Swern oxidation mechanisms

The unsubstituted hydrazones derived from aromatic ketones and aldehydes are converted to the corresponding alkyl chlorides, in high yield, under Swern oxidation conditions. In this unusual oxidation/reduction sequence, the substrate undergoes a net reduction. Unsubstituted hydrazones derived from cyclohexyl ketones yielded elimination products. The mechanism in Scheme 7 has been postulated.111... 

In this subsection we want to consider oxidations that employ dimethyl sulfoxide (DMSO) as the oxidizing reagent. These oxidations, which almost always are carried out in the presence of first oxalyl chloride and then NEt3, are referred to as Swern-oxidations. The mechanism of this reaction is known in detail (Figure 17.13). In the prelude, the O atom of DMSO acts as... 

Fig. 17.13. Mechanism of the Swern oxidation of alcohols. The actual reagent is an "activated DMSO" (compound B or D), which reacts with an alcohol with formation of A or C, respectively. Dissociation leads to the sulfonium salt E, which is then converted into the sulfonium ylide F after NEt3 addition and raising the temperature from -60 to -45 °C. /3-Elimination via a cyclic transition state generates the carbonyl compound and dimethyl sulfide from F.

Q Modern methods of oxidizing alcohols like Dess-Martin and Swern oxidations are explained by a unifying mechanism that covers the major methods to oxidize alcohols to aldehydes and ketones (Chapter 11). 

In Chapter 24 we mentioned the Swern oxidation briefly as an excellent method of converting alcohols to aldehydes. We said there that we would discuss this interesting reaction later and now is the time. The mechanism is related to the reactions that we have been discussing and it is relevant that the Swern oxidation is particularly effective at forming enals from allylic alcohols, the Swern oxidation... 

The primary alcohol Z-13 is oxidized to aldehyde 14 (Segment BC) using the Swern protocol. Typically, Swern oxidation is performed in CH2CI2 using oxalylchloride, dimethyl sulfoxide and triethylamine at -78 °C. In transformations of chiral, enolizable alcohols, milder bases such as A-methyl morpholine or sterically hindered bases such as diisopropylethylamine Hunig s base) are widely used. Swern oxidation is an inexpensive, fast (typically several minutes), mild and selective oxidation method for primary and secondary alcohols. For the detailed mechanism, see Chapter 5, p. 86. 

We shall leave detailed discussion of one more method till much later, in Chapter 46 (p. 000), since the mechanism involves some sulfur chemistry you will meet there. But we introduce it here because of its synthetic importance. Known as the Swern oxidation, it uses a sulfoxide [S(IV)] as the oxidizing agent. The sulfoxide is reduced to a sulfide, while the alcohol is oxidized to an aldehyde. 

Now let us consider some specific oxidation methods that hinge on the general mechanism shown above the Swern oxidation, and oxidations involving chromate esters. 

Oxidations involving chromium (VI) reagents such as H2Cr04 are simple to carry out and have been widely used. These reactions involve formation of chromate esters, and include an elimination step similar to the general mechanisms shown in Section 12.4A. Chromium (VI) is a carcinogen and an environmental hazard, however. For this reason, methods like the Swern oxidation and others are increasingly important. 

Suggest a mechanism by analogy with the Swern oxidation. 

Scheme 7.1 Mechanism of the Swern oxidation using TFAA.

One of the most used alcohol oxidations in organic synthesis is the Swern oxidation. A large number of variants exist for this reaction, but a common one involves DMSO, oxalyl chloride, and a base (pyridine, dimethylaminopy-ridine, and triethylamine are common). The currently accepted mechanism is shown below along with electron pushing for some steps. The first part of the mechanism involves activation of DMSO by reaction with oxalyl chloride. This is followed by nucleophilic attack of the alcohol on this activated species, creating an alkoxysulfonium intermediate. 

Mechanisms of Asymmetric Epoxidation Reactions 558 Nature s Hydride Reducing Agent 566 The Captodative Effect 573 Stereoelectronics in an Acyl Transfer Model 579 The Swern Oxidation 580 Gas Phase Eliminations 588 Using the Curtin-Hammett Principle 593 Aconitase—An Enzyme that Catalyzes Dehydration and Rehydration 595... 

Propose a mechanism to explain how dimethyl sulfoxide and oxalyl chloride react to form the dimethylchlorosulfonium ion used as the oxidizing agent in the Swern oxidation, (see Chapto" 11, problem 71). 

In recent years, chromium reagents have become less popular. Although inexpensive and effective, they are rather toxic and some are carcinogenic. Disposal of waste products also presents an issue. Many researchers now use the Swern oxidation—this uses dimethylsulfoxide as the oxidant, and the alcohol is activated with oxalyl chloride. The mechanism is shown in Figure 19.19. The advantages of the process are the lack of Cr(VI), anhydrous conditions and... 

C kinetic isotope effects (KIEs) of four cinnamyl alcohol oxidations have been determined by 13C NMR spectroscopy using competition reactions with reactants at natural 13C abundance. Primary 13C KIEs of the Pd(II)-catalysed oxidation and of the MnC>2 oxidation are similar ( 1.02) and indicate the C—H bond cleavages to be the irreversible and rate-limiting steps in the respective reactions. Low primary 13C KIEs in Swern and Dess-Martin oxidations, however, indicate that the initial C—H bond breakings and proton transfers are not the irreversible steps in these mechanisms, which control the rate.284... 

There are many methods for selectively oxidizing an alcohol to the corresponding aldehyde. Of course you have to think about the stability of your molecule when you decide which procedure to choose, but ecological and economic aspects are also very important. Chromium-free oxidations such as Swern conditions or Dess-Martin periodinane (DMP) are preferred over the classic methods that employ Jones reagent, Collins reagent or PCC/PDC. For the mechanism of the here used Swern protocol, see Chapter 5, p. 86. 

The primary alcohol at C-1 is oxidized to the corresponding aldehyde using the Swern protocol in the next step of this reaction scheme. For the detailed mechanism see Chapter 5, p. 86. 

Scheme 8.6 Proposed mechanism for Swern-Moffatt oxidation using TFAA...

A mechanism suggested for Swern-Moffatt oxidation with TFAA is shown in Scheme 8.6. In the first step, DMSO reacts with TFAA to form cationic reactive species I, which is known to be stable only below —At higher temperatures, rearrangement of I takes place to give species II. The reaction of II with an alcohol IQ upon treatment with a base leads to formation of a major by-product, trifluoroacetic acid (TFA) ester VII. Therefore, the first step should be carried out below —50 °C. In the second step, reactive species I is allowed to react with an alcohol HI at or below —50°C to obtain intermediate IV. IV may also undergo the Pummerer rearrangement to give a methyl thiomethyl (MTM) ether VI upon treatment with a base. In the third step, IV is treated with a base (usually triethylamine) to obtain the desired carbonyl compound V and dimethyl sulfide. 

Sulfoxides (essentially DMSO) can be used for oxidation of alcohols to carbonyl compounds as in the Moffatt, Swern and related oxidations [237, 238]. These mild and useful processes proceed through an oxosulfonium salt. In the Pfitzner-Moffatt procedure the alcohol is treated with DMSO, DCC and anhydrous phosphoric acid. The proposed mechanism involves an alkylsulfonium ylide as an intermediate. 

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