TITLE

PROCESS FOR THE SYNTHESIS OF DIAMINOPYRIDINE AND RELATED COMPOUNDS

This application claims the benefit of U.S. Provisional Application No. 60/953,261, filed August 1, 2007, which is by this reference incorporated in its entirety as a part hereof for all purposes.

Technical Field

This invention relates to the manufacture of a diaminopyridine, such as 2, 6-diaminopyridine and related compounds, which are used industrially as precursors and intermediates in the synthesis of a variety of useful materials.

Background

The compound 2, 6-diaminopyridine

is conventionally used as a starting material for the preparation of a variety of products, which include dyes, metal ligands, medicines, pesticides, and monomers for incorporation into polymers such as those described in US 5,674,969.

It is known to prepare a diaminopyridine by means of the Chichibabin amination reaction in which pyridine is

reacted with sodium amide in an organic solvent. This is a complicated reaction requiring relatively severe conditions (e.g. a temperature of 200°C at high pressure) . The reaction moreover is not economical since the comparatively expensive sodium amide has to be used in excess amount to counteract dimerization, and process complexities associated with separation, handling of the hazardous sodium amide and waste disposal drive up the cost of manufacture .

Another process for manufacturing a diaminopyridine is a three step transformation of epichlorohydrin. This process has generally low productivity, and requires the use of excess sodium cyanide and handling of HCN. In addition, purification of the intermediate hydroxyglutaronitrile is required to achieve acceptable yields of the DAP product.

Displacement of chlorines with ammonia or amines in dichloropyridines is known. One method, for example, manufactures aminopyridines from chloropyridines and ammonia in the presence of a copper sulfate catalyst, and is described in Rec. Trav. Chim., 58, 709-721 (1939) and DE No. 510,432. Yields in this process, however, are typically too low for commercial viability.

In JP 53/053,662, aminopyridines are prepared by treating chloropyridines that contain at least one chlorine atom in the 2- or 6-position of the pyridine nucleus with aqueous NH ₃ in the presence of metallic Cu or Al. The relatively large amounts of copper or aluminum powder, and the relatively high temperatures and pressures, needed to run this reaction make it undesirably difficult, and the yields of 2, 6-diaminopyridine are, again, generally too low for commercial viability.

A need thus remains for a low-temperature, low- pressure, high-selectivity process for the preparation of a diaminopyridine such as 2, 6-diaminopyridine and related compounds .

Summary

In one embodiment, there is described herein a process for the synthesis of a compound as represented by the structure of Formula (I)

by (a) contacting a compound as represented by the structure of Formula (II) :

with a copper source in an aqueous ammonia solution to form a reaction mixture _/ wherein the aqueous ammonia solution is buffered to a pH between about 4 and about 8; and (b) heating the reaction mixture; wherein R ¹ and R ² in Formula (I) and in Formula (II) are each independently selected from the group consisting of

(a) H;

(b) an alkyl, aryl or aralkyl radical;

(c) NR ³ R ⁴ where R ³ and R ⁴ are each independently (i) H,

(ii an alkyl, aryl or aralkyl radical,

(iii) where R is an alkyl, aryl or aralkyl radical, or

(iv) -C(O)-NR ⁵ R ⁵ where each R ⁵ is as defined above; or

(d) OR ⁶ where R ⁶ is

(i) H,

(ii) an alkyl, aryl or aralkyl radical, or

(iii) where R is as defined above.

In another embodiment, there is provided a process to prepare an oligomer or polymer by conversion of a compound as represented by the structure of Formula (I) , as prepared by the above process, to the oligomer or polymer.

In another embodiment, there is provided a compound of Formula (I) as obtained or obtainable by the above process.

Detailed Description

In the process described herein, synthesis of a diaminopyridine ("DAP") , such as one of the various

compounds represented by the structure of Formula (I) , proceeds by means of chlorine-ammonia displacement in the presence of a copper source.

In one embodiment, there is described herein a process for the synthesis of a compound as represented by the structure of Formula (I)

by (a) contacting a compound as represented by the structure of Formula (II) :

with a copper source in an aqueous ammonia solution to form a reaction mixture, wherein the aqueous ammonia solution is buffered to a pH between about 4 and about 8; and (b) heating the reaction mixture; wherein R ¹ and R ² in Formula

(I) and in Formula (II) are each independently selected from the group consisting of

(a) H;

(b) an alkyl, aryl or aralkyl radical; (c) NR ³ R ⁴ where R ³ and R ⁴ are each independently (i) H,

(ii an alkyl, aryl or aralkyl radical,

(iii) where R ⁵ is an alkyl, aryl or aralkyl radical, or (iv) -C(O)-NR ⁵ R ⁵ where each R ⁵ is as defined above; or

(d) OR ⁶ where R ⁶ is (i) H, (ii) an alkyl, aryl or aralkyl radical, or

(iii) where R ⁵ is as defined above.

As used herein, the term "alkyl" denotes a univalent group derived from an alkane by removing a hydrogen atom from any carbon atom: -C _n H _2n+ i where n = 1. The alkyl radical may be a C ₁ ~ C ₂ o straight-chain, branched or cycloalkyl radical . Examples of suitable alkyl radicals include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, n-hexyl, cyclohexyl, n-octyl, trimethylpentyl, and cyclooctyl radicals.

As used herein, the term "aryl" denotes a univalent group whose free valence is to a carbon atom of an aromatic ring. The aryl moiety may contain one or more aromatic rings and may be substituted by inert groups, i.e. groups whose presence does not interfere with the reaction. Examples of suitable aryl groups include phenyl, methylphenyl, ethylphenyl, n-propylphenyl, n-butylphenyl, t-butylphenyl, biphenyl, naphthyl and ethylnaphthyl radicals.

As used herein, the term "aralkyl" denotes an alkyl group which bears an aryl group. Examples of suitable aralkyl radicals include benzyl (i.e. the C ₆ H ₅ CH ₂ - radical) and phenylethyl (i.e. phenethyl, the C ₆ H ₅ CH ₂ CH ₂ - radical) .

In one embodiment of the process described herein, compounds as represented by the structure of Formula (I) are prepared by contacting compounds as represented by the structure of Formula (II) with a copper source in a buffered aqueous ammonia solution to form a reaction mixture, and heating the reaction mixture. In a particular embodiment of Formula (II), R ¹ and R ² may each be H. When R ¹ and R ² are each H, the compound as represented by the structure of Formula (II) is 2, 6-dichloropyridine ("DCP"), and the compound as represented by the structure of Formula (I) as made by this process is 2,6- diaminopyridine. Such a reaction is shown schematically below:

Compounds as represented by the structure of Formula (II) are commercially available or may be synthesized. For example, 2, 6-dichloropyridine may be obtained from Sigma-Aldrich (St. Louis, Missouri) , or may be synthesized by photochlorination of pyridine or 2-chloropyridine (see, e.g., WO 95/21158 and U.S. Patent No. 5,536,376). 3-amino-2, 6-dichloropyridine may be obtained from TCI America, Portland, Oregon. 2, 6-dichloro-

3, 5-diitιethylpyridine may be synthesized, for example, from 3, 5-dimethylpyridine (also known as 3, 5-lutidine) by ring- selective sequential lithiation [see Synlett (2002) (4), 628-630] . Compounds as represented by the structure of Formula (II) wherein R ¹ is methyl and R ² is methyl or phenyl can be synthesized from oxazinones with acetylenic compounds in toluene as described in Tetrahedron Letters (1989), 30(24), 3183-6.

The copper source may be elemental copper

[Cu(O)], or a copper compound such as a Cu (I) compound or a Cu (II) compound, such as a Cu (I) salt or a Cu (II) salt, or mixtures thereof. Examples of copper compounds suitable for use herein include without limitation CuCl, CuBr, CuI, Cu ₂ SO ₄ , CuNO ₃ , CuCl ₂ , CuBr ₂ , CuI ₂ , CuSO ₄ , and Cu (NO ₃ ) ₂ . CuBr and CuI are especially preferred. The copper source is believed to function in the reaction as a catalyst. Acting as a catalyst, the copper source would not participate in the reaction in any manner in which it would be chemically altered, but it is believed nevertheless to modify one or more parameters of the reaction to thereby enhance product formation. The copper source is consequently provided to the reaction mixture in a catalytically-effective amount, i.e. an amount that will achieve such purpose.

The amount of copper used in the reaction is typically about 0.5 to about 7 mol% based on the number of moles of Formula (II) compound present in the reaction mixture. Ammonia concentration typically ranges from about 5 to about 10 moles per mole of Formula (II) compound present in the reaction mixture.

The aqueous ammonia solution may be buffered by the addition thereto of a buffering agent. The buffering

agent is a material that does not participate directly in the reaction but does by its presence limit the pH of the reaction mixture to a preselected limit. The buffering agent is frequently a material that, in the context of a Brønsted-Lowry acid, is a weak acid/conjugate base pair, or a weak base/conjugate acid pair. The buffering agent will, in attaining an equilibrium by the gain or loss of protons, limit changes in the pH of the reaction mixture to a preselected range in relation to events such as the addition to the system of acid or alkali, or dilution of the reaction mixture. Addition of a buffering agent to the reaction mixture hereof creates a buffered solution in which the pH will be maintained at a pH of about 4.0 or more, about 4.5 or more, about 5.0 or more, or about 5.5 or more, and yet about 8.0 or less, about 7.5 or less, about 7.0 or less, or about 6.5 or less. The range of pH to which the buffering agent will limit the reaction mixture may be expressed in terms of any range formed any combination of the various maxima and minima, as set forth above .

The buffering agent may be selected, for example, from among the alkali metal, the alkaline earth metal or the ammonium phosphates, borates, sulphates, carbonates, bicarbonates, acetates, hydroxides, bromides, silicates, citrates, gluconates and tartrates; or an alkali metal salt of a lower alkanecarboxylic acid, such as acetic acid; or a basic alkali metal salt of phosphoric acid. Examples of suitable buffering agents also include without limitation sodium bicarbonate, sodium carbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium tetrapyrophosphate, orthophosphates and the water-soluble condensed phosphates such as tripolyphosphates and pyrophosphates. Also included are ammonium acetate, ammonium bromide, ammonium dihydrogen phosphate, ammonium

hydrogen phosphate, and ammonium borate. Also included are alkali metal compounds or alkaline earth metal compounds such as the sodium, potassium and calcium compounds, and, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, and potassium carbonate, calcium carbonate, sodium acetate, disodium hydrogen phosphate, trisodium phosphate and sodium borate. Also included are sodium sesquicarbonate, sodium silicate, potassium silicate, sodium pyrophosphate, tetrapotassium pyrophosphate, tripotassium phosphate, trisodium phosphate, anhydrous sodium tetraborate, sodium tetraborate pentahydrate, sodium tetraborate decahydrate, magnesium oxide, boric acid, malic acid, benzoic acid, and (methyl) succinic acid.

The buffering agent may be added to the reaction mixture in any convenient manner. When, for example, an ammonium salt of a weak acid is used as the buffering agent, the salt may be added directly as the salt (e.g. ammonium acetate) or may be formed in situ (e.g. by adding acetic acid or acetic anhydride to excess aqueous ammonia) . Typically, the buffering agent is present in the reaction mixture at a concentration of from about 20 to about 60 wt% based on the weight of the whole reaction mixture.

Although reaction conditions such as temperature, pressure and time may vary according to the choice of the specific copper source, the following conditions have typically been found suitable to achieve production of a desired Formula (I) compound: a heated reaction temperature generally in the range of from about 100°C to about 150°C; a reaction pressure generally in the range of from about 150 psi (1.03 MPa) to about 700 psi (4.83 MPa); and a reaction time generally in the range of about 5 to about 9 hours .

In one embodiment, the DAP reaction product of the process hereof is separated from the reaction mixture by removal of excess ammonia and part of the water followed by crystallization from the reaction mixture that contains the reaction product, the buffering agent and the catalyst. In another embodiment, the reaction product is separated by precipitating it as a hemisulfate by adding sulfuric acid to the reaction mixture.

The process hereof advantageously provides an increased selectivity to, and yield of, the desired Formula (I) product as compared to known processes. As used herein, the term "selectivity" for a product ("P") denotes the molar fraction or molar percentage of P in the final product mix, and the term "conversion" denotes how much reactant was used up as a fraction or percentage of the theoretical amount. The conversion multiplied by the selectivity thus equals the maximum "yield" of P, while the actual yield, also referred to as "net yield, " will normally be somewhat less than this because of sample losses incurred in the course of activities such as isolating, handling, drying, and the like. As used herein, the term "purity" denotes what percentage of the in-hand, isolated sample is actually the specified substance. The increased selectivity to, and yield of, the desired Formula (I) product obtained herein may result from what appears to be the effect of the buffering agent to minimize the occurrence of undesirable side reactions, thereby resulting in an increase in selectivity to the desired product. The invention is not, however, limited to any particular theory of operation.

The process described above also allows for effective and efficient synthesis of products made from a

diaminopyridine such as an oligomer or polymer thereof. These produced materials may have one or more of amide functionality, imide functionality, or urea functionality. Another embodiment of this invention thus provides a process for converting a diaminopyridine into an oligomer or polymer. A diaminopyridine may be made by a process such as described above, and then further subjected to a polymerization reaction to prepare an oligomer or polymer therefrom, such as those having the type of functionality named above. In a multi-step process, a polymer such as pyridobisimidazole-2, 6-diyl (2, 5-dihydroxy-p-phenylene) polymer may also be prepared from a diaminopyridine.

A diaminopyridine may be converted into a polyamide oligomer or polymer by reaction with a diacid (or diacid halide) in a process in which, for example, the polymerization takes place in solution in an organic compound that is liquid under the conditions of the reaction, is a solvent for both the diacid (halide) and the diaminopyridine, and has a swelling or partial salvation action on the polymeric product. The reaction may be effected at moderate temperatures, e.g. under 100°C, and is preferably effected in the presence of an acid acceptor that is also soluble in the chosen solvent. Suitable solvents include methyl ethyl ketone, acetonitrile, N, N- dimethylacetamide dimethyl formamide containing 5% lithium chloride, and N-methyl pyrrolidone containing a quaternary ammonium chloride such as methyl tri-n-butyl ammonium chloride or methyl-tri-n-propyl ammonium chloride. Combination of the reactant components causes generation of considerable heat and the agitation, also, results in generation of heat energy. For that reason, the solvent system and other materials are cooled at all times during the process when cooling is necessary to maintain the desired temperature. Processes similar to the foregoing

are described in US 3,554,966; US 4,737,571; and CA 2,355,316.

A diaminopyridine may also be converted into a polyamide oligomer or polymer by reaction with a diacid (or diacid halide) in a process in which, for example, a solution of the diaminopyridine in a solvent may be contacted in the presence of an acid acceptor with a solution of a diacid or diacid halide, such as a diacid chloride, in a second solvent that is immiscible with the first to effect polymerization at the interface of the two phases. The diaminopyridine may, for example, be dissolved or dispersed in a water containing base with the base being used in sufficient quantities to neutralize the acid generated during polymerization. Sodium hydroxide may be used as the acid acceptor. Preferred solvents for the diacid (halide) are tetrachloroethylene, methylenechloride, naphtha and chloroform. The solvent for the diacid (halide) should be a relative non-solvent for the amide reaction product, and be relatively immiscible in the amine solvent. A preferred threshold of immiscibility is as follows: an organic solvent should be soluble in the amine solvent not more than between 0.01 weight percent and 1.0 weight percent. The diaminopyridine, base and water are added together and vigorously stirred. High shearing action of the stirrer is important. The solution of acid chloride is added to the aqueous slurry. Contacting is generally carried out at from 0°C to 60°C, for example, for from about 1 second to 10 minutes, and preferably from 5 seconds to 5 minutes at room temperature. Polymerization occurs rapidly. Processes similar to the foregoing are described in US 3,554,966 and US 5,693,227.

A diaminopyridine may also be converted into a polyimide oligomer or polymer by reaction with a tetraacid

(or halide derivative thereof) or a dianhydride in a process in which each reagent (typically in equimolar amounts) is dissolved in a common solvent, and the mixture is heated to a temperature in the range of 100~250°C until the product has a viscosity in the range of 0.1~2 dL/g. Suitable acids or anhydrides include benzhydrol 3, 3' ,4,4'- tetracarboxylic acid, 1, 4-bis (2, 3-dicarboxyphenoxy) benzene dianhydride, and 3, 3' ,4,4' -benzophenone tetracarboxylic acid dianhydride. Suitable solvents include cresol, xylenol, diethyleneglycol diether, gamma-butyrolactone and tetramethylenesulfone. Alternatively, a polyamide-acid product may be recovered from the reaction mixture and advanced to a polyimide by heating with a dehydrating agent such as a mixture of acetic anhydride and beta picoline. Processes similar to the foregoing are described in US 4,153,783; US 4,736,015; and US 5,061,784.

A diaminopyridine may also be converted into a polyurea oligomer or polymer by reaction with a polyisocyanate, representative examples of which include toluene diisocyanate; methylene bis (phenyl isocyanates) ; hexamethylene diisocycanates; phenylene diisocyanates . The reaction may be run in solution, such as by dissolving both reagents in a mixture of tetramethylene sulfone and chloroform with vigorous stirring at ambient temperature. The product can be worked up by separation with water, or acetone and water, and then dried in a vacuum oven. Processes similar to the foregoing are described in US 4,451,642 and Kumar, Macromolecules 17, 2463 (1984). The polyurea forming reaction may also be run under interfacial conditions, such as by dissolving the diaminopyridine in an aqueous liquid, usually with an acid acceptor or a buffer. The polyisocyanate is dissolved in an organic liquid such as benzene, toluene or cyclohexane. The polymer product forms at the interface of the two phases upon vigourous

stirring. Processes similar to the foregoing are described in US 4,110,412 and Millich and Carraher, Interfacial Syntheses, Vol. 2, Dekker, New York, 1977. A diaminopyridine may also be converted into a polyurea by reaction with phosgene, such as in an interfacial process as described in US 2,816,879.

A diaminopyridine may also be converted into a pyridobisimidazole-2, 6-diyl (2, 5-dihydroxy-p-phenylene) polymer by (i) converting the diaminopyridine to a diamino dinitropyridine, (ii) converting the diamino dinitropyridine to a tetraamino pyridine, and (iii) converting the tetraamino pyridine to a pyridobisimidazole- 2, 6-diyl (2, 5-dihydroxy-p-phenylene) polymer.

A diaminopyridine may be converted to a diamino dinitropyridine by contacting it with nitric acid and a solution of sulfur trioxide in oleum, as discussed in WO 97/11058. A diamino dinitropyridine may be converted to a tetraamino pyridine by hydrogenation using a hydrogenation catalyst in the presence of a strong acid, and using a cosolvent such as a lower alcohol, an alkoxyalcohol, acetic acid or propionic acid, as discussed in US 3,943,125.

A tetraamino pyridine may be converted to a pyridobisimidazole-2, 6-diyl (2, 5-dihydroxy-p-phenylene) polymer by polymerizing a 2, 5-dihydroxyterephthalic acid with the trihydrochloride-monohydrate of tetraaminopyridine in strong polyphosphoric acid under slow heating above 100°C up to about 180°C under reduced presuure, followed by precipitation in water, as disclosed in US 5,674,969 (which is by this reference incorporated in its entirety as a part hereof for all purposes) ; or by mixing the monomers at a temperature from about 50°C to about 110°C, and then 145°C to form an oligomer, and then reacting the oligomer at a

temperature of about 160°C to about 250°C as disclosed in U.S. Patent Publication 2006/0287475 (which is by this reference incorporated in its entirety as a part hereof for all purposes). The pyridobisimidazole-2, 6-diyl (2, 5- dihydroxy-p-phenylene) polymer so produced may be, for example, a poly (1, 4- (2, 5-dihydroxy) phenylene-2, 6-pyrido[2, 3-d: 5, 6-d ¹ Jbisimidazole) polymer, or a poly [ (1,4- dihydrodiimidazo [4, 5-b: 4' , 5'-e]pyridine-2, 6-diyl) (2,5- dihydroxy-1, 4-phenylene) ] polymer. The pyridobisimidazole portion thereof may, however, be replaced by any or more of a benzobisimidazole, benzobisthiazole, benzobisoxazole, pyridobisthiazole and a pyridobisoxazole; and the 2,5- dihydroxy-p-phenylene portion thereof may be replace the derivative of one or more of isophthalic acid, terephthalic acid, 2,5-pyridine dicarboxylic acid, 2, 6-naphthalene dicarboxylic acid, 4,4' -diphenyl dicarboxylic acid, 2,6- quinoline dicarboxylic acid, and 2,6-bis(4- carboxyphenyl) pyridobisimidazole.

Examples

The advantageous attributes and effects of this invention may be seen in the example described below. The embodiments of the invention on which this example is based are illustrative only, and the selection of those embodiments to illustrate the invention does not indicate that materials and conditions other than as described in this example are not suitable for practicing this invention, or that subject matter other than as described in this example is excluded from the scope of the appended claims and equivalents thereof. The significance of the example is better understood by comparing the results obtained therefrom with the results obtained from certain reactions that are designed to serve as controlled experiments (Controls A and B) and provide a basis for such comparison since they are run without a buffering agent.

Materials

The following materials were used in the examples and the controls. All commercial reagents were used as received unless otherwise noted. 2, 6-Dichloropyridine (98% purity), CuI (99% purity), and CuBr (98% purity) were purchased from the Aldrich Chemical Company (Milwaukee, Wisconsin, USA). Cu powder (99.5% purity) was purchased from Alfa Aesar (Ward Hill, Massachusetts, USA) . Ammonium acetate (98% purity) was purchased from Fluka (Buchs, Switzerland) . Aqueous ammonia (28-30 wt% ammonia) was purchased from EM Science, now EMD Chemicals Inc. (Gibbstown, New Jersey, USA) .

Methods

Percent conversion, based on the mole fraction of reacted starting materials, and yield, based on the mole fraction of 2, 6-diaminopyridine produced in the reaction, were determined by quantitative gas chromatography (HP5890 Series II equipped with FID detector) using an internal standard of triethyleneglycol, unless otherwise specified. The meaning of abbreviations is as follows : "g" means gram(s), "GC" means gas chromatography, *h" means hour (s), "mol" means mole(s), "mL" means milliliter (s) , "MPa" means kilopascal, and "psi" means pounds per square inch.

Example 1

In a 600 mL autoclave equipped with a gas entrapment stirrer, a solution of 5 g CuI in 120 g aqueous ammonia (30% NH3 by weight) was added and mixed with 77 g ammonium acetate and 60 g of 2, 6-dichloropyridine. After purging with nitrogen, 24 g of liquid ammonia were added resulting in a pressure of about 150 psi (1.03 MPa). Subsequently, the reaction mixture was heated to 150°C for 8 h under stirring. Over the course of the reaction, the pressure decreased from an initial pressure of 680 psi (4.69 MPa) to 450 psi (3.10 MPa). The reaction mixture was allowed to cool to room temperature, and the pressure was brought back to atmospheric pressure. The reaction mixture was analyzed using a quantitative GC analytical method. The conversion of 2, 6-dichloropyridine was greater than 99.5%. The reaction mixture contained 0.37 mol 2,6- diaminopyridine and 0.03 mol 2-chloro-6-amino pyridine. The yields for 2, 6-diaminopyridine and 2-chloro-6-amino pyridine were 91% and 7%, respectively.

Control A

This reaction was conducted in the same manner as described in Example 1, but no ammonium acetate was added to the reaction mixture, demonstrating that lower selectivity is obtained in an unbuffered solution. The conversion of 2, 6-dichloropyridine was greater than 99.5%. The reaction mixture contained 0.29 mol 2, 6-diaminopyridine and less than 0.005 mol 2-chloro-6-amino pyridine. The yield for 2, 6-diaminopyridine was 72%.

Control B

This reaction demonstrates that lower selectivity for a DAP product is obtained under conditions such as described in JP 53/053,662 in an unbuffered solution as compared to the conditions shown in Example 1. This run was conducted using the same equipment as described in Example 1 using 59 g of 2, 6-dichloropyridine, 150 g of aqueous ammonia (30% NH ₃ by weight) and 9 g of copper powder. After purging with nitrogen, the reaction mixture was heated to 240°C for 5 h under stirring at 1100 psi (7.58 MPa) . The reaction mixture was allowed to cool to room temperature and the pressure was brought back to atmospheric pressure. The reaction mixture was analyzed using a quantitative GC analytical method. The conversion of 2, 6-dichloropyridine was greater than 99.5%. The reaction mixture contained less than 0.04 mol 2,6- diaminopyridine. The yield for 2, 6-diaminopyridine was less than 10%. The use of high temperature in this run did not help to achieve a desirable yield.

Where a range of numerical values is recited or established herein, the range includes the endpoints thereof and all the individual integers and fractions within the range, and also includes each of the narrower

ranges therein formed by all the various possible combinations of those endpoints and internal integers and fractions to form subgroups of the larger group of values to the same extent as if each of those narrower ranges was explicitly recited. Where a range of numerical values is stated herein as being greater than a stated value, the range is nevertheless finite and is bounded on its upper end by a value that is operable within the context of the invention as described herein. Where a range of numerical values is stated herein as being less than a stated value, the range is nevertheless bounded on its lower end by a non-zero value.

In this specification, unless explicitly stated otherwise or indicated to the contrary by the context of usage, amounts, sizes, ranges, formulations, parameters, and other quantities and characteristics recited herein, particularly when modified by the term "about", may but need not be exact, and may also be approximate and/or larger or smaller (as desired) than stated, reflecting tolerances, conversion factors, rounding off, measurement error and the like, as well as the inclusion within a stated value of those values outside it that have, within the context of this invention, functional and/or operable equivalence to the stated value;