Reactions of Oxacyclopropanes

Although ordinary ethers are relatively inert, the strained structure of the oxacyclopropanes makes possible nucleophilic ring-opening reactions. This section presents details of these processes. 

Nucleophilic ring opening of oxacyclopropanes by n2 is regioselective and stereospecihc 

Oxacyclopropane is subject to bimolecular ring opening by anionic nucleophiles. Because of the symmetry of the substrate, substimtion occurs to the same extent at either carbon. The reaction proceeds by nucleophilic attack, with the ether oxygen functioning as an intramolecular leaving group. 

This Sn2 transformation is unusual for two reasons. First, alkoxides are usually very poor leaving groups. Second, the leaving group does not actually leave it stays bound to the molecule. The driving force is the release of strain as the ring opens. 

What is the situation with unsymmetric systems Consider, for example, the reaction of 2,2-dimethyloxacyclopropane with methoxide. There are two possible reaction sites at the primary carbon (a), to give l-methoxy-2-methyl-2-propanol, and at the tertiary carbon (b), to yield 2-methoxy-2-methyl-l-propanol. Evidently, this system transforms solely through path a. 

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Figure 15-5 Important commercial reactions of oxacyclopropane (oxirane, ethylene oxide)...

Some acid-catalyzed solvolysis reactions of oxacyclopropanes appear to proceed by SN1 mechanisms involving carbocation intermediates. Evidence for the SN1 mechanism is available from the reactions of unsymmetrically substituted oxacyclopropanes. For example, we would expect the conjugate acid of 2,2-dimethyloxacyclopropane to be attacked by methanol at the primary carbon by an SN2 reaction and at the tertiary carbon by an SN1 reaction ... 

Why do we not simply write the isomeric free carbocations as intermediates in the acid-catalyzed ring openings The reason is that the cyclic oxonium ion has an octet sfructure, whereas the carbocation isomer has a carbon with an electron sextet. Indeed, experimentally, inversion is observed when reaction takes place at a stereocenter. Like the reaction of oxacyclopropanes with anionic nucleophiles, the acid-catalyzed process includes backside displacement—in this case, on a highly polarized cyclic alkyloxonium ion. 

Outline a short synthesis of tra s-2-methylcyclohexanol from cyclohexene. (Hint Review the reactions of oxacyclopropanes in Section 9-9.)... 

Acidic conditions also can be used for the cleavage of oxacyclopropane rings. An oxonium ion is formed first, which subsequently is attacked by the nucleophile in an SN2 displacement or forms a carbocation in an SN1 reaction. Evidence for the SN2 mechanism, which produces inversion, comes not only from the stereochemistry but also from the fact that the rate is dependent on the concentration of the nucleophile. An example is ring opening with hydrogen... 

Reactions with sulfur ylides proceed differently. The products are oxacyclo-propanes (oxiranes) —not alkenes. The addition step proceeds as with the phosphorus ylides, but the negatively charged oxygen of the dipolar adduct then displaces the sulfonium group as a neutral sulfide. This is an intramolecular Sn2 reaction similar to the formation of oxacyclopropanes from vicinal chloroalcohols (Section 15-11C) ... 

Polymers usually are prepared by two different types of polymerization reactions — addition and condensation. In addition polymerization all of the atoms of the monomer molecules become part of the polymer in condensation polymerization some of the atoms of the monomer are split off in the reaction as water, alcohol, ammonia, or carbon dioxide, and so on. Some polymers can be formed either by addition or condensation reactions. An example is polyethylene glycol, which, in principle, can form either by dehydration of 1,2-ethanediol (ethylene glycol), which is condensation, or by addition polymerization of oxacyclopropane (ethylene oxide) 1... 

Among the more interesting developments in ring-opening reactions of epoxides (oxiranes, oxacyclopropanes) has been the observation that the process can be made enantioselective by the use of suitable Lewis acid-base pairs. Thus, with silicon tetrachloride in the presence of HMPA [(Me2N)3P=0], chlorohydrins can be generated. Then, if one enantiomer of a chiral phosphoramidate (such as the bis-... 

Ring opening of oxacyclopropanes is also catalyzed by acids. The reaction in this case proceeds through initial cyclic alkyloxonium ion formation followed by ring opening as a result of nucleophilic attack. 

The antibiotic fosfomycin works by interfering with bacterial cell-wall synthesis through oxacyclopropane ring opening. Thus, the enzyme crucial for wall construction is deactivated by reaction of the SH group of one of its cysteine amino acids (for structure, see Problem 45 of Chapter 2) with the strained ether function. 

Whereas nucleophihc ring opening of oxacyclopropanes by anions is at the less substituted ring carbon according to the rules of the 5 2 reaction, acid-catalyzed opening favors the more substituted carbon, because of charge control of nucleophilic attack. 

How can this be explained The situation is very similar to the acid-catalyzed nucleophilic ring opening of oxacyclopropanes (Section 9-9), in which the intermediate contains a protonated oxygen in the three-membered ring. In both reactions, the nucleophile attacks the more highly substituted carbon of the ring, because this carbon is more positively polarized than the other. 

Treatment of oxacyclopropanes with water in the presence of catalytic acid or base leads to ring opening to the corresponding vicinal diols. These reactions follow the mechanisms described in Section 9-9 The nucleophile (water or hydroxide) attacks the side opposite the oxygen in the three-membered ring, so the net result of the oxidation-hydrolysis sequence constitutes an anti dihydroxylation of an alkene. In this way, tram-2-butene gives me50-2,3-butanediol, whereas ds-2-butene furnishes the racemic mixture of the 1R, >R and 2S,3S enantiomers. 

Alkynes can also be prepared from other alkynes. The reaction of terminal alkynyl anions with alkylating agents, snch as primary haloalkanes, oxacyclopropanes, aldehydes, or ketones, results in carbon-carbon bond formation. As we know (Section 13-2), such anions are readily prepared from terminal alkynes by deprotonation with strong bases (mostly alkyllithium reagents, sodinm amide in liqnid ammonia, or (jrignard reagents). Alkylation... 

The lesser known four-membered cyclic ether, oxacyclobutane (oxe-tane), (CH2)30, also is cleaved readily, but less so than oxacyclopropane. Oxacyclopentane (oxolane, tetrahydrofuran) is a relatively unreactive water-miscible compound with desirable properties as an organic solvent. It often is used in place of diethyl ether in Grignard reactions and reductions with lithium aluminum hydride. 

Strained cyclic ethers (e.g., oxacyclopropanes) react with acid like ordinary ethers do, only faster. Order of reactivity is again 3 > 2° S 1 . At a I carbon, the reaction clearly takes places via an Sn2 mechanism to displace the protonated oxygen. 

The exception is the SN2 displacement reaction to cleave an oxacyclopropane. The release of bond-angle strain upon opening the three-membered ring overcomes the unfavorable energetics associated with producing a poor leaving group. 

What remains is to identify compound B, which gives an oxacyclopropane stereoisomeric to that formed from compound A, but at a slower rate, and D, which gives the same product as C, but also more slowly. Because both types of reactions under consideration require an axial leaving group, it makes sense to flip the chairs of the remaining starting compounds (in which the —Br is currently equatorial) and see what we get. 

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