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5.4 HYDROGEN ATOM DONORS. Reduction by hydrogen-atom donors involves free-radical intermediates. Tri- n -butyltin hydride is the most prominent example of this type of reducing agent. It is able to reductively replace halogen by hydrogen in organic compounds.
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5.4 HYDROGEN ATOM DONORS Reduction by hydrogen-atom donors involves free-radical intermediates. Tri-n-butyltin hydride is the most prominent example of this type of reducing agent. It is able to reductively replace halogen by hydrogen in organic compounds. The order of reactivity for the halides reflects the relative ease of the halogen-atom abstraction. RI > RBr > RCl > RF Mechanistic studies have indicated a free-radical chain mechanism In. + Bu3SnH → InH + Bu3Sn. Bu3Sn. + R-X → R. + Bu3SnX R. + Bu3SnH → RH + Bu3Sn.
Tri-n-butyltin hydride shows substantial selectivity toward polyhalogenated compounds, allowing partial dehalogenation. The reason for the greater reactivity of more highly halogenated carbons toward reduction lies in the stabilizing effect that the remaining halogen has on the radical intermediate. This selectivity has been used, for example, to reduce dihalocyclopropanes to monohalocyclopropanes. This reaction has been developed also in the catalytic version, with NaBH4 as the stoichiometric reagent, and it presents same advantages in the isolation and purification of the product.
Tri-n-butyltin hydride also serves as a hydrogen-atom donor in radical-mediated methods for reductive deoxygenation of alcohols. The alcohol is converted to a thiocarbonyl derivative. These thioesters undergo a radical reaction with tri-n-butyltin hydride. For example
NET ADDITION OF HYDROGEN REDUCTIVE REMOVAL OF A FUNCTIONAL GROUP CARBON-CARBON BOND FORMATION 5.5. DISSOLVING-METAL REDUCTIONS Another group of synthetically useful reductions employs a metal as the reducing agent. The organic substrate under these conditions accepts one or more electrons from the metal. The subsequent course of the reaction depends on the structure of the reactant and reaction conditions. DISSOLVING METAL REDUCTION
5.5.1. Hydrogen Addition Although the method has been supplanted for synthetic purposes by the use of hydride donors, the reduction of ketones to alcohols by alkali metals in ammonia or alcohols provides some mechanistic insight into dissolving-metal reductions.
The outcome of the reaction of ketones with metal reductants is determined by the fate of the initial ketyl intermediate formed by a single-electron transfer. The intermediate, depending on its structure and the reaction medium, may be protonated, or may disproportionate, or dimerize. In hydroxylic solvents, such as liquid ammonia, or in the presence of an alcohol, the protonation process dominates over dimerization.
a,b-Unsaturated carbonyl compounds are cleanly reduced to the enolate of the corresponding saturated ketone on reduction with lithium in ammonia. Usually, an alcohol is added to the reduction solution to serve as the proton source. This is one of the best methods for generating a specific enolate of a ketone. The stereochemistry of conjugated reduction is controlled by a stereoelectronic preference for protonation perpendicular to the enolate system, and, given that this requirement is met, it will normally correspond to protonation of the most stable conformation of the dianion intermediate from its least hindered side.
The enolate generated by conjugate reduction can undergo characteristic alkylation and addition reactions. When this is the objective of the reduction, it is important to use only one equivalent of the proton donor. Ammonia, being a weaker acid than an aliphatic ketone, does not protonate the enolate, and it remains available for reaction. If the saturated ketone is the desired product, the enolate is protonated either by use of excess proton donor during the reduction or on workup.
Dissolving-metal systems constitute the most general method for partial reduction of aromatic rings. The reaction is called the Birch reduction. The usual reducing medium is lithium or sodium in liquid ammonia. The reaction occurs by two successive electron transfer/protonation steps. • Alkyl and alkoxy aromatics, phenols, and benzoate anions are the most useful reactants for Birch reduction. • The isolated double bonds in the dihydro product are much less easily reduced than the conjugated ring, so the reduction stops at the dihydro stage. • In aromatic ketones and nitro compounds, the substituents are reduced in preference to the aromatic ring.
Substituents influence Position of protonation Alkyl and alkoxy aromatics Benzoate anions 2,5-dihydro derivative 1,4-dihydro derivatives Substituents also govern the position of protonation. Alkyl and alkoxy aromatics normally give the 2,5-dihydro derivative. Benzoate anions give 1,4-dihydro derivatives.
The structure of the products is determined by the site of protonation of the radical-anion intermediate formed after the first electron-transfer step. In general, electron-releasing substituents favor protonation at the ortho position, whereas electron-attracting groups favor protonation at the para position.
Addition of a second electron gives a pentadienyl anion, which is protonated at the center carbon. This preference is believed to be the result of the greater 1,2 and 4,5 bond order and a higher concentration of negative charge at the 3-carbon. The reduction of methoxybenzenes is of importance in the synthesis of cyclohexenones via hydrolysis of the intermediate enol ethers:
The anionic intermediates formed in Birch reductions can be used in tandem reactions. Reduction of alkynes with sodium in ammonia, lithium in low-molecular-weight amines or sodium in hexamethylphosphoric triamide containing t-butanol as a proton source leads to the corresponding E-alkene. The reaction is assumed to involve successive electron-transfer and proton-transfer steps.
