Williamson substitution

The second method involves substitution reactions on a preformed polymer with a stiff backbone. The advantage of this method is that it provides better control over the MW of the starting polymer. However, the substitution may not be 100%. The first example involved the substitution on a poly( 1,1,1-propellane) copolymer [116]. A copolymer with 80% functionalizable units has been successfully modified with a [G-1]-Br poly(benzyl ether) dendron (see Scheme 13a). Further studies exploring the feasibility and steric limitations of the substitution route have been performed on poly(p-phenylene) [113, 116]. The Williamson substitution reaction on... 

Ether formation illustrating a Williamson substitution of a polysaccharide with methyl chloride. 

A long standing method for the preparation of ethers is the Williamson ether synthesis Nucleophilic substitution of an alkyl halide by an alkoxide gives the carbon-oxygen bond of an ether... 

Next in what amounts to an intramolecular Williamson ether synthesis the alkoxide oxygen attacks the carbon that bears the halide leaving group giving an epoxide As m other nucleophilic substitutions the nucleophile approaches carbon from the side oppo site the bond to the leaving group... 

In early work, vinyl chloride had been heated with stoichiometric amounts of alkaU alkoxides in excess alcohol as solvent, giving vinyl ethers as products (210). Supposedly this involved a Williamson ether synthesis, where alkaU alkoxide and organic haUde gave an ether and alkaU haUde. However, it was observed that small amounts of acetylene were formed by dehydrohalogenation of vinyl chloride, and that this acetylene was consumed as the reaction proceeded. Hence acetylene was substituted for vinyl chloride and only catalytic amounts of alkaU were used. Vinylation proceeded readily with high yields (211). 

Methyl chloride can be converted iato methyl iodide or bromide by refluxing ia acetone solution ia the presence of sodium iodide or bromide. The reactivity of methyl chloride and other aUphatic chlorides ia substitution reactions can often be iacteased by usiag a small amount of sodium or potassium iodide as ia the formation of methyl aryl ethers. Methyl chloride and potassium phthalimide do not readily react to give /V-methy1phtha1imide unless potassium iodide is added. The reaction to form methylceUulose and the Williamson synthesis to give methyl ethers are cataly2ed by small quantities of sodium or potassium iodide. 

The reactions of pyrrolidinocyelohexenes with acid have also been Considered from a stereochemical point of view. Deuteration of the 2-methylcyclohexanone enamine gave di-2-deuterio-6-methylcyclohexanone under conditions where ds-4-/-butyI-6-methyIpyrrolidinocycIohexene was not deuterated (2J4). This experiment supported the postulate of Williamson (2JS), which called for the axial attack of an electrophile and axial orientation of the 6 substituent on an aminocyclohexene in the transition state of such enamine reactions. These geometric requirements explain the more difficult alkylation of a cyclohexanone enamine on carbon 2, when it is substituted at the 6 position, as compared with the unsubstituted case. 

Halothiophenes, which are not activated through the presence of —I—M-substituents, undergo substitution smoothly under more forcing conditions with copper salts in pyridine or quinoline. Hence 3-cyanothiophene and 5-methyl-2-cyanothiophene have been obtained from the corresponding bromo compounds. 2-Bromothiophene reacts readily with aliphatic cuprous mercaptides in quinoline at 200°C to give thioethers in high yields. The use of the copper-catalyzed Williamson synthesis of alkoxythiophenes from iodo- or bromo-thiophenes and alcoholate has been mentioned before. The reaction of 2-bromothiophene with acetanilide in nitrobenzene in... 

This is not a new reaction. This is just an Sn2 reaction. We are simply using the alkoxide ion (ethoxide in this case) to function as the attacking nucleophile. But notice the net result of this reaction we have combined an alcohol and an alkyl halide to form an ether. This process has a special name. It is called the Williamson Ether Synthesis. This process relies on an Sn2 reaction as the main step, and therefore, we must be careful to obey the restrictions of Sn2 reactions. It is best to use a primary alkyl halide. Secondary alkyl halides cannot be used because elimination will predominate over substitution (as seen in Sections 10.9), and tertiary alkyl halides certainly cannot be used. 

A typical Hansch analysis has been applied to the 50% inhibitory concentrations (ICjo) of oxidative phosphorylation of 11 doubly substituted salicylanilides (Table 37.1) as reported by Williamson and Metcalf [17]. Multiple linear regression leads to the following model ... 

Alternatively, the Sn2 nucleophilic substitution reaction between alcohols (phenols) and organic halides under basic conditions is the classical Williamson ether synthesis. Recently, it was found that water-soluble calix[n]arenes (n = 4, 6, 8) containing trimethylammonium groups on the upper rim (e.g., calix[4]arene 5.2) were inverse phase-transfer catalysts for alkylation of alcohols and phenols with alkyl halides in aqueous NaOH solution to give the corresponding alkylated products in good-to-high yields.56... 

The Williamson ether synthesis remains the most practical method for the preparation of tetrahydrofurans, as can be exemplified by the two examples shown in the following schemes. A simple synthesis of 2-substituted tetrahydrofuran-3-carbonitriles 84 is achieved by generating the alkoxide under a phase transfer condition via reaction between 4-chlorobutyronitrile and non-enolizable aldehydes <00SL1773>. A synthesis of 2-alkylidene-tetrahydrofuran 85 was recorded, in which a dianion can be generated through treatment of the amide shown below with an excess of LDA, and is followed by addition of l-bromo-2-chloroethane. In this way, the more basic y-carbon is alkylated and leads eventually to the nucleophilic cyclization <00SL743>. 

The application of phase-transfer catalysis to the Williamson synthesis of ethers has been exploited widely and is far superior to any classical method for the synthesis of aliphatic ethers. Probably the first example of the use of a quaternary ammonium salt to promote a nucleophilic substitution reaction is the formation of a benzyl ether using a stoichiometric amount of tetraethylammonium hydroxide [1]. Starks mentions the potential value of the quaternary ammonium catalyst for Williamson synthesis of ethers [2] and its versatility in the synthesis of methyl ethers and other alkyl ethers was soon established [3-5]. The procedure has considerable advantages over the classical Williamson synthesis both in reaction time and yields and is certainly more convenient than the use of diazomethane for the preparation of methyl ethers. Under liquidrliquid two-phase conditions, tertiary and secondary alcohols react less readily than do primary alcohols, and secondary alkyl halides tend to be ineffective. However, reactions which one might expect to be sterically inhibited are successful under phase-transfer catalytic conditions [e.g. 6]. Microwave irradiation and solidrliquid phase-transfer catalytic conditions reduce reaction times considerably [7]. 

Ethers may be prepared by (1) dehydration of alcohols and (11) Williamson synthesis. The boiling points of ethers resemble those of alkanes while their solubility Is comparable to those of alcohols having same molecular mass. The C-O bond In ethers can be cleaved by hydrogen halides. In electrophilic substitution, the alkoxy group activates the aromatic ring and directs the Incoming group to ortho and para positions. 

Hydroxyl Group. Reactions of the phenolic hydroxyl group include the formation of salts, esters, and ethers. The sodium salt of the hydroxyl group is alkylated readily by an alkyl halide (Williamson ether synthesis). Normally, only alkylation of the hydroxyl is observed. However, phenolate ions are ambident nucleophiles and under certain conditions, ring alkylation can also occur. Proper choice of reaction conditions can produce essentially exclusive substitution. Polar solvents favor formation of the ether nonpolar solvents favor ring substitution. 

A rapid one-pot method for converting 1,3-diols into oxetanes by the intramolecular Williamson reaction has recently been described. The monolithium salt is generated by treatment of the diol with one equivalent of butyllithium in cold THF, followed by addition of one equivalent of tosyl chloride to give a monotosylate, which is cyclized by addition of a second equivalent of butyllithium (equation 83). Yields of 70-90% are reported for a variety of alkyl- and aryl-substituted oxetanes (81S550). Another simple method for converting 1,3-diols into oxetanes consists of converting them to cyclic carbonate esters by ester... 

Eadie, in Ref 69, reports on a considerable amount of work done on the ability of beeswax and paraffin wax to remain coated on HMX surfaces when immersed in liq TNT. Thru measurements of contact angles, a technique used earlier on RDX/wax systems reported on by Rubin in Ref 23, it was determined that the TNT preferentially wets the HMX and the wax is stripped away. He concludes that the most important property of a desensitizing wax is that it should be readily dispersed uniformly thruout the TNT phase. He also suggests that a better desensitizer for investigation for use would be a wax or substituted hydrocarbon having a low interfacial tension with TNT. The smaller the wax droplet size the more efficiently it will be distributed and the more effectively it should desensitize. Williamson (Ref 64) in his examination of the microstructures of PETN/TNT/wax fusion-casts detected that wax is dispersed thru the cast as isolated descrete globules which he refers to as blebs or irregular or streak-like areas, surrounded by TNT (see also Ref 54)... 

A patent was obtained ill 1853 by Elliot and Russell for an improved furnace to bo used in place of the usuel black-ash furnace. This improvement consists in the substitution of a revolving cylinder of iron, lined with fire-bricks, for the chambers of the ordinary furnace, and with the later modifications by Messrs. Stevenson and Williamson, of the Jafrow Chemical Works, South Shields, Newcastle-on-Tyne. Its advantages appear to be of sufficient importance to induce its general adoption by soda manufacturers. 

In fact, the reaction of alkoxides with alkyl halides or alkyl sulfates is an important general method for the preparation of ethers, and is known as the Williamson synthesis. Complications can occur because the increase of nucleo-philicity associated with the conversion of an alcohol to an alkoxide ion always is accompanied by an even greater increase in eliminating power by the E2 mechanism. The reaction of an alkyl halide with alkoxide then may be one of elimination rather than substitution, depending on the temperature, the structure of the halide, and the alkoxide (Section 8-8). For example, if we wish to prepare isopropyl methyl ether, better yields would be obtained if we were to... 

The so-called Williamson synthesis of ethers is by far the most important ether synthesis because of its versatility it can be used to make unsymmetrical ethers as well as symmetrical ethers, and aryl alkyl ethers as well as dialkyl ethers. These reactions involve the nucleophilic substitution of alkoxide ion or phenoxide ion for halide (equation 70).26°... 

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