WO2011053334A1

WO2011053334A1 - Method for preparing deuterated aromatic compounds

Info

Publication number: WO2011053334A1
Application number: PCT/US2009/068924
Authority: WO
Inventors: Eric Maurice Smith; Kalindi Dogra; Christina M. Older
Original assignee: E. I. Du Pont De Nemours And Company
Priority date: 2009-10-26
Filing date: 2009-12-21
Publication date: 2011-05-05
Also published as: EP2493835A4; CN102574753B; KR101538534B1; JP2013508360A; CN102574753A; JP5662461B2; EP2493835A1; KR20120101029A; TW201114735A

Abstract

There is provided a method for preparing a deuterated aromatic compound. The method comprises (a) providing a liquid composition including an aromatic compound having aromatic hydrogens, said aromatic material being dissolved or dispersed in a first deuterated solvent; and (b) treating the liquid composition with a first acid having a pKa no greater than 1, to form a first deuterated material. The equivalent ratio of the deuterium atoms to the aromatic hydrogens is at least 2.

Description

TITLE

METHOD FOR PREPARING DEUTERATED AROMATIC COMPOUNDS

RELATED APPLICATION DATA

This application claims priority under 35 U.S.C. § 1 19(e) from U.S Provisional Application No. 61/254,843 filed on October 26, 2009, which incorporated by reference herein in its entirety.

BACKGROUND INFORMATION

Field of the Disclosure

This disclosure relates in general to methods for preparing deuterated aromatic compounds.

Description of the Related Art

Deuterium has a natural abundance of approximately 0.015%. Deuterated compounds, in which the level of deuterium is enriched, are well known. Deuterated aromatic compounds have been used to study chemical reactions and metabolic pathways. They also have uses as raw materials for pharmaceuticals, agricultural chemicals, functional materials, and analytical tracers. Methods of forming deuterated aromatic

compounds include treatment of the non-deuterated analog with materials such as D₂SO₄ or D₃PO₄ ^»BF₃/D₂O over a period of many hours or days. It is also known to treat the non-deuterated analog with a deuterated solvent in the presence of a Lewis acid H/D exchange catalyst, such as aluminum trichloride or ethyl aluminum chloride. Alternatively, the non-deuterated analog can be treated with D₂O under high temperature and high pressure conditions, such as supercritical D₂O or microwave irradiation and may be either acid or base-catalyzed. Such methods can be costly and/or time consuming. Other known methods of forming deuterated aromatic compounds include the use of transition metal catalysts to affect the H/D exchange of the non-deuterated analog with D₂ gas, or D₂O, or a deuterated organic solvent such as CeD₆.

There is a continuing need for improved methods for forming deuterated aromatic compounds. SUMMARY

There is provided a method for preparing a deuterated aromatic compound, said method comprising:

(a) providing a liquid composition comprising an aromatic

compound having aromatic hydrogens, said aromatic material being dissolved or dispersed in a first deuterated solvent; and

(b) treating the liquid composition with a first acid having a pKa no greater than 1 , to form a first deuterated material;

wherein the equivalent ratio of deuterium atoms to aromatic hydrogens is at least 2.

There is also provided the above method which further comprises:

(c) isolating the first deuterated material;

(d) dissolving or dispersing the first deuterated material in a second deuterated solvent, to form a second liquid composition; and (e) treating the second liquid composition with a second acid having a pKa no greater than 1 , to form a second deuterated material.

The foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as defined in the appended claims.

DETAILED DESCRIPTION

Many aspects and embodiments have been described above and are merely exemplary and not limiting. After reading this specification, skilled artisans appreciate that other aspects and embodiments are possible without departing from the scope of the invention.

Other features and benefits of any one or more of the embodiments will be apparent from the following detailed description, and from the claims. The detailed description first addresses Definitions and

Clarification of Terms followed by the Method of Deuteration, and finally Examples.

1 . Definitions and Clarification of Terms

Before addressing details of embodiments described below, some terms are defined or clarified. As used herein, the term "aromatic compound" is intended to mean an organic compound comprising at least one unsaturated cyclic group having delocalized pi electrons. The term is intended to encompass both hydrocarbon aromatic compounds and heteroaromatic compounds. The terms "hydrocarbon aromatic ring" or "hydrocarbon aromatic compound" refer to an aromatic ring or compound in which the aromatic moieties have only carbon and hydrogen atoms. The terms "heteroaromatic ring" or "heteroaromatic compound' refer to an aromatic ring or compound wherein in at least one aromatic moiety one or more of the carbon atoms within the cyclic group has been replaced by another atom, such as nitrogen, oxygen, sulfur, or the like.

The term "aromatic hydrogen" refers to a hydrogen directly bonded to an aromatic ring.

The term "deuterated" refers to a compound or group in which deuterium is present in at least 100 times the natural abundance level.

The term "deutero-acid" refers to a compound capable of ionizing to donate a deuterium ion to a Bransted base. As used herein, no ionizable hydrogens are present in a deutero-acid.

The term "perdeuterated" refers to compounds or groups in which all hydrogens have been replaced with deuterium. The term

perdeuterated is synonymous with "100% deuterated".

As used herein, the terms "comprises," "comprising," "includes," "including," "has," "having" or any other variation thereof, are intended to cover a non-exclusive inclusion. For example, a process, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus. Further, unless expressly stated to the contrary, "or" refers to an inclusive or and not to an exclusive or. For example, a condition A or B is satisfied by any one of the following: A is true (or present) and B is false (or not present), A is false (or not present) and B is true (or present), and both A and B are true (or present).

Also, use of "a" or "an" are employed to describe elements and components described herein. This is done merely for convenience and to give a general sense of the scope of the invention. This description should be read to include one or at least one and the singular also includes the plural unless it is obvious that it is meant otherwise.

Group numbers corresponding to columns within the Periodic Table of the elements use the "New Notation" convention as seen in the CRC Handbook of Chemistry and Physics, 81 ^st Edition (2000-2001 ).

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety, unless a particular passage is citedin case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

To the extent not described herein, many details regarding specific materials and processing acts are conventional and may be found in textbooks and other sources.

2. Method of Deuteration

The method comprises:

(a) providing a liquid composition comprising an aromatic

(b) treating the liquid composition with a first acid having a pKa in water of no greater than 1 , to form a first deuterated material; wherein the equivalent ratio of deuterium atoms to aromatic hydrogens is at least 2.

In some embodiments, the aromatic compound has at least one hydrocarbon aromatic ring. In some embodiments, the compound has multiple hydrocarbon aromatic rings. In some embodiments, the rings are further substituted with one or more substituents. Exemplary substituent groups include, but are not limited to, alkyl groups, alkoxy groups, silyl groups, siloxane groups, aryl groups, aryloxy groups and amino groups. In some embodiments, the compound has no heteroaromatic rings.

In some embodiments, the aromatic compound has fused aromatic rings. Examples of such compounds include, but are not limited to, naphthalene, anthracene, naphthacene, pentacene, phenanthrene, chrysene, pyrene, and triphenylene.

The deuterated solvent is a material which is a liquid at room temperature and in which the aromatic compound can be dissolved or dispersed to form a homogeneous liquid composition. The choice of deuterated solvent will depend on the choice of aromatic compound.

The deuterated solvent has at least one deuterium which can be exchanged for hydrogen. The deuterated solvent may have hydrogens, however, the hydrogens should be significantly less likely to exchange than the deuterium. In some embodiments, the deuterated solvent is perdeuterated. In some embodiments, the deuterated solvent is a perdeuterated organic liquid. Some exemplary deuterated solvents include, but are not limited to, D₂O, perdeuterated benzene ("benzene- D6"), perdeuterated toluene ("toluene-D8"), perdeuterated xylenes

("xylene-D10"), CDCI₃, and CD₃OD.

The acid has a pKa in water that is no greater than 1 . For acids having more than one ionizable proton, the pKa refers to the ionization of the first proton. In some embodiments, the pKa is no greater than -1 ; in some embodiments, no greater than -2.

In some embodiments the acid is a deutero-acid. The pKa of the deutero-acid is herein considered to be the same as the pKa for the analogous protonic acid. The deutero-acid may have covalently bonded hydrogens, but only ionizable deuteriums. Some examples of deutero- acids include, but are not limited to, deutero-sulfuric acid (D₂SO₄), deutero-trifluoroacetic acid (CF3CO₂D), d1 -methanesulfonic acid

(CH3SO3D), d1 -benzenesulfonic acid (C₆H₆SO₃D), deutero-triflic acid (CF3SO3D) and deutero-fluorosulfuric acid (FSO₃D).

In the method, the aromatic compound is dispersed in the solvent to form the first liquid composition. The liquid composition is then treated with the acid. This can be accomplished by adding the acid to the liquid composition with stirring. The acid can be in the form of a liquid, liquid solution, or solid that is dispersible in the solvent. In some embodiments, the acid is on a polymeric support. In some embodiments, the acid is on a silica support, such as a dispersion of silica particles. When the acid is on any type of support, it is referred to herein as "supported acid". In some embodiments, a fluorosulfonic acid is on a silica support. In some embodiments, the acid itself is a polymeric material, such as Nafion®. The polymeric material may be in the form of particles, beads,

membranes, etc. The supported acid or solid polymeric acid material can be immersed in the liquid composition to effect treatment. Alternatively, the liquid composition can be passed by or through the supported acid or solid polymeric acid material in a continuous process.

In general, the equivalent ratio of deuterated solvent to aromatic compound is in the range of 2-150; in some embodiments, 5-100. The equivalent ratio of acid to aromatic compound is in the range of 0.1 -10; in some embodiments, 1 -5. In some embodiments, the equivalent ratio of acid to aromatic compound is in the range of 0.1 -10.0.

The equivalent ratio of deuterium atoms to aromatic hydrogens is at least about 2. It will be understood that the term "deuterium atoms" refers to covalently bonded D in the solvent and/or ionizable D in the acid. For the deutero-acid, the number of equivalents of deuterium atoms is equal to the number of moles times the number of ionizable deuteriums. For the deuterated solvent, the number of equivalents of deuterium atoms is equal to the number of moles of solvent times the number of deuterium atoms in the compound. For the aromatic compound, the number of equivalents of aromatic hydrogens is equal to the number of moles of aromatic

compound times the number of aromatic hydrogens in the compound. In some embodiments, the equivalent ratio of deuterium atoms to aromatic hydrogens is in the range of about 2-50; in some embodiments, about 10-30.

In some embodiments, the acid is a protonic acid. In some embodiments, the equivalent ratio of protonic acid to aromatic compound is in the range of 0.1 -10.0. In some embodiments, a deutero-acid is used with the deuterated solvent. In these embodiments, the equivalent ratio of total D to aromatic hydrogens is at least about 2.

In some embodiments, the treatment with acid is carried out at atmospheric pressure. By "atmospheric pressure" it is meant that the pressure is not adjusted in any way. In some embodiments, atmospheric pressure is in the range of 730-770 torr.

In some embodiments, the treatment with acid is carried out at room temperature. By "room temperature" it is meant that the composition is not heated or cooled. In some embodiments, room temperature is in a range of 20-25°C. In some embodiments, the treatment with acid is carried out at an elevated temperature. In most cases the temperature will not exceed the boiling point of the solvent. In some embodiments, the temperature is in a range of 25-75°C; in some embodiments, 40-60°C.

In some embodiments, the treatment with acid is carried out at room temperature and atmospheric pressure.

In some embodiments, the treatment with acid is carried out for nor more than 24 hours; in some embodiments, no more than two hours; in some embodiments, no more than one hour.

In some embodiments, the first deuterated compound has 30-100% of the aromatic hydrogens replaced with deuterium; in some

embodiments, 40-90% replaced; in some embodiments, 50-80% replaced.

In some embodiments, at least some of the non-aromatic hydrogens are also replaced with deuterium.

In some embodiments, it is desirable to treat the first deuterated compound to further deuterate it. In this case, the following additional steps are carried out:

(c) isolating the first deuterated material;

(d) dissolving or dispersing the first deuterated material in a second deuterated solvent, to form a second liquid composition; and

(e) treating the second liquid composition with a second acid having a pKa no greater than 1 , to form a second deuterated material. The first deuterated material can be isolated using any known techniques. Such techniques include, but are not limited to, precipitation, evaporation, distillation, chromatography, and the like.

The first deuterated material is then dissolved or dispersed in a second deuterated solvent, as in step (a), to form a second liquid composition. The second deuterated solvent can be the same as or different than the first deuterated solvent. In some embodiments, the second deuterated solvent is the same as the first deuterated solvent.

The second liquid composition is then treated with a second acid, as in step (b). The second acid can be the same as or different than the first acid. In some embodiments, the second acid is the same as the first acid.

The materials are added so that the equivalent ratio of deuterium atoms to aromatic hydrogens remaining in the first deuterated material is at least 2; in some embodiments, 2-50; in some embodiments, 10-30. In some embodiments, the same molar ratio of aromatic material to solvent to acid is used as in step (b). Thus, the ratio of equivalents of deuterium atoms to equivalents of aromatic hydrogens originally present in the aromatic compound is at least 2; in some embodiments, 2-50; in some embodiments, 10-30.

In some embodiments, step (e) is carried out at room temperature and atmospheric pressure. In some embodiments, step (e) is carried out for 24 hours or less; in some embodiments, for two hours or less; in some embodiments, for one hour or less.

In some embodiments, the second deuterated material is isolated and further treated with deuterated solvent and acid, analogous to steps (c) through (e).

The process described herein is advantageous in that it does not introduce any inorganic impurities into the deuterated products. In many applications, inorganic impurities, such as metals and/or halogens, can have undesirable effects. The process results in more exchange than processes using weaker acids. Surprisingly and unexpectedly, a relatively low equivalent ratio of deuterium atoms to aromatic hydrogens is sufficient to effect significant exchange. EXAMPLES

The concepts described herein will be further described in the following examples, which do not limit the scope of the invention

described in the claims.

Examples 1 -6

These examples illustrate the process of the invention with different aromatic compounds.

The starting compounds and conditions are given in Table 1 , below.

The starting non-deuterated compound was dissolved in benzene-D6 in a dry glass vial. To this was added deuterated triflic acid. The pKa of triflic acid is reported to be in the range of -13 to -15. The resulting liquid was stirred at the temperature indicated with periodic sampling to determine the extent of deuteration by UPLC-MS and/or GC-MS. When the desired amount of deuterium exchange had taken place the reaction was quenched with Na2CO3 in D₂O. The organic layer was isolated,

concentrated and purified by column chromatography on a silica column. The final mass was determined by UPLC-MS and/or GC-MS.

The results are given in Table 2.

Table 1 . Compounds and Conditions

6 NPB Benzene-D6 CF3SO3D 10.2 20h / 50°C

(0.12g, 1 meq.) (2.62g, (0.16g, 5meq.)

50meq.)

D/H ratio is the equivalent ratio of D to aromatic H; h is hours; r.t. is room temperature

CBP is:

Table 2. Results

Example 7 and Comparative Examples A and B

This example and comparative examples illustrate the effect of acid pKa.

For Example 7, the procedure of Example 1 was repeated. For Comparative Example A, the procedure of Example 1 was repeated substituting phosphoric acid for the deuterated triflic acid.

For Comparative Example B, the procedure of Example 1 was repeated substituting acetic acid for the deuterated triflic acid.

The results are shown in Table 3, below.

Table 3. Results

In Example 7, there is complete exchange after one hour of treatment. In the comparative examples, the acids have a pKa greater than 1 . Even after 20 hours there is no H exchanged for D.

Note that not all of the activities described above in the general description or the examples are required, that a portion of a specific activity may not be required, and that one or more further activities may be performed in addition to those described. Still further, the order in which activities are listed are not necessarily the order in which they are performed.

In the foregoing specification, the concepts have been described with reference to specific embodiments. However, one of ordinary skill in the art appreciates that various modifications and changes can be made without departing from the scope of the invention as set forth in the claims below. Accordingly, the specification and figures are to be regarded in an illustrative rather than a restrictive sense, and all such modifications are intended to be included within the scope of invention. Benefits, other advantages, and solutions to problems have been described above with regard to specific embodiments. However, the benefits, advantages, solutions to problems, and any feature(s) that may cause any benefit, advantage, or solution to occur or become more pronounced are not to be construed as a critical, required, or essential feature of any or all the claims.

It is to be appreciated that certain features are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any subcombination. Further, reference to values stated in ranges include each and every value within that range.

Claims

CLAIMS What is claimed is:

1 . A method for preparing a deuterated aromatic compound, said method comprising:

(a) providing a liquid composition comprising an aromatic

2. The method of Claim 1 , wherein the equivalent ratio is in the range of 2-50.

3. The method of Claim 1 , wherein the equivalent ratio is in the range of 10-30.

4. The method of Claim 1 , wherein the aromatic compound has at least one hydrocarbon aromatic ring having aromatic hydrogens.

5. The method of Claim 1 , wherein the acid is a deutero-acid.

6. The method of Claim 1 , wherein the equivalent ratio of deutero-acid to aromatic hydrogens is in the range of 0.1 -10.

7. The method of Claim 1 , wherein the pKa is no greater than

-2.

8. The method of Claim 1 , wherein step (b) is carried out at room temperature and atmospheric pressure.

9. The method of Claim 1 , wherein step (b) is carried out for no more than 24 hours.

10. The method of Claim 1 , wherein step (b) is carried out for no more than two hours.

1 1 . The method of Claim 1 , further comprising:

(c) isolating the first deuterated material;

(e) treating the second liquid composition with a second acid

having a pKa no greater than 1 , to form a second deuterated material.