult to understand mechanistically, with controversy lasting into the 1990s.

The case with electron-withdrawing groups is obvious, because the Birch alkylation serves as a trap for the penultimate dianion D. This dianion appears even in alcohol-free reactions. Thus the initial protonation is para rather than ipso, as seen in the B-C transformation.{{cite journal |author1=Bachi, J. W. |author2=Epstein, Y. |author3=Herzberg-Minzly, H. |author4=Loewnenthal, J. E. |year=1969 |title=Synthesis of compounds related to gibberellic acid. III. Analogs of ring a of the gibberellins |journal=J. Org. Chem. |volume=34 |pages=126–135 |doi=10.1021/jo00838a030}}{{OrgSynth|author=Taber, D. F.|author2=Gunn, B.P|author3=Ching Chiu, I|title=Alkylation of the Anion from Birch Reduction of o-Anisic Acid: 2-Heptyl-2-Cyclohexenone|prep=cv7p0249|collvolpages=249|collvol=7|volume=61|page=59|year=1983}}{{cite journal |author1=Guo, Z. |author2=Schultz, A. G. |year=2001 |title=Organic synthesis methodology. Preparation and diastereoselective birch reduction-alkylation of 3-substituted 2-methyl-2,3-dihydroisoindol-1-ones |journal=J. Org. Chem. |volume=66 |issue=6 |pages=2154–2157 |doi=10.1021/jo005693g |pmid=11300915}}

File:Birch-Benzoic Mech.svgFor electron-donating substituents, Birch initially proposed meta attack, corresponding to the location of greatest electron density in a neutral benzene ring, a position endorsed by Krapcho and Bothner-By.{{cite journal |author1=Birch, A. J. |author2=Nasipuri, D. |year=1959 |title=Reaction mechanisms in reduction by metal-ammonia solutions |journal=Tetrahedron |volume=6 |issue=2 |pages=148–153 |doi=10.1016/0040-4020(59)85008-0}} These conclusions were challenged by Zimmerman in 1961, who computed electron densities of the radical and diene anions, revealing that the ortho site which was most negative and thus most likely to protonate. But the situation remained uncertain, because computations remained highly sensitive to transition geometry. Worse, Hückel orbital and unrestricted Hartree-Fock computations gave conflicting answers. Burnham, in 1969, concluded that the trustworthiest computations supported meta attack;{{cite journal |author=Burnham, D. R. |year=1969 |title=Orientation in the mechanism of the Birch reduction of anisole |journal=Tetrahedron |volume=25 |issue=4 |pages=897–904 |doi=10.1016/0040-4020(69)85023-4}} Birch and Radom, in 1980, concluded that both ortho and meta substitutions would occur with a slight preference for ortho.

• {{cite journal |author1=Birch, A. J. |author2=Hinde, A. L. |author3=Radom, L. |year=1980 |title=A theoretical approach to the Birch reduction. Structures and stabilities of the radical anions of substituted benzenes |journal=J. Am. Chem. Soc. |volume=102 |issue=10 |pages=3370–3376 |doi=10.1021/ja00530a012}}
• {{cite journal |author1=Birch, A. J. |author2=Radom, L. |year=1980 |title=A theoretical approach to the Birch reduction. Structures and stabilities of cyclohexadienyl radicals |journal=J. Am. Chem. Soc. |volume=102 |issue=12 |pages=4074–4080 |doi=10.1021/ja00532a016}}

In the earlier 1990s, Zimmerman and Wang developed an experiment technique to distinguish between ortho and meta protonation. The method began with the premise that carbanions are much more basic than the corresponding radical anions and thus protonate less selectively. Correspondingly, the two protonations in Birch reduction should exhibit an isotope effect: in a protium–deuterium medium, the radical anion should preferentially protonate and the carbanion deuterate. Indeed, a variety of methoxylated aromatics exhibited less ortho deuterium than meta (a 1:7 ratio). Moreover, modern electron density computations now firmly indicated ortho protonation; frontier orbital densities, most analogous to the traditional computations used in past studies, did not.

Although Birch remained reluctant to concede that ortho protonation was preferred as late as 1996,See diagrams in:

• {{cite journal |author=Birch, A. J. |year=1992 |title=Steroid hormones and the Luftwaffe. A venture into fundamental strategic research and some of its consequences: The Birch reduction becomes a birth reduction |journal=Steroids |volume=57 |issue=8 |pages=363–377 |doi=10.1016/0039-128X(92)90080-S |pmid=1519267 |s2cid=24827957}}
• {{cite journal |author=Birch, A. J. |year=1996 |title=The Birch reduction in organic synthesis |journal=Pure Appl. Chem. |volume=68 |issue=3 |pages=553–556 |doi=10.1351/pac199668030553 |s2cid=41494178|doi-access=free }}

Zimmerman and Wang had won the day: modern textbooks unequivocally agree that electron-donating substituents promote ortho attack.

• {{cite journal |doi=10.1002/0471264180.or023.01| author = Caine, D. | journal = Org. React. | year = 1976 | volume = 23 | pages = 1–258 | type = review |title=Reduction and Related Reactions of α,β-Unsaturated Carbonyl Compounds with Metals in Liquid Ammonia |isbn=0471264180}}

• Solvated electron — the reducing agent
• Bouveault–Blanc reduction — another reaction using solvated electrons
• Synthesis of methamphetamine — an application

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