Alkyl halides from ethers

Fig. 32. Route for the preparation of cellulose ethers from alkyl halides.

Notable examples of general synthetic procedures in Volume 47 include the synthesis of aromatic aldehydes (from dichloro-methyl methyl ether), aliphatic aldehydes (from alkyl halides and trimethylamine oxide and by oxidation of alcohols using dimethyl sulfoxide, dicyclohexylcarbodiimide, and pyridinum trifluoro-acetate the latter method is particularly useful since the conditions are so mild), carbethoxycycloalkanones (from sodium hydride, diethyl carbonate, and the cycloalkanone), m-dialkylbenzenes (from the />-isomer by isomerization with hydrogen fluoride and boron trifluoride), and the deamination of amines (by conversion to the nitrosoamide and thermolysis to the ester). Other general methods are represented by the synthesis of 1 J-difluoroolefins (from sodium chlorodifluoroacetate, triphenyl phosphine, and an aldehyde or ketone), the nitration of aromatic rings (with ni-tronium tetrafluoroborate), the reductive methylation of aromatic nitro compounds (with formaldehyde and hydrogen), the synthesis of dialkyl ketones (from carboxylic acids and iron powder), and the preparation of 1-substituted cyclopropanols (from the condensation of a 1,3-dichloro-2-propanol derivative and ethyl-... 

Ethers are prepared from alkyl halides by the treatment of metal alkoxide. This is known as Williamson ether synthesis (see Sections 4.3.6 and 5.5.2). Williamson ether synthesis is an important laboratory method for the preparation of both symmetrical and unsymmetrical ethers. Symmetrical ethers are prepared by dehydration of two molecules of primary alcohols and H2SO4 (see Sections 4.3.7 and 5.5.3). Ethers are also obtained from alkenes either by acid-catalysed addition of alcohols or alkoxymercuration-reduction (see Section 5.3.1). 

Fig, 9.34, Apparatus used for the preparation and sampling of Grignard reagents for NMR spectroscopy. The apparatus was evacuated through J2 and the Mg baked. Excess ether and alkyl halide were distilled onto the metal, and the apparatus was sealed off at S3. Upon warming to 0°C and shaking, a rapid reaction occurred. The apparatus was evacuated at Jj, the break-seal B was broken, and ether and excess alkyl halide were removed. Fresh dry ether and the letramethyl silane standard were distilled in, the apparatus was sealed off at S, and a small portion of the solution was filtered through the frit F into the NMR tube, which was sealed off at S2. (Adapted from D. F. Evans and J. P. Mahler, / Chem. Soc.t 1962, 5125.)... 

Although a substantial number of reactions are described in the text, they belong to a relatively modest number of mechanistic types. The preparation of alkyl halides from alcohols and HX, the cleavage of ethers, and the preparation of amines from alkyl halides and ammonia (and many other reactions) all, for example, occur by a nucleophilic substitution mechanism. The following is a brief review of the main mechanistic pathways discussed in the text. 

The simplest unfunctionalised carbon nucleophiles (15 and 17) are made from alkyl halides with various metals such as Li(0) or Mg(0) or by exchange with available organometallic reagents such as butyl-lithium (BuLi) in anhydrous coordinating solvents like ether (Et20) or THF (tetrahydro-furan 16). Enolates 11 are very important and will be discussed at length in later chapters. 

Alcohols, ethers, and alkyl halides have a carbon atom with only one single bond to a heteroatom. We assign these the alcohol oxidation level , and they are all easily made from alcohols without oxidation or reduction. 

We can apply these ideas to the synthesis of the herbicide 2,4-D (2,4-dichlorophenoxyacetic add). The most reasonable disconnection of an ether is the C-0 bond because we know that ethers can be made from alkyl halides by substitution with an alkoxide anion. We don t at this stage need to decide exactly which alkyl halide or alkoxide to use, so we just write the synthons. 

Reduction of carbon-halogen bond by metal yields carbanion. Reaction of alkyl halide with Mg in the presence of anhydrous ether as solvent generates Grignard reagent. The Grignard reagent behaves like a carbanion. Alkyllithiums are also obtained from alkyl halides and behave as carbanions. 

Alcohols and ethers are both common products of nucleophilic substitution. They are synthesized from alkyl halides by Sn2 reactions using strong nucleophiles. As in all Sn2 reactions, highest yields of products are obtained with unhindered methyl and 1 ° alkyl halides. 

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