The preparation of ethers usually employs either strongly acidic or basic conditions. The traditional process for the preparation of symmetrical or unsymmetrical ethers is the Williamson synthesis, which involves condensation of a sodium or potassium alkoxide or aryl oxide with an organic halide. This process is still the most commonly used procedure, even though it results in the production of stoichiometric quantities of salt and does not work well with base labile compounds.

Some alternatives to the Williamson process have been described, however most of these processes suffer from disadvantages, such as poor yields or the use or production of environmentally unfriendly reagents or byproducts. Some of these disadvantages of the prior art processes are summarised by Bethmont et al. in Tetrahedron Letters, 1995,36,4235.

The reaction of an alcohol with an organic halide to produce an ether has been described by Gelles et al. (J. Chem. Soc. (1954) 2918) and more recently by Cablewski et al. (J. Org.

Chem. 1994,59,3408-3412) and Raner et al. (J. Org. Chem. 1995,60,2456-2460). A problem associated with reaction of an alcohol and an organic halide to produce an ether is the concomitant production of hydrogen halide. If not removed, the hydrogen halide can result in cleavage of the formed ether. One way of preventing a build up of hydrogen halide described by Gelles et al (supra), is to add a base, such as pyridine, to the reaction medium.

U. S. Patent 4613682 to Eickholt describes a method for the preparation of aromatic ethers by reacting a phenolic compound with an organic halide. The process is carried out by passing the reactants in the vapour phase over a solid catalyst containing a metal oxide or a metal until the corresponding ether (i. e. the product of reaction of the phenol with the organic halide) is formed. The byproduct hydrogen halide formed may be reacted with a halide acceptor, such as methanol.

Methods for esterification of carboxylic acids have been summarized (Raber, D. J. et al., J. Org. Chem., and reviewed (Haslam, E. Tetrahedron, and Mulzer, J.,"Comprehensive Organic Synthesis,"Vol. 6, Trost, B. M. et al., Series Eds., Winterfeldt, E. Vol. Ed., [Pergamon: New York, 1991] pp. 323-80). With rare exceptions (Carlson, P. H. J. et al J. Org. Chem., 1981 46,3936) they can be grouped into two broad categories. One involves attack by an alcohol on to the carbon atom of the carboxylic acid or an acyl derivative. The simplest case is direct esterification of the acid by the alcohol, but this occurs at a reasonable rate only in the presence of acid catalysts. Owing to unfavourable equilibria or acid-lability, not all such attempted esterifications succeed. Sterically constrained acids are difficult to react and there are opportunities for competing dehydration of a-and p-branched alcohols.

If the carboxyl group of the acid is activated as the acid chloride (Yadav, J. S. et al. Synth Commun., or anhydride (Ishihara, K., et al. J. Org. Chem. 1996,61 4560), esterification can proceed by transfer of the acyl moiety to an alcohol. However, the additional synthetic step lowers the atom economy, a stoichiometric amount of HCl or carboxylic acid respectively is by-produced, and adverse side reactions may occur.

Alternatively, in alkylative esterifications, the carboxylate ion can be employed as a nucleophile. Even sterically crowded acids can be esterified this way. Examples include reactions of carboxylate salts, either preformed or generated in situ, with suitable alkylating agents such a trialkyloxonium salts, alkyl halides, dialkyl sulfates, alkyl chlorosulfites, alkyl phosphites and diazomethane. Although such reactions may proceed to ambient temperature, they do not appear to have been conducted catalytically. The leaving group of the alkylating agent (commonly a bromide, iodide or phosphite) contributes to the waste produced (including some hazardous salts), in stoichiometric amounts at least. Importantly, salts account for the bulk of industrial chemical wastes. They can pollute soil and ground water and have been implicated in the formation of acid-dew.

It has now been found that the hydrogen halide formed upon reaction of an alcohol or

carboxylic acid with an organic halide can be reacted with alcohol (or thiol) in situ to generate, or regenerate, organic halide for ether or ester production.

Accordingly the present invention provides a process for the synthesis of ethers or esters comprising reacting an alcohol or carboxylic acid with an organic halide to produce an ether or ester respectively and a hydrogen halide, wherein further organic halide for the production of ether or ester is generated in situ by reaction of the hydrogen halide with an alcohol.

This cyclic process for the formation of ethers and esters from alcohols provides a convenient and environmentally beneficial route to a wide range of commercially useful ethers, esters, lactones, polyethers, polyesters, cyclic ethers and ether and ester compositions, as well as their sulphur containing counterparts. The process reduces the production of environmentally unfriendly hydrogen halides and, in view of the fact that the process can be conducted at or near neutrality, can be employed for reactions involving acid or base labile compounds. The process also produces little waste materials and can be performed without the solid metal oxide or metal catalysts described in US Patent 4,613,682. The reaction may also be conducted in the liquid phase, there being no need to conduct the reaction in the vapour phase as described in the US 4,613,682.

The cyclic nature of the process of the present invention is illustrated below in Scheme 1.

Scheme 1 RYH + R'X (trace) = RYR'+ HX Equation 1 HX + R"ZH Z Equation 2 RYH + R"X = RYR"+ HX Equation 3 where R is the residue of an alcohol, thiol, carboxylic acid, thioacid or dithioacid, R'is the residue of an organic halide, R"is the residue of an alcohol or thiol, X is halide

Y is-C02,-O-,-S-,-C (O) S-, or-C (S) S-, and<BR> Z is-O-or-S-.

Since R'X is present in a trace (or"catalytic") amount the reaction shown in equation 1 will only proceed to a minor extent. Accordingly the overall reaction can be considered to be the sum of the reactions shown in Equations 2 and 3: RYH + R"ZH RYR"+ H2Z Equation 4 A side reaction which can also occur is the etherification of R"ZH and R"X as shown below in Equation 5.

R"ZH + R"X HX Equation 5 In the situation where R is the residue of an alcohol or thiol, R = R", and Y = Z, this side reaction is equivalent to the reaction shown in Equation 3 and represents a route to the desired ether or thioether. In such cases where the desired product is RYR"it is also preferred that R= R', as the minor product produced by the reaction of Equation 1 would correspond to the desired product. Other minor reactions, such as the etherification of R"ZH with R'X may also occur to some extent.

In the situation where R is the residue of a carboxylic acid, thioacid or dithioacid it is advantageous for R'to be the same as R"as the product of the reaction shown in Equations 1 and 3 would be the same. However in view of the small quantity of R'X used to"catalyse" the reaction sequences, the amount of RYR'produced would be quite minimal. The nature of the reactants may be selected in such a way that the major contaminating products can be removed, e. g. by distillation, throughout the process.

It is also possible to start the reaction sequence by addition of a small amount of HX. In this embodiment the HX would react with the alcohol or thiol, R"ZH, to generate the organic

halide, R"X, as per Equation 2. The organic halide can then react with RYH as per Equation 3 to produce the desired product, RYR", and regenerate HX.

In another embodiment, where R is the residue of a carboxylic acid, thioacid or dithioacid, the reaction between the acid and the organic halide can be initiated with the addition of an alkali metal halide salt as shown in Scheme 2 below.

Scheme 2 RC (Z') ZH + QX (trace) RC (Z')-Z-Q+ + HX Equation 6 HX + R"Z"H R"X + H2Z Equation 2 RC (Z')-Z-+ R"X = RC (Z')-ZR"+ X~ Equation3 where Q is an alkali metal cation, R, R"and X are as defined above, and Z, Z'and Z"are independently selected from O and S.

The following side reaction may occur to some extent R"X + R"Z"H = R"Z"R"+ HX Equation 5 As used herein the term"ester", unless otherwise indicated, refers to carboxylic esters (-C (O) O-), thioester (-C (O) S-) and dithioesters (-C (S) S-).

As used herein the term"alcohol"unless otherwise indicated, refers to organic compounds containing one or more hydroxy (OH) or sulphydryl (SH) groups.

As used herein the term"carboxylic acid"unless otherwise indicated, refers to organic acids having one or more carboxylic (-C (O) OH) groups, thioacid (-C (O) SH) groups or dithioacid (-C (S) SH) groups, and salts or anhydrides thereof.

The cyclic nature of the process for preparing ethers is further illustrated below in Scheme 3. Although the scheme depicts the production of an oxyether, it is to be understood that thioethers can be prepared using analogous methodology. This reaction scheme illustrates the preparation of a symmetrical ether, although it is to be also understood that the process is also applicable to the preparation of unsymmetrical, cyclic and poly-ethers, as well as ether compositions. The following scheme is equivalent to Scheme 1 where R = R'= R"and Y and Z are O.

Scheme 3 ROH + RX = ROR + HX Equation 1 (and 3) HX + ROH = RX + H2O Equation 2 2ROH R 20 + H20 Sum According to Equation 1 an excess of alcohol (or thiol) (ROH) and a minor amount of corresponding organic halide (RX) undergo a displacement reaction to afford ether (R20) and hydrogen halide (HX), or its ions H+ and X-. As used herein the term"hydrogen halide" refers to HX and/or its constituent ions.

The liberated hydrogen halide attacks another alcohol molecule to form water and to regenerate RX (Equation 2).

If the rates of both reactions are comparable, the concentration of hydrogen halide will be low throughout the process and the concentration of RX should remain relatively constant.

Although the hydrogen halide and organic halide are stoichiometric reactants or products in Equations 1 and 2, they do not appear in the sum. Hence, the role of the organic halide in this process for preparing symmetrical ethers can be regarded as"catalytic", the net process involving the condensation of two molecules of alcohol to give ether plus water.

In processes for preparing unsymmetrical ethers, ie. when the"R"group of the alcohol differs from the"R"group of the organic halide, the organic halide generated from the hydrogen halide will be a different species from the original organic halide. In the case of the preparation of a polyether there will be a wide range of organic halides produced, depending on the number of ether linkages in the alcohol which reacts with the hydrogen halide.

For the etherification to proceed, the halide is preferably a good nucleophile (to accommodate Equation 2), a good leaving group (to satisfy Equation 1) and poorly basic to preclude competing elimination reactions. The halides Br and I-possess these properties and represent the preferred halides for use in the present process. Other halides, such as Cl-, may also be useful, as may other anions having the abovementioned properties.

Although hydroxy and alkoxy functionalities are not readily displaced from carbon atoms, protonation in strong acid greatly facilitates their leaving. For this reason, aqueous HBr and HI are commonly used to cleave ethers. The reaction of the hydrogen halide with the alcohol to regenerate organic halide minimises the concentration of hydrogen halide present in the reaction medium, thereby retarding the back reaction.

It would be expected on the basis of Equation 2 that removal of water should favourably shift the position of equilibrium and limit the reverse reaction in Equation 3. However, it has been reported in the literature (N. T. Farinacci and L. P. Hammett, J. Am. Chem. Soc., 1937,59, 2542; Streitwieser, A. Jr."Solvolytic Displacement Reactions" (McGraw-Hill: New York, 1962) pp. 34-38) that the rate of solvolytic displacement of alkyl halides by alcohols (see Equation 1) can be significantly accelerated by the addition of small amounts of water. Accordingly, for some reactions conducted in the liquid phase, complete removal of water may be detrimental. Despite these competing mechanisms involving water it is preferable for at least some of the water produced during the etherification to be removed.

One method of removing water is via azeotropy with aromatic hydrocarbons, such as toluene or xylenes, although the presence of these aromatic compounds in the reaction medium tends

to inhibit nucleophilic substitutions, possibly due to the poor solvating properties of these low- polarity hydrocarbons. Drying agents, such as molecular sieves and CaSO4, may also be used, although removal of hydrogen halide along with the water can occur which is detrimental to the regeneration of the organic halide.

One way of minimising the effects of removal of water on the ability of the hydrogen halide to regenerate the organic halide, is to provide another process for the generation of hydrogen halide. One method of achieving this is via the addition of a hydrogen halide generating compound, such as iodoform, tetrachloromethane or tetrabromoethane. These compounds decompose slowly in the presence of the alcohol to form HI and HBr, which produce the organic halide necessary for the etherification reaction. This procedure can also be used to replenish hydrogen halides lost by co-distillation with water. After completion of the reaction, unspent hydrogen halide generating compound could be recoverable by crystallisation and filtration.

It has been found that various factors affect the rate and extent of the reactions shown above in equations 1 and 2. As has been reported by Gelles et al (supra) when the concentration of alcohol is 10 to 50 times larger than the concentration of organic halide, the first order rate constant for Equation 1 can rise substantially. Thus the rate and extent of the reaction in equation 1 can depend on the relative concentrations of RX and ROH as well the concentration of water present.

The temperature, ionic strength and ionising powers of the solvent, in the case of reactions performed in the liquid phase, can also have an influence on the nature of the products, with SN2 reactions being favoured at higher temperatures and in media of low polarity. From Scheme 3, the process according to the invention could be initiated with either RX or HX in the presence of ROH. However, the starting mixture of RX and ROH (Equation 1) would be less polar than ROH and the readily ionisable HX (in Equation 2). Hence, depending upon the starting materials used, it is possible that alternative mechanisms may operate in the initial stages of the reaction, as compared to the reaction in the later stages. As a result, in some

cases, the products and their distributions may vary. Furthermore, as the etherification proceeds, the varying composition of the reaction mixture may have an influence on the nature of the products. Changes in polarity of the medium may result in a switching of the mechanism between SN2 and SN1. In the case of the latter mechanism, this may, in some circumstances, result in racemization of the products.

It has also been reported that, passing along the series, methyl, primary alkyl, secondary alkyl, tertiary alkyl group, the mechanism of nucleophilic substitution changes from SN2 to SN1 in the region of the secondary groups. Accordingly if it is intended to prepare chiral products, the reactants and reaction conditions should be selected to favour SN2 processes.

As indicated above, the initial organic halide may be generated in situ by the addition of a hydrogen halide, or by the addition of a compound which generates a hydrogen halide.

However, for acid labile reactants, it is preferred to commence the cyclic reaction sequence with an organic halide.

The cyclic nature of the process for preparing esters is further illustrated below in Scheme 4.

This reaction scheme illustrates the preparation of a linear carboxylic ester, although it is to be understood that the process is also applicable to the preparation of lactones and polyesters, as well as ester compositions, and their thioester and dithioester equivalents. The following scheme is equivalent to Scheme 1 where R'= R", Y is-CO2-and Z is O Scheme 4 RCO2H + R'X (trace) RC02R'+ HX Equation 1 HX + R"OH R"X + H20 Equation 2 RC02H + R"OH RC02R"+ H20 Equation 3 As with the etherification shown in Scheme 3, the halide is preferably a good leaving group (to satisfy Equation 1) and poorly basic to restrict competing elimination reaction. The

halides Br and I-possess these properties and represent the preferred halides for use in the esterification reaction.

It is also preferable for R"OH to be converted readily into R"X, e. g. by activation through protonation as an oxonium ion. Under basic conditions the forward reaction of Equation 2 would be inefficient. These requirements for the regeneration of R"X from R"OH make it desirable to have the free carboxylic acid as the starting material. However free carboxylic acids are generally poor nucleophiles. Accordingly the use of carboxylate anions as reactants may be preferable in some circumstances. Carboxylic acids commonly have pKa's of around 4 and accordingly a pH within the range 4 to 7 may provide sufficient dissolution for the constraints associated with Equations 1 and 2 to be met and for the overall reaction to proceed.

The terms"residue of an alcohol"and"residue of thiol"as used herein refer to organic moieties capable of supporting hydroxyl or sulfhydryl functionalities respectively.

The term"residue of an organic halide"as used herein refers to organic moiety capable of supporting a halide functionality.

The terms"residue of a carboxylic acid","residue of a thioacid"and"residue of a dithioacid" refer to organic moieties capable of supporting carboxylic acid, thioacid and dithioacid functionalities respectively.

As used herein the terms"trace"or"trace amount"when used in relation to a reactant, such as an organic halide or alkali metal halide, indicate that the amount added to the reaction is not stoichiometric, but is an amount sufficient to initiate or promote the reaction to the extent that the desired product is obtained. The trace amount could refer to an amount added to the reaction mixture, or to a concentration of the reactant generated in situ.

The reactant RYH may be a carboxylic acid, a thioacid, a dithioacid, an alcohol or a thiol.

Preferably RYH is a carboxylic acid or an alcohol. The carboxylic acid may be any organic compound bearing one or more carboxylic acid groups, optionally together with one or more non-deleterious substituents. The carboxylic acid or its corresponding carboxylate, should be capable of reacting with an organic halide to produce an ester. Examples of suitable monoacids include saturated or unsaturated alkanoic or alkenoic acids, such as straight chain or branched, saturated or unsaturated fatty acids, preferably having 1 to 18 carbon atoms, such as acetic acid, propanoic acid, butanoic acid, hexanoic acid, cyclohexanoic acid; and aromatic acids, such as benzoic acid, p-toluic acid. Examples of suitable polyacids include malonic acid and terephthalic acid. The carboxylic acid may be a mixture of two or more carboxylic acids, such that the final product will be a composition of esters, which could be fractionated if desired.

Examples of thioacids and dithioacids useful in accordance with the present invention include those which correspond to the carboxylic acids described above in which one or more of the carboxylic acid groups are replaced with the thioacid or dithioacid group.

The alcohol may be any organic compound bearing one or more hydroxy groups (optionally with one or more non-deleterious substituents) which are capable of reacting with an organic halide to produce an ether. Examples of suitable monoalcohols include saturated or unsaturated monoalkanols, such as the products of hydrogenation of straight-chained or branched, saturated or unsaturated fatty acids or derivatives thereof, aliphatic or cyclic alkanols, preferably having 1 to 18 carbon atoms, such as methanol, ethanol, propanol, butanol, hexanol, cyclohexanol; and aromatic alcohols, such as phenol and naphthol.

Examples of suitable polyols include ethylene glycol, 1,2-propylene glycol, 1,2-butylene glycol, neopentyl glycol, glycerol, diglycerol, triglycerol, tetraglycerol, trimethylolpropane, di-tri-methylolpropane, pentaerythritol, di-pentaerythritol, and sugar alcohols, such as sorbitan, glucose, fructose and sucrose. The alcohol may also be a mixture of two or more alcohols, such that the final product of the reaction will be a composition of symmetrical and unsymmetrical ethers, which could be fractionated if desired.

Examples of thiols useful in accordance with the present invention include those which correspond to the alcohols described above in which one or more of the hydroxy groups is replaced with a sulfhydryl group.

The organic halides, R'X and R"X, may be any organic halides capable of reacting with carboxylic acids or alcohols (or thio equivalents) to produce esters or ethers respectively. The groups R'and R"may be residues of the alcohols or carboxylic acids described above.

Preferably the halide is attached to an aliphatic carbon atom. In the case of ether preparation, it is preferred that the group R'corresponds to the group R.

The alcohol (or thiol), R"ZH, of Equation 2 may be any of the alcohols or thiols described above in relation to RYH. For symmetrical ether production R = R". The alcohol or thiol should be capable of reacting with HX to regenerate organic halide R"X.

The organic acid RC (Z') ZH of Equation 6 may be any of the acids described above in relation to RYH.

The salt QX represents an alkali metal halide. Preferably the alkali metal halide is selected from LiCl, LiBr, LiI, NaCI, NaBr, NaI, CsCI, CsBr, CsI, KCI, Kbr and KI.

The reaction is preferably carried out using the alcohol (or thiol) as the solvent, although other solvents may be added if it is necessary to change the polarity of the solvent to achieve the desired product. In the case of alcohols which are viscous or semi-solid the reaction may be carried out in a solvent which can dissolve the alcohol and provide the desired polarity characteristics.

Examples of suitable solvents include nitromethane, nitroethane, nitropropane, dimethylformamide, dimethylacetamide and acetonitrile.

The reaction may be carried out at any suitable temperature and pressure. The temperature

and pressure selected for a particular reaction will depend on the nature of the reactants and the solvent used. Generally the reaction will be carried out at a temperature between 40° and 400°C, more preferably between 70°C and 250°C. The reaction will generally be conducted at atmospheric pressure, although in the case of some volatile alcohols or solvents, or in the case of some reactants which require reaction temperatures higher than the vapour pressure of the solvent system, the reaction can be performed in a pressurized vessel.

It should be noted that in the preparation of unsymmetrical ethers according to the method of the invention there will necessarily be some symmetrical product formed by reaction of the alcohol with the organic halide generated by reaction of the hydrogen halide with the alcohol.

The unsymmetrical product may be separated from the symmetrical product (if desired) using standard techniques, such as distillation, liquid chromatography, crystallisation and recrystallisation, zone refining or solvent partitioning.

The process according to the invention may also be used to prepare useful mixtures of ethers by starting with a mixture of alcohols. These mixtures of ethers may be useful as anti-knock agents for motor fuels, solvents, heat transfer oils, polymers or chromatographic supports.

When the reaction is performed with a polyol the likely product is a polyether, although if the alcohol has a number of hydroxy groups attached to a central core it is possible to produce dendrimers.

In the case of diols it is possible to produce polyethers, which may be straight-chain or cyclic.

It is also possible to react a diol to produce an intramolecular ring closure, thereby producing a cyclic ether.

The process according to the invention may be operated in batch or continuous mode. In the batch mode the alcohol and the organic halide are added to a reaction vessel and, if necessary, the mixture is heated to the desired temperature for an appropriate time to produce the desired ether or ether compositions. The water produced by the process may optionally be removed

during the reaction by known methods. As the concentration of water increases during progress of the reaction the hydrogen halide could be removed from the reaction system by dissolution in the water. As mentioned above the reaction rate could be maintained by the progressive addition of organic halide.

In the continuous mode, if the product ether is more volatile than either the alcohol or organic halide, the alcohol may be added continuously to an excess of organic halide, heated if necessary, the ether and water formed being removed by distillation. The mixed vapours may be fractionated and the ether and the water separately condensed. Alternatively, the ether may be sufficiently insoluble in water for separation to occur after condensation of the product vapours without fractionation.

In some circumstances it may be desired or necessary to post-treat the ether product, for example to remove traces of RX or HX or to dry the ether. This may be done by standard methods.

Similar consideration to those described above in relation to ether production also apply in the case of ester production.

Although the temperature is not critical for the operation of the process, the reaction rates will increase in the usual manner as temperature increases. As mentioned above the preferred temperature for the process is in the range of 40° to 400°C. Similarly pressure is not a significant factor for the operation of the process, although the increased operating temperature possible by using elevated pressures may be an advantage in some cases.

The process according to the invention provides a method for the synthesis of ethers, and esters from alcohols which avoids the use of strong acid (eg. concentrated sulfuric acid) catalysts and dehydrating agents of the Williamson process and the prior art processes, with the attendant cost and effluent disposal problems being also avoided.

Reference will now be made to the following examples which illustrate some preferred embodiments of the invention. However it is to be understood that the following detailed description of the invention is not to supersede the generality of the invention previously described.

EXAMPLES EXAMPLE 1 (a) Heating neat 2-phenethanol A tube was charged with 2-phenethanol (0.5 g, 4.1 mmol) and heated at 220°C. After 22 hours, less than 1% conversion to di-2-phenylethyl ether was detected by gas chromatographic (GC) analysis.

(b) Neat 2-phenylethanol was heated at 160°C. This reaction did not afford 2- phenylethylether.

(c) Preparation of di-2-phenylethyl ether with (2-bromoethyl) benzene as a catalyst A solution of 2-phenethanol (0.5 g, 4.1 mmol) and (2-bromoethyl) benzene (0.086 g, 0.5 mmol) was kept at 220°C for 21 hours in a small, closed reaction vessel. The mixture was cooled.

GC analysis showed 76% conversion of alcohol to di-2-phenylethyl ether. EIMS at 70eV [m/z (rel. int.)], 226 (M+, 1), 135 (9), 134 (9), 133 (5), 105 (100), 91 (14), 79 (13), 77 (16), 65 (8), 51 (7).

(d) The above process (b) was repeated with the addition of 10 mol per cent (2- bromoethyl) benzene. This reaction resulted in an accumulation of 2-phenylethylether, and the concentration of (2-bromoethyl) benzene remaining constant within the limits of the GC and nmr analytical methods.

EXAMPLE 2 2-phenylethanol was heated with Bu4NBr as the potential source of bromide, however this reaction did not afford the desired ether, but returned the starting alcohol and a small amount of 2-phenylethyl N-butylether, presumed to be the Hoffman degradation product. (2- Bromoethyl) benzene and di-2-phenylethylether formed only after addition of a few drops of

acid (HOAc) to the reaction mixture. These results are consistent with the pathway proposed above in Scheme 3.

EXAMPLE 3 Preparation of di-sec-phenethyl ether with (1-bromoethyl) benzene as a catalyst (120°C) A solution of sec-phenethanol (2.5 g, 20 mmol) and (1-bromoethyl) benzene (0.38 g, 2 mmol) was kept at 120°C for 20 hours and then cooled. GC analysis showed 64% conversion of alcohol to di-sec-phenethyl ether. EIMS at 70eV [m/z (rel. int.)] ; 211 (1), 181 (1), 167 (1), 148 (1), 121 (14), 106 (20), 105 (100), 77 (20), 51 (9), 43 (7).

EXAMPLE 4 Etherification of the acid-sensitive compound, cyclopropylmethyl carbinol.

(a) Cyclopropylmethyl carbinol was heated at 125°C for 3 days in the absence of acid to afford 2% of di (cyclopropylmethyl) ether. However, when cyclopropylmethyl carbinol and 9 mol per cent cyclopropylmethyl bromide were heated together at 115°C, di (cyclopropylmethyl) ether accumulated, initially without significant depletion of the starting bromide or rearrangement, until the conversion was approximately 51 %, after 24 hours. Given the remarkable acid-lability of cyclopropyl methyl carbonyl this indicates that the concentration of HBr was low.

However, as the reaction progressed, water accumulated and the liberated HBr began dissolving in the aqueous medium, rather than forming the desired ether. This resulted in an appreciable slowing of the reaction. Decomposition of unreacted cyclopropylmethyl carbinol and the ether also occurred to give cyclobutyl-and homoallyl alcohols along with mixtures of ethers containing cyclopropyl, cyclobutyl and homoallyl functionalities.

When the amount of cyclopropylmethyl bromide was reduced from 9 mol per cent to 4.8 mol per cent relative to cyclopropylmethyl carbinol, the reaction proceeded at approximately half the rate; conversion to the desired ether being 28 % after 24 hours.

Etherification was also achieved using cyclopropylmethyl chloride as the catalyst, or by using hydrogen iodide to generate the cyclopropylmethyl iodide in situ.

(b) Heating neat cyclopropylmethanol (120°C) Cyclopropylmethanol (1.0 g, 14 mmol) was heated at 120°C for 24 hours, and then cooled. GC analysis showed less than 1% conversion of the alcohol to di- cyclopropylmethyl ether.

(c) Preparation of di-cyclopropylmethyl ether with bromomethyl cyclopropane as a catalyst A solution of cyclopropanemethanol (1.082 g, 0.015 mol) and bromomethylcyclopropane (0.203 g, 0.0015 mol) was heated to 115°C in a small, closed reaction vessel. After 24 hours heating, the conversion of alcohol to di-cyclopropylmethyl ether was 51 %. EIMS at 70eV [m/z (rel. int.)]; 125 (1), 111 (1), 98 (34), 84 (1), 83 (1), 70 (26), 56 (5), 55 (100), 53 (5), 41 (7).

(d) Preparation of di-cyclopropylmethyl ether with chloromethyl cyclopropane as a catalyst A solution of cyclopropanemethanol (0.72 g, 10 mmol) and chloromethyl cyclopropane (0.09 g, 1 mmol) was heated to 100°C in a small, closed reaction vessel. After 20 hours, the conversion of alcohol to di-cyclopropylmethyl ether was 13%.

It is evident from examples 1 to 3 that the process is useful in the etherification of primary and secondary alcohols and compounds which are base-labile.

EXAMPLE 5-WATER REMOVAL (a) In a protocol based on the findings of Lee and Cheng (Lee. A. S.-Y.; Cheng, C.-L.

Tetrahedron 1997,53,14255) and modified herein, cyclopropyl methyl carbonyl was heated with 0.1 equivalent of CBr4 or CHI3 in sealed systems at 100°C. It was anticipated that HBr and HI would form in the solutions by slow decomposition of the respective halo carbons. In both cases the desired ether was

obtained. As expected, the reaction mixtures also contained the corresponding cyclopropylmethyl halides and when water accumulated in the mixture, acid- catalysed decomposition of the starting material and product occurred. This example indicates that CHI3 and CBr4 decompose slowly in the presence of alcohol to form HI and HBr, which then catalyse the etherification in accordance with Scheme 1. This indicates that losses of HBr and HI by co-distillation with water could be counter balanced by the replenishment of these acids from slowly decomposing CBr4 or CHI3.

(b) Preparation of di-cyclopropylmethyl ether with iodoform as a catalyst A solution of cyclopropanemethanol (0.36 g, 5 mmol) and iodoform (0.39 g, 1 mmol) was heated to 120°C in a small, closed reaction vessel. After 24 hours, the conversion of alcohol to di-cyclopropylmethyl ether was 48%.

(c) Preparation of di-cyclopropylmethyl ether with tetrabromomethane as a catalyst A solution of cyclopropanemethanol (0.36 g, 5 mmol) and tetrabromomethane (0.33 g, 1 mmol) was heated to 115°C in a small, closed reaction vessel. After 24 hours, the conversion of alcohol to di-cyclopropylmethyl ether was 27%.

EXAMPLE 6-Ethers from acid-and base-labile starting materials As mentioned above, established methods for etherification that employ either acidic or basic conditions would be unlikely to give a good yield of cyclopropylmethyl 2-phenylethylether from (2-bromoethyl) benzene and cyclopropylmethyl carbinol. Milder (and preferably neutral) conditions according to the present invention are beneficial. Cyclopropylmethyl carbinol was heated with (2-bromoethyl) benzene (9.1 mol %) at 125°C for 20 hours. After this time the volatile products comprised cyclopropylmethyl 2-phenylethyl ether (11 %) and di-cyclopropylmethyl ether (23 %), along with cyclopropylmethyl bromide, by gas chromatographic analysis. The starting alcohol and bromide had been depleted but were still present. A second addition of cyclopropylmethyl carbinol led to continued accumulation of di (cyclopropylmethyl) ether. This example is consistent with the reaction proceeding by the pathway proposed in Scheme 3.

EXAMPLE 7 Cyclopropylmethyl carbinol was heated with 0.1 equivalent of HBr or HI (starting from equation 2), resulting in the production of homoallylic and cyclobutyl halides as the major products. A mixture of ethers, which included di (cyclopropylmethyl) ether, formed as the reaction progressed. The different outcome of this experiment indicates that when the alcohol is acid-labile, side reactions can compete with the formation of the organic halide.

Accordingly in the case of acid-labile alcohols it is preferable to start the reaction cycle from equation 1, with negligible initial concentration of HX.

EXAMPLE 8 A mixture of 1,6-hexane diol (112 mmol) and 1,6-dibromohexane (ll. Ommol) was heated at 200°C. Water and some volatile organic material was removed by distillation during the reaction. After 12 hours a polymer with MI, = 849, polydispersity = 1.97 (polystyrene equivalent molecular weight determined by GPC) was obtained in 79% yield.

H'nmr confirmed the presence of ether linkages in the polymer (Hl adjacent to ether linkage, gives chemical shift of 3.40 ppm, H1 adjacent to hydroxy group, gives chemical shift of 3.62 ppm) with the ratio of hydroxy groups to ether linkages ca. 1: 7.5.

EXAMPLE 9 (a) Heating of neat n-butanol A pressure vessel was charged with 0.5 g of n-butanol and heated at 200 ° C for 2 hours. GC analysis indicated no conversion to di-n-butyl ether.

(b) Preparation of di-n-butyl ether with 1-bromobutane as a catalyst An aliquot (0.5 g) of a solution of n-butanol (5.0 g, 67.5 mmol) and 1-bromobutane (0.925 g, 6.75 mmol) was sealed in a glass lined tube and heated at 200°C for 1 hour. GC analysis showed 26% conversion of alcohol to di-n-butyl ether (ie 1,1'-oxybisbutane) and no detectable depletion of the 1-bromobutane. EIMS [m/z (rel. int.)]; 130 (M+, 1), 87 (14), 58 (5), 57 (100), 56 (18), 55 (5), 43 (5), 4 1 (42).

(c) Use of different inorganic salts for the preparation of di-n-butyl ether.

The use of lithium bromide A reaction mixture comprising 1-butanol (5-. 0 g, 67.5 mmol), 1-bromobutane (0.961 g, 7.0 mmol) and lithium bromide (0.589 g, 6.8 mmol) was prepared. Two pressure vessels were charged with 0.5 g of the reaction mixture each, then heated for 2 hours at 200 ° C.

For each of the duplicates, GC analysis showed 57% and 52% conversion of alcohol to di-n- butyl ether.

The use of potassium bromide A reaction mixture was prepared consisting of n-butanol (1.0 g, 13.5 mmol), 1-bromobutane (0.185 g, 1.35 mmol), potassium bromide (0.161 g, 1.35 mmol) and water (0.21 g, 11.6 mmol).

Two pressure vessels were charged with 0.5 g of the reaction mixture each, then heated to 200 ° C.

GC analysis showed 45% after 1 hour and 56% after 2 hours conversion of alcohol to 1,1'- oxybisbutane, conversions that were twice as high as for experiments where no KBr was present.

The use of cesium bromide A reaction mixture was prepared consisting of ; n-butanol (1.0 g, 13.5 mmol), 1-bromobutane (0.185 g, 1.35 mmol), cesium bromide (0.287 g, 1.35 mmol) and water (0.349 g, 19.4 mmol).

Two pressure vessels were charged with 0.5 g of the reaction mixture each, then heated to 200 ° C.

GC analysis showed 40% after 1 hour and 53% after 2 hours conversion of alcohol to 1,1'- oxybisbutane.

(d) Preparation of di-n-butyl ether with hydrobromic acid as a catalyst A reaction mixture was prepared consisting of ; n-butanol (1.0 g, 13.5 mmol), 48% aqueous hydrobromic acid (0.221 g, 1.3 mmol) and lithium bromide (0.117 g, 1.35 mmol). Two pressure vessels were charged with 0.5 g of the reaction mixture each, then heated to 200 ° C.

GC analysis showed conversion of 39% after 1 hour and 47% after 2 hours of alcohol to 1,1'- oxybisbutane. There was 8% of 1-bromobutane detected after 1 hour and 8% after 2 hours of the process.

EXAMPLE 10 Preparation of ethers from secondary alcohols (a) Heating neat 2-butanol.

A pressure vessel was charged with-0.3 g of 2-butanol, placed in an oven at 150°C for 5 hours.

GC analysis showed no reaction.

(b) Preparation of 2, 2'-oxybisbutane with 2-bromobutane as a catalyst A reaction mixture was prepared consisting of ; 2-butanol (1.0 g, 13.5 mmol) and 2-bromobutane (0.196 g, 1.4 mmol). A pressure vessel was charged with 0.59 g of the reaction mixture and heated to 150°C. After 5 hours, GC analysis showed 8% conversion of alcohol to 2,2'- oxybisbutane with an unchanged level of 2-bromobutane. EIMS [m/z (rel. int.)]; 130 (M+, 1), 115 (1), 101 (9), 83 (3), 59 (21), 57 (39), 45 (100).

(c) Preparation of 2,2'-oxybisbutane with 2-bromobutane as a catalyst and lithium bromide A reaction mixture was prepared consisting of ; 2-butanol (1.0 g, 13.5 mmol), 2-bromobutane (0.181 g, 1.3 mmol) and lithium bromide (0.115 g, 1.3 mmol). A pressure vessel was charged with 0.426 g of the reaction mixture and heated to 150°C. After 5 hours, GC analysis showed 18% conversion of alcohol to 2,2'-oxybisbutane.

(d) Preparation of 2-butyl ether with 2-bromobutane as a catalyst.

A reaction mixture was prepared consisting of ; 2-butanol (13.5 mmol) and 2-bromobutane (1.35 mmol). A pressure vessel was charged with 0.5 g of the reaction mixture, placed in an oven at 130°C. After 24 hours, 21% of 2-butanol was converted to di-2-butyl ether and 2-bromobutane was present at approximately its starting concentration.

(e) Di-2-octylether.

A mixture of 2-octanol (277 mmol) and aqueous hydroiodic acid ca. 47%, (6.6 g ; ca. 24 mmol hydrogen iodide) was heated with stirring, under an argon atmosphere at 140°C-I75°C for 8 hours and at 175 ° C-194 ° C for a further 21.6 hours. The water was distilled from the mixture

along with some organic matter, leaving a residue (18.9 g), 34% of which was attributed to the two diastereoisomers of 2, 2'-oxybis-octane. 2-Iodo-octane (16% by peak area) was detected in the reaction mixture. The diastereoisomeric ether was purified by distillation under reduced pressure. Microanalysis: Found; carbon, 79.0%; hydrogen, 14.5%. Expected; carbon, 79.3%; hydrogen, 14.1%.

'HNMR (CDCl3): 80.9 (br s, 6H); 6 1. 1 (doublet of doublets, 6H); 81.3 (m, 20H), 83.36 (brm, 2H), cf literature values of Adams et al.; Journal of Catalysis, 58, (1979) pp 238-252.

"C NMR (CDCI,): 873.3,72.9,37.5,37.2,31.9,29.4,25.8,25.6,22.6,21.0,14.0.

EXAMPLE 11 Process examples (a) Preparation of 1,1'-oxybisbutane in a Continuous Flow Reactor (CFR).

A mixture of n-butanol (500 g, 6.75 mol), 1-bromobutane (92 g, 0,67 mol), lithium bromide (6.7 g, 0.077 mol) and water (17 g, 0.94 mol) was pumped through a continuous flow microwave reactor is T. Cablewski, A. F. Faux and C. R. Strauss, J. Org. Chem., (1994), 59, 3408. The temperature at the outlet was 170°C. Flow rate was set at 12 mL/min. After one pass through the microwave zone lasting 10 min, the conversion of alcohol to 1,1'- oxybisbutane was estimated at 2%.

(b) Preparation of 1,1'-oxybisbutane in a Microwave Batch Reactor as described in K. D.

Raner, C. R. Strauss, R. W. Trainor and J. S. Thorn, J. Org. Chem., (1995), 60,2456. A polytetrafluoroethylene vessel (200 mL capacity) was loaded with n-butanol (60 g, 0.81 mol), 1-bromobutane (11 g, 0.08 mol), lithium bromide (0.8 g, 0.009 mol) and water (2 g, 0.11 mol). The solution was stirred and microwave-heated. Heating for 20 min at 180°C gave 8% of 1,1'-oxybisbutane and for 60 min at 200°C afforded a conversion of 35%.

(c) Preparation of 1,1'-oxybisbutane in a glass column (1090 mm long and 50 mm internal diameter) filled with glass beads. With a peristaltic pump, a reaction mixture consisting of n-butanol and 1-bromobutane (10 mol %) was pumped (30 mL per hour) through an externally heated glass column. Maximum temperature achieved was about 140°C

and the conversions of alcohol to 1,1'-oxybisbutane was about 0.4%.

EXAMPLE 12 (a) Preparation of di-2-phenyl ethyl ether with (2-bromoethyl) benzene as a catalyst and lithium bromide A reaction mixture of 2-phenethanol (2.4 g, 20 mmol), (2-bromoethyl) benzene (0.37 g, 2 mmol), lithium bromide (0.17 g, 2 mmol) and 1 drop of water (for dissolving LiBr) was prepared. Pressure vessels were charged with 0.3 g of the reaction mixture and heated at 220°C for 2,4, or 24 hours. Conversion of alcohol to di-2-phenyl ethyl ether was estimated at 59,68, and 89% respectively.

(b) Preparation of di-2-phenyl ethyl ether with lithium bromide as a catalyst A reaction mixture of 2-phenethanol (2.4 g, 20 mmol), lithium bromide (0.17 g, 2 mmol) and 2 drops of water (for dissolving LiBr) was prepared. Pressure vessels were charged with 0.3 g of the reaction mixture then placed in an oven at 220° C for 2,4, or 24 hours. Conversion of alcohol to di-2-phenyl ethyl ether was estimated at 6,12, and 41% respectively and (1%) of (2-bromoethyl) benzene was formed.

EXAMPLE 13 Preparation of mixed ethers.

(a) Preparation of n-butyl phenyl ether (ie n-butoxybenzene) A reaction mixture of phenol (1.88g, 20 mmol) and n-butanol (1.48 g, 20 mmol) was prepared. Pressure vessels were charged with 0.3 g of the reaction mixture then heated at 200°C for 2,4, or 24 hours. After 24 hours only traces of di-n butyl ether and n- butoxybenzene were observed.

(b) Preparation of n-butyl phenyl ether with 1-bromobutane as a catalyst and water A reaction mixture was prepared consisting of ; phenol (10 mmol), n-butanol (10 mmol), 1- bromobutane (1 mmol), and water (10 mmol). A pressure vessel was charged with 0.4 g of the reaction mixture and heated at 200°C. After 1 hour, di-n-butyl ether was formed predominantly. After 20 hours di-n-butyl ether (20%) and butyl phenyl ether (16%) had

formed. The EIMS of the latter product at 70eV [m/z (rel. int)]; 150 (M+, 18), 135 (1), 121 (1), 94 (100), 79 (11), 66 (10), 51 (7), 41 (11).

EXAMPLE 14 Preparation of dibenzvl ether.

(a) Heating neat benzyl alcohol.

5 g of benzyl alcohol was heated for 6 hours at 150°C. No ether was detected.

(b) Preparation of dibenzyl ether with benzyl bromide as a catalyst A solution of benzyl alcohol (50 mmol) and benzyl bromide (5 mmol) was stirred and heated at 150°C for 2 hours. There was 60% conversion of benzyl alcohol to dibenzyl ether. EIMS at 70eV [m/z (rel. int)]; 165 (1), 107 (14), 105 (7), 92 (100), 91 (93), 79 (20), 77 (29), 65 (32), 63 (9), 51 (23), 50 (10).

(c) Preparation of dibenzyl ether with benzyl bromide as a catalyst and lithium bromide A mixture of benzyl alcohol (50 mmol), benzyl bromide (5 mmol) and lithium bromide (5 mmol) was stirred and heated at 150°C for 2 hours. There was 68% conversion of benzyl alcohol to dibenzyl ether.

(d) Preparation of dibenzyl ether with benzyl bromide as a catalyst A solution of benzyl alcohol (10 mmol) and benzyl bromide (1 mmol) was loaded into a pressure vessel and heated at 200 °C for 15 minutes. There was 62% conversion of benzyl alcohol to dibenzyl ether.

(e) Preparation of benzyl ether with benzyl chloride as a catalyst A solution of benzyl alcohol (10 mmol) and benzyl chloride (1 mmol) was heated in two pressure vessels at 200 ° C, respectively for 15 minutes and for 1 hour. There was 27% conversion of benzyl alcohol to dibenzyl ether after 15 min and 67% conversion after 1 hour.

EXAMPLE 15 4,4'-dichlorobenzyl ether.

A mixture of 4-chlorobenzyl alcohol (3.7 mmol) and 4-chlorobenzyl bromide (0.21 mmol) was heated in a sealed tube (volume ca. 1 mL) at 152 ° C for 5 hours. By GC and GC-MS analysis, 4,4'-dichlorobenzyl ether comprised 65% of the product mixture, with the remainder being mainly unreacted starting materials. EIMS at 70eV (m/z, rel. int.): 268 (0.4), 266 (0.5), 165 (1), 154 (4), 141 (21), 127 (37), 128 (50), 125 (98), 91 (100), 89 (44), 77 (44). Theether (mp49-51oC) was recrystallised from ethanol.'H NMR (CDCI,) 84.5 (s, 4H, CH), 7.6 (2s, 8H, C6H4), showed good agreement with literature values [of S. Toru, S. Takagishi, T. Inokuchi, and H. Okumoto Bull. Chem. Soc. Jpn., 60,775-776 (1987)];"C NMR (CDCI,) 871.4,128.6,129.0,130.9,136.5 EXAMPLE 16 Examples of oligoether formation: Oligomers of Ethylene Glycol (a) A solution of aqueous hydrobromic acid (2.5 g, ca. 19 mmol hydrogen bromide) and ethylene glycol (14.1 g, ca. 226.7 mmol) was heated at 175°C-180°C for 5 hours, under an atmosphere of argon, with stirring. A condenser was fitted to distil out water and other volatile materials. After the reaction, 7.9 g remained in the reaction vessel and 8.5 g of distillate was recovered. A sample of material from the reaction vessel was silylated and analysed by GC and GC-MS. The silylated derivatives of the following glycols were identified: starting ethylene glycol, 37%; digol, 34%; trigol, 16% and tetraethylene glycol, 7%. These identifications were made by comparison with silylated derivatives of the authentic materials.

(b) A mixture of ethylene glycol (22.1 g; 357 mmol), 2-bromoethanol (2.792; 22.3 mmol) and lithium bromide (1.6 g; 18.8 mmol), was heated at reflux for 5 hours. A sample of material from the reaction vessel was silylated and the silylated derivatives analysed by GC and GC-MS. The approximate composition of the major components in the product mixture was as follows: 2-bromoethanol, 4.2%; starting ethylene glycol, 60%; digol, 24.9%; trigol, 7.2%; and tetraethylene glycol, 1.8%.

(c) A solution of ethylene glycol (190 mmol) and tetrabromomethane (16.4 mmol) was heated at 128°C to 136°C for 18.5 hours, with stirring under argon. A condenser was used to remove the volatiles (4.8 g). The residues remaining in the flask (6.6 g) comprised oligomers of ethylene glycol, the approximate composition being as follows: <BR> <BR> <BR> <BR> HO- (CH2-CH2-O)-H :<BR> <BR> <BR> <BR> <BR> <BR> <BR> n=l, peak area = 6.0% n=2, peak area = 15.6% n=3, peak area = 13.3% n=4, peak area = 8.6% n=5, peak area = 5.2% n=6, peak area = 3.3% n=7, peak area = 2.1% n=8, peak area = 1.2% In addition to the major peaks in the chromatogram, a series of minor peaks was found, and these minor peaks had mass spectra typical of mono-brominated compounds, of general structure, Br (CH2-CH2-0),-H and composition as follows: n=1, peak area = 19.8% n=2, peak area = 2.5% n=3, peak area = 5.5% n=4, peak area = 3.9% n=5, peak area = 2.6% n=6, peak area = 1.4% (d) Trigol A solution oftrigol (101 mmol) and tetrabromomethane (12.3 mmol) was heated at ca. 130°C for 23 hours, with stirring under an atmosphere of argon. A condenser was used to remove the volatile products (0.4 g). A sample of the residues remaining in the flask (17.5 g) was silylated and analysed by GC and GC-MS and compared

with data from reference materials. The product comprised oligomers of ethylene glycol, the approximate composition being as follows: <BR> <BR> <BR> HO-(CH,-CH,-0),-H :<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> n=1, peak area = 6.8% n=2, peak area = 12.7% n=3, peak area = 34.5% n=4, peak area = 10.6% n=5, peak area = 4.8% n=6, peak area = 7.3% n=7, peak area = 2.6% n=8, peak area = 1.3% n=9, peak area = 1.2% In addition to the major peaks in the chromatogram a series of minor peaks was found, and these had mass spectra typical of mono-brominated compounds of the general formula, Br (CH2-CH2-O) n-H : n=l, peak area = 4.4% n=2, peak area = 1.0% n=3, peak area = 4.5% n=4, peak area = 1.6% n=5, peak area = 0.8% n=6, peak area = 0.1% EXAMPLE 17 (a) Preparation of isobutyl pivaloate A solution of trimethyl acetic acid (pivalic acid ; 1.022 g, 10 mmol) and isobutyl alcohol (3.706 g, 50 mmol) was heated to 150°C in a pressure tube. After 1 hour, GC analysis showed 27% conversion of pivalic acid to isobutyl pivaloate. After heating for 18 hours at 150°C, the conversion was 72%. EIMS of the product at 70eV [m/z (rel. int.; %)]; 159 (1), 143 (1),

115 (1), 103 (26), 85 (28), 57 (100), 56 (33).

(b) Preparation of isobutyl pivaloate A solution of trimethyl acetic acid (pivalic acid; 1.022 g, 10 mmol) and isobutyl alcohol (3.706 g, 50 mmol) was heated to 200°C in a pressure tube. After 1 hour, GC analysis showed 53% conversion of pivalic acid to isobutyl pivaloate. After heating for 18 hours at 200 ° C, the conversion was 93%.

(c) Preparation of isobutyl pivaloate with 1-bromo-2-methyl propane as a catalyst A solution of trimethyl acetic acid (pivalic acid; 1.022 g, 10 mmol), isobutyl alcohol (3.706 g, 50 mmol) and 1-bromo-2-methyl propane (0.282 g, 2 mmol) was heated to 150°C in a pressure tube. After 1 hour, GC analysis showed 31 % conversion of pivalic acid to the ester.

After heating for 18 hours, the conversion was 93%. A mixture of tert-butyl isobutyl ether and di-isobutyl ether was also detected (<2 % of the product distribution).

(d) Preparation of isobutyl pivaloate with 1-bromo-2-methyl propane as a catalyst and lithium bromide A solution of trimethyl acetic acid (pivalic acid; 1.022 g, 10 mmol), isobutyl alcohol (3.706 g, 50 mmol), 1-bromo-2-methyl propane (0.282 g, 2 mmol) and lithium bromide (0.419 g, 4.8 mmol) was heated to 150 ° C in a pressure tube. After 1 hour, GC analysis showed 30% conversion of pivalic acid to the ester. After heating for 18 hours, the conversion was 95%.

EXAMPLE 18 (a) Preparation of n-butyl 2,4,6-trimethylbenzoate without a catalyst A solution of 2,4,6-trimethylbenzoic acid (0.256 g, 1.6 mmol) and n-butanol (0.577 g, 7.8 mmol) was loaded into a pressure tube and heated. After 24 hours at 150°C, only 2% conversion of acid to the ester had occurred, as determined by GC analysis. EIMS of n-butyl 2,4,6-trimethylbenzoate at 70eV [m/z (rel. int.)] ; 220 (M+, 25), 165 (6), 164 (45), 163 (11), 148 (10), 147 (94), 146 (100), 119 (27), 118 (11), 117 (13), 115 (9), 103 (8), 91 (28), 78 (6), 77 (14), 65 (6), 51 (6), 41 (24).

(b) Preparation of n-butyl 2,4,6-trimethylbenzoate with 1-bromobutane as a catalyst.

A solution of 2,4,6-trimethylbenzoic acid (0.256 g, 1.6 mmol), n-butanol (0.577 g, 7.8 mmol) and 1-bromobutane (0.063 g, 0.46 mmol) was prepared and approximately 0.2 g of the reaction mixture was loaded into a pressure tube. After 1 hour and 24 hours respectively, at 150°C, GC analysis showed 2 and 22 % conversion of the acid to the n-butyl ester.

(c) Preparation of n-butyl 2,4,6-trimethylbenzoate with lithium bromide A solution of 2,4,6-trimethylbenzoic acid (0.256 g, 1.6 mmol), n-butanol (0.577 g, 7.8 mmol) and lithium bromide (0.0528 g, 0.61 mmol) was loaded into a pressure tube and heated for 24 hours at 150°C. GC analysis showed 29% conversion of the acid to the ester.

(d) Preparation of 2-propyl 2,4,6-trimethylbenzoate with 2-bromopropane as a catalyst.

A reaction mixture was prepared consisting of ; 2,4,6-trimethylbenzoic acid (0.25 g, 1.5 mmol), 2-propanol (0.45 g, 7.5 mmol) and 2-bromopropane (0.044 g, 0.36 mmol). A pressure tube was loaded with approximately 0.2 g of the reaction mixture and heated at 150°C for 18 hours. GC analysis 14% conversion of the acid to the ester.

EIMS [m/z, (rel. int.)]; 206 (M+, 18), 147 (86), 146 (100), 119 (30), 91 (32), 77 (18), 41 (23).

(e) Preparation of 2-propyl 2,4,6-trimethylbenzoate with 2-bromopropane and lithium bromide as catalyst A reaction mixture was prepared consisting of ; 2,4,6-trimethylbenzoic acid (0.2 g, 1.2 mmol), 2-propanol (0.38 g, 3.05 mmol), 2-bromopropane (0.035 g, 0.12 mmol) and lithium bromide (0.042 g, 0.24 mmol). Pressure tubes were each loaded with approximately 0.2 g of the reaction mixture and heated at 150°C for 1 hour and 18 hours. GC analysis respectively showed 10% and 37% conversion of the acid to the ester.

(f) Preparation of 2-propyl 2,4,6-trimethylbenzoate with excess of 2-bromopropane and lithium bromide A reaction mixture was prepared consisting of ; 2,4,6-trimethylbenzoic acid (0.25 g, 1.5 mmol), 2-bromopropane (0.92 g, 7.5 mmol) and lithium bromide (0.026 g, 0.3 mmol).

Pressure tubes were loaded with approximately 0.2 g of the reaction mixture and heated at

150°C for 4 hours. GC analysis showed 39% conversion of the acid to the ester.

EXAMPLE 19 (a) Preparation of n-butyl cinnamate with 1-bromobutane as a catalyst A solution of cinnamic acid (1.482 g, 10 mmol), n-butanol (3.706 g, 50 mmol) and 1- bromobutane (0.274 g, 2 mmol) was prepared and approximately 0.5 g of the reaction mixture was loaded into a pressure tube. After 1.5 hour, 3 and 20 hours respectively, at 150°C, GC analysis showed 65,77 and 94 % conversion of the acid to the butyl ester. EIMS [m/z (rel. int.)] ; 204 (M+, 14), 148 (73), 131 (100), 103 (68), 77 (66), 51 (34).

(b) Preparation of n-butyl cinnamate with lithium bromide A solution of cinnamic acid (0.741 g, 5 mmol), n-butanol (1.853 g, 25 mmol) and lithium bromide (0.087 g, 1 mmol) was loaded into a pressure tube and heated for 24 hours at 150°C. GC analysis showed that 98% of the acid was converted to the ester. Di-n- butylether was a by-product, comprising 3% of the product mixture.

EXAMPLE 20 Preparation of n-butyl ester of 9-anthracenecarboxylic acid with lithium bromide.

A solution of 9-anthracenecarboxylic acid (0.125 g, 0.56 mmol), n-butanol (0.208 g, 2,8 mmol) and lithium bromide (0.012 g, 0.14 mmol) was loaded into a pressure tube and heated for 1 hour at 210° C. GC analysis showed that 23% of the acid was converted to the ester.

EIMS [m/z (rel. int.)]; 278 (M+, 100), 222 (88), 205 (68), 177 (67), 176 (57), 150 (12), 88 (16).

Di-n-butyl ether comprised 14% of the product mixture.

EXAMPLE 21 Preparation of n-butyl benzoate with 1-bromobutane as a catalyst Benzoic acid (8.24 g, 68 mmol), n-butanol (5.0 g, 68 mmol) and n-butyl bromide (1.1 g, 8 mmol) were stirred at 120°C butyl alcohol to n-butyl benzoate. EIMS at 70eV [m/z (rel. int.)]; 178 (M+, 1), 123 (64), 122 (17), 106 (8), 105 (100), 79 (11), 77 (63), 56 (23), 51 (34), 50 (12), 41 (17).

Throughout this specification and the claims which follow, unless the context requires otherwise, the word"comprise", and variations such as"comprises"and"comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more of said steps or features.