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11-06-04 22:04
No 540064
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Birch Reduction of Aromatic Compounds
Reduction of Benzene and Derivatives by Sodium in Ammonia
A facile reduction of benzene and substituted benzenes is achieved by treatment with the electron rich solution of alkali metals, usually lithium or sodium, in liquid ammonia. This reaction, which is called the Birch Reduction, is related to the reduction of alkynes to trans-alkenes. Reduction is believed to occur by a stepwise addition of two electrons to the benzene ring, each electron addition being followed by a protonation, as illustrated in the following diagram. The initial electron addition gives a radical-anion for which many resonance contributors may be written. Following delivery of a proton by the weak acid ammonia, the resulting delocalized radical accepts a second electron to give an anion. The anion generated by the second electron addition is delocalized over three carbon atoms, and is protonated on the central carbon. The isolated (unconjugated) double bonds in the product do not react under these conditions.
When substituents are present, they may influence the regioselectivity of the Birch reduction. The product is determined by the site of the first protonation, since the second protonation is nearly always opposite (para to) the first. Electron-donating substituents such as ethers and alkyl groups favor protonation at an unoccupied site meta to the substituent; whereas electron-attracting substituents such as carboxyl favor para protonation. The influence of a carboxyl group dominates poly substituted rings, and alkoxy groups have a greater directing influence than alkyl substituents. An oxy anion group, as in the conjugate base of phenol, prevents reduction from occurring. Two examples of such Birch reductions are shown below. Although the substrate molecule in the first reaction may appear very complex, it is essentially a rigid framework with a benzene ring at each end. The phenolic function on the left hand ring becomes a phenolate anion under the reduction conditions, and does not react further. The right hand aromatic ring is an ether, and it reduces as expected. The carboxylic acid in the second example is immediately converted to its conjugate base. Although this carboxylate anion is negatively charged, it still has an electrophilic carbon atom which acts to stabilize an adjacent negative charge as shown. After protonation of the para carbanion by ammonia, the carboxylate dianion remains unchanged until it is doubly protonated by a strong acid, such as NH4(+) or H3O(+).
Further examples of Birch reductions are presented in the following diagram. The preference for protonation at unsubstituted sites (unless electron withdrawing groups are present), and for unconjugated products is again illustrated in the first reaction. Note that the isolated double bonds are not reduced at the low temperatures of refluxing liquid ammonia (–33 ºC). Reactions #2 & 4 illustrate a particularly useful application of the Birch reduction. Aryl ethers are reduced to 1,4-dienes, as expected, but one of the double bonds is an enol ether and is readily hydrolyzed to the corresponding ketone. If mild acid catalysis is used, the other double bond remains unchanged; more vigorous acid (or base) treatment shifts this double bond to a conjugated location if simple proton shifts permit. The 3rd reaction again illustrates the regio-directive influence of a carboxyl group, even in the carboxylate form. The alpha-anion is sufficiently stable that it may induce an elimination reaction (first stage) and upon regeneration be alkylated by a reactive alkyl halide (second stage). The last example shows the Birch reduction of pyridine to a bis-enamine, hydrolysis of which gives a diketone.
Reduction of π-Electron Systems by Active Metals
Dissolving Metal Reductions of π-Electron Systems
Reduction of alkynes and benzene rings by solutions of sodium or lithium in liquid ammonia have been described. Other reactive metals, such as zinc and magnesium have played a role in reductions of aldehydes and ketones (Clemmensen reduction), alkyl halides and vicinal-dihalides. The ability of certain metals to donate electrons to (reduce) electrophilic or unsaturated functional groups has proven useful in several reductive procedures. The facility with which various of these metals donate electrons is given by their reduction potentials. From these potentials the qualitative order of reducing power is: Li > K > Na > Mg > Al = Ti > Zn > Fe > Sn.
1. Reduction of Isolated Carbonyl Groups
Lithium, sodium and potassium reduce ketones by a one-electron transfer that generates a radical anion known as a ketyl. Once such a reactive species is formed, it may react further by several modes, as described in the following diagram. If a proton source is present, the ketyl undergoes carbon protonation, and the resulting oxy radical adds another electron to generate an alkoxide salt. Alternatively, ketyls may dimerize to pinacol salts. Isolation of alcohol or pinacol products requires further protonation by acids at least as strong as water or ethanol. The H+ notation refers to any of several possible proton sources, including ammonia, alcohols and the ammonium cation (a strong acid in the liquid ammonia system). Benzophenone (diphenyl ketone) forms a deep blue ketyl which is stable in solvents that lack acidic hydrogens, such as hydrocarbons and ethers. It is widely used as an indicator of oxidizing or acidic impurities during the purification of such solvents.
The solvents used for alkali metal reductions include hydrocarbons, ethers and, most commonly, liquid ammonia. Alcohols may also be used, but usually as co-solvents, since they react vigorously with these metals. Examples of metal reductions of ketones to alcohols and pinacols (a dimeric diol) are shown below. In the first example, reduction of benzophenone in liquid ammonia gives both alcohol and pinacol products. The ketyl intermediate in this reaction is stabilized by phenyl substituents, and competitive carbon atom protonation and dimerization generate alkoxide salts that remain in solution until hydrolyzed prior to product isolation. In the second reaction, two isolated ketone functions are reduced to alcohols. The ketyl intermediates are not stabilized, and their rapid protonation is assured by the alcohol co-solvent. Conformational motion is restricted by the rigid polycyclic carbon framework of the substrate, and an interesting stereoselectivity is revealed: both alcohols are formed as the equatorial isomer. Aldehydes are not usually reduced in this manner, because they react with ammonia to form unreactive imine condensation products.
When pinacol products are desired, a less reactive metal having stronger (less ionic) C-O bonds is chosen for the reduction. Magnesium is often used, and best results have been achieved when the metal is activated by amalgamation (alloyed with mercury) and Lewis acids are present. Equations #3 & 4 (above) illustrate pinacol reduction. A di-positive cation may serve to hold two associated ketyl moieties close to each other so that bonding is facilitated (as shown in equation #3). Hydrolysis of metal alkoxides releases the product.
Ester functions undergo similar reductions on treatment with sodium. The most useful reaction of this kind is the acyloin condensation. To avoid protonation at carbon, this reaction is normally carried out in hydrocarbon solvents. The acyloin condensation creates alpha-hydroxy ketones. Two examples of this reaction are shown here. The second illustrates the usefulness of this reaction for constructing medium and large-sized rings. By clicking the "Show Mechanism" button a diagram for a possible mechanism for the acyloin condensation will be displayed. The reduction of alpha-diketones to acyloins, as shown on the second line, can be carried out independently.
2. Reductive Removal of α-Substituents
The partial negative charge on the carbon atom of a ketyl may serve to eliminate an electronegative substituent at an alpha-location. If further reduction is not desired, aluminum or zinc are often selected for this reductive elimination. The following examples illustrate three such transformations, the first being a useful conversion of acyloins to ketones.
3. Reduction of Conjugated π-Electron Systems
Two or more different fuctional groups are sometimes found together, and interaction of one upon another may lead to unexpected chemistry. The addition reactions of conjugated dienes are one example of this phenomenon. A similar situation occurs in conjugated enones, compounds in which a carbonyl group is bonded to a carbon-carbon double bond.
C=C–C=O
(an α,β-unsaturated ketone or enone)
Such functional combinations are often prepared by an aldol condensation, and are particularly useful as synthetic intermediates. Because the π-electron systems of the two functional groups are conjugated (the π-orbitals overlap in space), the radical anion formed by electron addition from a reducing metal is a resonance hybrid of six canonical structures. In addition to the two ketyl contributors described above, two structures having radical and nucleophilic character at the beta-carbon are shown in the following diagram, and two others in which the radical anion character is localized on the double bond are probably least important.
The usual fate of the extended ketyl described here is protonation (or other electrophilic bonding) at the beta-carbon atom. This creates an enoxy radical which immediately accepts an electron to form an enolate anion. Protonation or alkylation of this enolate species then gives a saturated ketone, which may be isolated or further reduced depending on the reaction conditions. Four examples of such reactions are shown below.
In example #1 the enone substrate is drawn in the yellow box. If the lithium reduction is carried out in liquid ammonia without any acidic co-solvents, the enolate anion is stable and remains unchanged until an electrophilic reagent such as methyl iodide is added. This is shown for the reaction to the right. If an acidic co-solvent such as ethanol is present, the enolate anion is protonated, and the resulting ketone is then reduced to an alcohol (reaction to the left). Although the radical anion intermediate usually undergoes protonation at the beta-carbon, this is not a fast reaction in liquid ammonia. Example #2 presents an interesting case in which intramolecular alkylation of the beta-nucleophile occurs faster than protonation. Example #3 is a case of cross-conjugation. The carbonyl group is conjugated with one or the other double bond, but not both simultaneously. Two different radical anions may be formed by electron addition, and these exist in equilibrium with each other. Protonation at a beta-carbon effectively traps a radical anion as its related enolate anion, preventing any further interconversion. This protonation is fastest at the less substituted site (upper enone), and if the resulting enolate anion is not converted to its keto form by in situ protonation, it will not react further until quenchied by ammonium ion.
Conjugated dienes are also reduced by sodium or lithium solutions in liquid ammonia. 1,3-Cyclohexadiene is reduced to cyclohexene, but the unconjugated 1,4-diene is not. If a double bond is conjugated with a benzene ring, as in styrene, it is likewise reduced.
The Leuckart Reaction
The Leuckart Reaction
A useful procedure for the reductive alkylation of ammonia, 1º-, & 2º-amines, in which formic acid or a derivative thereof serves as the reducing agent, is known as the Leuckart Reaction. Some examples of this reaction are shown below.
The manner in which a hydride moiety is transferred from formate to an iminium intermediate is a matter for speculation, but may be summarized roughly as shown on the right. Both aldehydes and ketones may be used as the carbonyl reactant. By using ammonia as a reactant, this procedure may be used to prepare 1º-amines; however, care must be taken to avoid further alkylation to 2º & 3º-amines. Polyalkylation is sometimes desired, as in example #3 where dimethylation is accomplished with formaldehyde. This is sometimes referred to as the Eschweiler-Clarke procedure, and it has proven to be a useful method for converting 1º-amines to precursors for Hofmann or Cope elimination reactions.
Carbonyl Hydrates & Hemiacetals
Stable Carbonyl Hydrates & Hemiacetals
Although most aldehydes and ketones do not form stable hydrates or hemiacetals, a number of interesting exceptions are known. Some examples are shown here.
The factors that act to favor hydrate or hemiacetal formation include inductive charge repusion (chloral) dipole repusion (ninhydrin) and angle strain (cyclopropanaone). It is important to note that cases in which 5 or 6-membered cyclic hemiacetals can form usually favor such constitutions. The simple sugars offer many examples of this kind. Because these additions are readily reversible, all compounds of this type exhibit carbonyl-like chemical reactivity.
To beeeee, or not to be
