WO2013049013A2

WO2013049013A2 - Preparation of bromomethylated derivatives via protection with trihaloacetic anhydride

Info

Publication number: WO2013049013A2
Application number: PCT/US2012/057038
Authority: WO
Inventors: Jose J. Gutierrez
Original assignee: Board Of Regents, University Of Texas System
Priority date: 2011-09-26
Filing date: 2012-09-25
Publication date: 2013-04-04
Also published as: WO2013049013A3

Abstract

Discussed herein is the direct bromomethylation of aromatic compounds (e.g., aniline derivatives) via in situ protection with a trihaloacetyl protecting group. Also discussed is the radical bromination of trihaloacetyl protected dimethyl aromatic compounds (e.g., dimethyl anilines). The resulting products mono- and di-bromomethylated products may be used to form novel products.

Description

TITLE: PREPARATION OF BROMOMETHYLATED DERIVATIVES VIA PROTECTION

WITH TRIHALOACETIC ANHYDRIDE

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention was made with government support from the National Science Foundation

(NSF), Grant number DMR-0934157. The U.S. Government has certain rights to this invention.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention generally relates to formation of bromomethylated aromatic compounds. More specifically, the invention relates to the formation of bromomethylated aromatic

compounds using trihaloacetic acid protection of reactive aromatic substituents.

2. Description of the Relevant Art

Bromomethylation of activated aryl compounds can be carried out in the presence of para- formaldehyde and hydrogen bromide. Bromomethylation of aniline derivatives, however, is inherently complicated due to the basic nature of the amine and the highly acidic nature of the reagents. Since protonation of the amine deactivates the aromatic ring, the acidic environment of a bromomethylation reaction is unfavorable for aromatic substitution.

Bromomethylated aromatic compounds are used for the synthesis of drug compounds and aromatic electronic materials. It is desirable to improve the properties of drugs and/or electronic materials by altering the substituents on the aromatic ring. Bromomethylation of aniline, and other electron rich aromatic derivatives is desirable for the study of novel compounds.

SUMMARY OF THE INVENTION

P-anisidine was not able to be bromomethylated due to protonation which leads to deactivation of the ring. Equally, p-nitroanisole could not be bromomethylated due to

deactivation caused by the nitro group, corroborating that even in the presence of a strong activator such as methoxy group, a strong deactivator is able to prevent bromomethylation.

Acetylation of p-anisidine was not strong enough to delocalize the lone pair in nitrogen so as to prevent protonation thus not yielding a bromomethylated product. Both trifluoro and

trichloroacetic anhydrides provided enough derealization to allow bromomethylation. The difference in the bromomethylated yields for each of these lies in the basicity of the given trihaloacetyl group. Since the electronegativity of fluorine is relatively high, the basicity of the trifluoroacetyl group is lower than that of trichloroacetyl group. Since trifluoroacetyl is a weaker base than trichloroacetyl, it falls off easier than does trichloroacetyl, so less material is bromomethylated being that the presence of the trihaloacetyl group is needed for successful bromomethylation.

In one embodiment, a compound has the structure (I):

(I) where Y is NH₂, NH-C(0)CX₃, OH, 0-C(0)CX₃, SH, S-C(0)CX₃;

R¹ is an alkyl group; and

X is F, CI, or Br.

In another embodiment, a compound has the structure (II):

(Π) where Y is NH₂, NH-C(0)CX₃, OH, 0-C(0)CX₃, SH, S-C(0)CX₃;

R¹ is an alkyl group; and

X is F, CI, or Br.

In an embodiment, a compound having the structure (III):

(HI) where Y is NH₂, NH-C(0)CX₃, OH, 0-C(0)CX₃, SH, S-C(0)CX₃

R¹ is an alkyl group; and X is F, CI, or Br;

may be made by reacting a compound having the structure (IV):

(IV)

where X is F, CI, or Br, and Z is NH, O, or S;

with a formaldehyde source in the presence of bromine embodiment, a compound having the structure (VI):

where Y is NH₂, NH-C(0)CX₃, OH, 0-C(0)CX₃, SH, S-C(0)CX₃; R¹ is an alkyl group; and

X is F, CI, or Br;

may be made by reacting a compound having the structure (VII):

(VII)

where X is F, CI, or Br, and Z is NH, O, or S;

with bromine radicals,

embodiment, a compound has the structure (IX)

(IX)

where Y is NH₂, NH-C(0)CX₃, OH, 0-C(0)CX₃, SH, S-C(0)CX₃ R¹ is an alkyl group; and

X is F, CI, or Br.

embodiment, a compound having the structure (IX):

(IX) where Y is NH₂, NH-C(0)CX₃, OH, 0-C(0)CX₃, SH, S-C(0)CX₃; R¹ is an alkyl group; and

X is F, CI, or Br;

may be made by reacting a compound having the structure (III):

(III) with a phosphorus compound to produce the intermediate (X)

(X)

where R² is PPh₃ or P(0)(OR¹)₂; and

reacting the compound (X) with a dialdehyde having the structure (XI)

(XI)

to produce the compound (IX).

In an embodiment, a compound has the structure (XII)

(XII)

where Y is NH₂, NH-C(0)CX₃, OH, 0-C(0)CX₃, SH, S-C(0)CX₃ R¹ is an alkyl group;

X is F, CI, or Br; and

n is 2-1000.

embodiment, a compound having the structure (XII):

(XII) where Y is NH₂, NH-C(0)CX₃, OH, 0-C(0)CX₃, SH, S-C(0)CX₃; R¹ is an alkyl group;

X is F, CI, or Br; and

n is 2-1000

may be made by reacting a compound having the structure (II):

(II)

with a phosphorus compound to produce the intermediate (XIII)

(xiii) where R² is PPh₃ or P(0)(OR¹)₂; and

reacting the compound (XIII) with a dialdehyde having the structure (XI)

(xi)

to produce the compound (XII).

In an embodiment, a compound has the structure (XIV):

(XIV) where Y is a compound of the structure -ZR⁴ where Z is O, N, or S, and wherein R⁴ represents one or more hydrogens or -C(0)R¹;

R¹ is an alkyl group or a CX₃ group;

R³ is hydrogen or -CH₂Br; and

X is a halogen. embodiment, a compound has the structure (IX)

(IX) where Y is is a compound of the structure -ZR⁴ where Z is O, N, or S, and wherein R⁴ represents one or more hydrogens or -C(0)R¹;

R¹ is an alkyl group or a CX₃ group; and

X is a halogen.

BRIEF DESCRIPTION OF THE DRAWINGS

Advantages of the present invention will become apparent to those skilled in the art with the benefit of the following detailed description of embodiments and upon reference to the accompanying drawings in which:

FIG. 1 depicts overlaid 1H NMR spectra of various aniline derivatives. While the invention may be susceptible to various modifications and alternative forms, specific embodiments thereof are shown by way of example in the drawings and will herein be described in detail. The drawings may not be to scale. It should be understood, however, that the drawings and detailed description thereto are not intended to limit the invention to the particular form disclosed, but to the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present invention as defined by the appended claims.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

It is to be understood the present invention is not limited to particular devices or methods, which may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. As used in this specification and the appended claims, the singular forms "a", "an", and "the" include singular and plural referents unless the content clearly dictates otherwise. Furthermore, the word "may" is used throughout this application in a permissive sense (i.e., having the potential to, being able to), not in a mandatory sense (i.e., must). The term "include," and derivations thereof, mean "including, but not limited to." The term "coupled" means directly or indirectly connected.

A method to synthesize bromomethylated p-anisidine, and potential reactions derived from this molecule, are shown in the Scheme 1. Scheme 1 presents a procedure for obtaining regioselective mono-bromomethylation of p-anisidine.

In an embodiment, a compound having the structure (I) may be made using the process depicted in Scheme 1.

(I)

where Y is NH₂, NH-C(0)CX₃, OH, 0-C(0)CX₃, SH, S-C(0)CX₃;

R¹ is an alkyl group; and

X is F, CI, or Br.

SCHEME 1

In an embodiment, Y is NH-C(0)CF₃ or NH-C(0)CC1₃. In an embodiment, R¹ is methyl. In other embodiments, after bromomethylation is complete, the protecting trihaloacetate group may be removed to give the deprotected compound where Y is NH₂.

Compounds having the structure (I) may be made from a process that includes reacting a compound having the structure (IV):

(IV) where X is F, CI, or Br, and Z is NH, O, or S; with a formaldehyde source in the presence of bromine ions. Formaldehyde source include, but are not limited to, formaldehyde (gas), formaldehyde (solution), and para- formaldehyde.

In an embodiment, compounds having the structure (I) may be made by dissolving p- anisidine in CHCI₃. In some embodiments, a homogenous solution is formed. To the reaction mixture 1.1 equivalents of trihaloacetic anhydride were added drop-wise with stirring. In some embodiments, it is desirable to slowly stir the mixture to prevent vigorous reaction. In some embodiments, the reaction may be visually assessed for completion by noting a color change. For example, within the first few minutes a light violet color developed in the solution indicating reaction of the anhydride with the active group (e.g., nitrogen). Thin-layer chromatography ("TLC") may be used to assess reaction completion.

After trihaloacetylation is complete, bromomethylation may be attempted using an appropriate bromomethylation process. In one embodiment, paraformaldehyde/HBr may be used to bromomethylate the protected aromatic. For example, acetic acid may be added in a similar volume to that of chloroform in the reaction mixture resulting from the acetylation reaction. 4 equivalents of HBr and paraformaldehyde are added next, and reaction mixture may be heated under inert atmosphere (e.g., heated at 80-90 °C for 4 hours). The product may be isolated by washing the resulting mixture and purifying the organic fraction by chromatographic techniques. For example, partition between chloroform and water followed by a silica column filtration was used to isolate product. The resulting product may be dried under reduced pressure.

Bromomethylation of p-anisidine, p-methoxyphenyl acetamide and p-nitroanisole were studied. The procedure described above for bromomethylation of aryl compounds using 4 equivalents was used with p-anisidine, p-methoxyphenyl acetamide and p-nitroanisole. The results are summarized in Table 1. No product was obtained when the reaction mixture, using p- anisidine, was heated at 80 C to 90 C for over 12 hours (entry 1). Even after extended reaction times, most of the starting material was recovered unreacted. Similar results were observed for p-methoxyphenyl acetamide and p-nitroanisole under same conditions. In situ

trifluoroacetylation and bromomethylation of p-anisidine (2a) yielded (30-40%) product. In situ trichloroacetylation and bromomethylation of p-anisidine (2b) yielded (70-80%) product.

Starl iii'j Protecting Broniomet hy latioii % material A ent

TABLE 1

P-anisidine was not able to be bromomethylated due to protonation which leads to deactivation of the ring. Equally, p-nitroanisole could not be bromomethylated due to deactivation caused by the nitro group, corroborating that even in the presence of a strong activator such as methoxy group, a strong deactivator is able to prevent bromomethylation. Acetylation of p-anisidine was not strong enough to delocalize the lone pair in nitrogen so as to prevent protonation thus not yielding a bromomethylated product. Both trifluoro and trichloroacetic anhydrides provided enough delocalization to allow bromomethylation. The difference in the bromomethylated yields for each of these lies in the basicity of the given trihaloacetyl group. Due to the electronegativity of fluorine is so high, the basicity of the trifluoroacetyl group is lower than that of trichloroacetyl group. Since trifluoroacetyl is a weaker base than trichloroacetyl, it falls off easier than does trichloroacetyl, so less material is bromomethylated being that the presence of the trihaloacetyl group is needed for successful bromomethylation. FIG. 1 illustrates the overlaid spectra of p-anisidine, trihaloacetylated p-anisidine and bromomethylated p-anisidine. The two doublets, representing the aromatic protons in p- anisidine (bottom) shift downfield when the trihaloacetyl group is bound to the amine (middle) illustrating the de-shielding effect caused by the amide. The broad singlet in p-anisidine

(bottom) at 3.4 ppm represents the amine group. This peak disappears in the trihaloacetylated product (middle), and a similar broad singlet appears at 8.2 ppm, this is the amide proton, which is highly de-shielded due to the high number of electronegative atoms surrounding it. The sharp peak in the bromomethylated product (top) at 4.4 ppm, which does not appear in the two other spectra represents the bromomethyl group, single peak shows that mono-bromomethylated material was obtained. The peaks at the aromatic region of bromomethylated product show a singlet, doublet, doublet pattern distinctive of asymmetrically trisubstituted phenyl ring. Sharp singlet at about 3.8 ppm which appears in all three spectra represents the methoxy group, and as seen, it is not majorly affected by neither the trihaloacetyl group or the bromomethyl substitution.

Bromomethylation of p-anisidine can be achieved after the amine has been bonded to a trihaloacetyl group so to prevent protonation, which would deactivate ring. Trihaloacetyl with higher yield is tricholroacetyl due to higher basicity.

Bromo methylene derivatives may also be produced by free radical halogenation of methyl substituted aromatics. Similar to acid catalyzed bromomethylation, free radical halogenation may be influenced by the side groups coupled to the aromatic system. In some embodiments, a compound having the structure (II) may be made by free radical bromination of methyl side groups of a trihaloacetate protected molecule.

(Π) where Y is NH₂, NH-C(0)CX₃, OH, 0-C(0)C¾, SH, S-C(0)CX₃;

R¹ is an alkyl group; and

X is F, CI, or Br.

Compounds having the structure (II) may be formed by a process where that includes reacting a compound having the structure (VII):

(VII)

with bromine radicals. Bromine radicals may be produced by reacting bromine (B¾) or N- bromosuccinimide ( BS) with the precursor compound (VII) using radical initiation. Radical initiation includes, but is not limited to, ultraviolet irradiation, incandescent irradiation, as well as certain chemicals, such as benzoyl peroxide.

Free radical bromination of various substituted aromatic systems was studied. The amino group on 2,5-dimethylaniline was protected with acetic anhydride. 6.0059 g (50mmol) of 2,5- dimethylaniline was added to a 3 -neck round bottom flask containing 15 ml of acetic anhydride. The reaction mixture was heated to 115°C and left overnight. The reaction mixture was then allowed to cool to room temperature and was added water, where the reaction mixture solidified instantly. The solid was vacuum filtered and washed with hexanes and left to dry under vacuum overnight. Melting point was checked of the resulting solid.

Benzylic bromination of 2,5-dimethylacetamide was attempted by various methods. First, 0.7996 g (5mmol) of 2,5-dimethylacetemide was added to a 20 ml scintillation vial containing 10 ml of hexanes. 1.8335 g (10 mmol) of N-bromosuccinimide was then added to the reaction mixture. The reaction mixture was exposed to a 100 W incandescent light bulb for half an hour. The reaction mixture was washed with water and the organic layer was ran against 2,5- dimethylacetamide via TLC with 90: 10 (hexanes :ethylacetate) eluent. Second, 0.8028 g

(5mmol) of 2,5-dimethylacetamide was added to a scintillation vial containing 10 ml of hexanes. 1.8335 g (lOmmol) of N-bromosuccinimide was then added to the reaction mixture. 0.0612 g (0.5mmol) of benzoyl peroxide was finally added to the reaction mixture as the radical initiator of the benzylic bromination along the 100 W incandescent light bulb. The reaction mixture was washed with water and the organic layer was ran against 2,5-dimethylacetamide via TLC with 90: 10 (hexanes/ethylacetate) eluent. Third, 5.001 g (3 mmol) of 2,5-dimethylacetamide was added to a 20 ml scintillation vial containing 12 ml of ethyl acetate. 1.1159 g (6mmol) of N- bromosuccinimide was added to the reaction mixture. 0.0463 g ( 0.4mmol) of benzoyl peroxide was finally added to the reaction mixture. The reaction mixture was exposed to a 100 W incandescent light bulb. The reaction mixture was heated to 75°C for half an hour where the mixture turned a light brown color. After another 45 minutes of mixing, the reaction mixture was allowed to cool to room temperature. The reaction mixture was washed with water and a solid was filtered and washed with ethylacetate. The solid was ran against 2,5- dimethylacetamide via TLC with 90: 10 (hexanes: ethylacetate) eluent.

A second route was then pursued by the protection of 2,5-dimethylaniline with trifluoroacetic anhydride. 5.9825 g (49 mmol) of 2,5-dimethylaniline was added to a 100 ml 3- neck round bottom flask containing 25 ml of xylenes. 21 ml (65 mmol) of trifluoroacetic anhydride was then added to the reaction mixture. The reaction mixture was heated to 120°C and left overnight. The reaction mixture was then allowed to cool to room temperature where it was washed with water and cooled in an ice-water bath where it immediately crystallized. The product was vacuum filtered and washed with hexanes. The product was left to dry under vacuum overnight. Melting point was checked of the resulting solid.

Benzylic bromination of 2,5-dimethy-2,2,2-trifluoroacetamide was attempted by various methods. First, 0.5149 g (2.3 mmol) of 2,5-dimethyl-2,2,2-trifluoroacetamide was added to a 20 ml scintillation vial containing 10 ml of ethylacetate. 0.8213 g (4.5 mmol) of bromosuccinimide was added to the reaction mixture. Finally, 0.0092 g ( 0. lmmol) of benzoyl peroxide was added to the reaction mixture. The reaction mixture was then heated to 75°C for an hour and exposed to a 100 W incandescent light bulb. The reaction mixture was then allowed to cool to room temperature where it was then washed with water and the organic layer was ran against 2,5- dimethyl-2,2,2-trifluoroacetamide via TLC with 90: 10 (hexanes: ethylacetate) eluent.

Second, 0.4924 g (2.3 mmol) of 2,5-dimethyl-2,2,2-trifluoroacetamide was added to a 25 ml, 3-neck round bottom flask containing 15 ml of ethylacetate. 0.8959 g (4.9mmol) of N- bromosuccinimide was then added to the reaction mixture. 0.0556 g (0.5mmol) of benzoyl peroxide was finally added to the reaction mixture. The reaction mixture was heated to 80°C and exposed to a 100 W incandescent light bulb. After half an hour, the mixture turned red. The reaction mixture was left to run overnight where the reaction mixture had turned dark brown. The mixture was washed with water and the organic layer was tested against 2,5-dimethyl-2,2,2- trifluoroacetamide via TLC with 90: 10 (hexanes: ethylacetate) eluent. The organic ethyl acetate layer was evaporated and column chromatography was performed to purify the brominated product. Column chromatography was performed to separate product from 2,5-dimethyl-2,2,2- trifluoroacetamide, N-bromosuccinimide, succinimide and other impurities. (90: 10).

Hexanes:Ethylacetate was used as the eluent in a silica packed column.

Third, 0.5019 g (2.3 mmol) of 2,5-dimethyl-2,2,2-trifluoroacetamide was added to a 25 ml, 3-neck round bottom flask containing 15 ml of dibromomethane. 0.8419 g (4.6 mmol) of N- bromosuccinimide was added to the reaction mixture. Finally 0.0617 g (0.5mmol) of benzoyl peroxide was added to the reaction mixture. The reaction mixture was heated to 95°C and was left overnight. The reaction mixture was then allowed to cool to room temperature where it was washed with water and the organic layer was tested against 2,5-dimethyl-2,2,2- trifluoroacetamide via TLC with 90: 10 (hexanes:ethylacetate) eluent. Column chromatography was performed to separate product from 2,5-dimethyl-2,2,2-trifluoroacetamide, N- bromosuccinimide, succinimide and other impurities. (90: 10) Hexanes:Ethylacetate was used as the eluent in a silica packed column.

Fourth, 0.5039 g (2.3mmol) of 2,5-dimethyl-2,2,2-trifluoroacetamide was added to a 25 ml, 3-neck round bottom flask containing 15 ml of dibromomethane. 1.2273 g (6.7 mmol) of N- bromosuccinimide was then added to the reaction mixture followed by the addition of 0.0656 g (5.5mmol) of benzoyl peroxide. The reaction mixture was heated to 95°C and left for 17 hours. The reaction mixture then turned a dark red-brownish color. The reaction mixture was allowed to cool to room temperature where it was washed with water and the organic layer was tested against 2,5-dimethyl-2,2,2-trifluoroacetamide via TLC with 90: 10 (hexanes:ethylacetate) eluent. The ethylacetate later was evaporated. Column chromatography was performed to separate product from 2,5-dimethyl-2,2,2-trifluoroacetamide, N-bromosuccinimide, succinimide and other impurities. (90: 10) Hexanes:Ethylacetate was used as the eluent in a silica packed column. ^lH NMR was performed after each reaction where during TLC, a reaction occurred.

Protection of 2,5-dimethylaniline with acetic anhydride yielded 6.30 g (83.39 % yield) of 2,5-dimethylacetamide, which had a melting point of 139-141°C where the starting reagents were both liquid at room temperature. Bromination attempts for 2,5-dimethylacetamide were all unsuccessful. Benzylic bromination is favored with electron withdrawing substituents opposed to electron donating substituents, which are favored for aromatic bromination via electrophilic aromatic substitution. 2,5-dimethylacetamide protected with trifluoroacetic anhydride to yield 2,5-dimethyl-2,2,2-trifluoroacetamide provides sufficient deactivation the ring needs for benzylic bromination where the lone pair on the nitrogen is not readily distributed towards the ring where that may be the case with 2,5-dimethylacetamide where the functional group is moderately activating.

The protection of 2,5-dimethylaniline with trifluoroacetic anhydride yielded 8.8375 g (82.4% yield) 2,5-dimethyl-2,2,2-trifluoroacetamide, which had a melting point of 77-78°C where the two starting reagents were liquid at room temperature. ^lH NMR (600mhz) for the protection of 2,5-dimethylaniline with trifluoroacetic anhyride shows the methyl group at position 2 (2.2364 ppm), methyl group at position 5 (2.3494 ppm). Doublets appearing at 7.0285 ppm and 7.1331 for protons on carbon positions 3 and 4, respectively. One singlet for the proton on carbon position 6 at 7.514 ppm and 7.8849 for proton on the amino group. The difference for the methyl groups' protons is due to the asymmetry between the two methyl groups. Protons on carbon position 5 appear upstream in contrast with protons on carbon position 2 which are closer to the amino group, which drives them a little more downfield. A successful dibromination would result in the disappearance of the methyl group singlets at 2.2364 ppm and 2.3494 ppm and two new peaks at CI¾Br NMR region, 4.5, with similar separation as the two-methyl group protons. ^lH NMR for the first successful bromination (second reaction) of 2,5-dimethyl-2,2,2- trifluoroacetamide shows, as expected, a decrease in the methyl group singlet further downfield. A new peak appears at 4.4612 ppm, which is expected to represent the CH₂Br protons.

Interestingly, it appears as though the reaction is heavily favored at carbon position 2 since only one peak appears for the brominated methyl group and a decrease in one methyl group. ^lH NMR for the second successful bromination (fourth bromination) of 2,5-dimethyl-2,2,2- trifluoroacetamide, which used a higher N-bromosuccinimide to substrate ratio (3 : 1), shows very similar peaks as with the first bromination with (2: 1) ratio of N-bromosuccinimide to substrate, with the addition of a new peak at the C¾Br NMR region. The two C¾Br proton peaks are separated as expected and as observed with the two 2,5-dimethyl-2,2,2-trifluoroacetamide methyl protons. The difference in ratios between the two CI¾Br proton peaks and the appearance of one of the methyl group peaks at 2.2638 ppm leads us to conclude that the reaction did not go to completion.

Furthermore, a fraction's ^lH NMR during column chromatography of the reaction mixture helps explain that we have a mixture of monobrominated 2,5-dimethyl-2,2,2-trifluoroacetamide, 2-bromomethyl-(5-methyl)-2,2,2-trifluoroacetamide and 5-bromomethyl-(2-methyl)-2,2,2- trifluoroacetamide. If dibromination was the case, the two CH^Br proton peaks should have both decreased. Only the brominated methyl protons at carbon position 2 decreased. ¹³C dept (Distortionless Enhancement by Polarization Transfer) was taken to observe the types of carbons in the sample. ¹³C dept 135 NMR is an NMR experiment in which the tip of the final pulse is oriented at 135°. This experiment distinguishes between primary, secondary, and tertiary carbons by phasing primary carbons, and tertiary carbons opposite to secondary carbons

(quaternary carbons are absent). In 2,5-dimethyl-2,2,2-trifluoroacetamide, only primary and tertiary carbons are present. However in 2-bromomethyl-(5-methyl)-2,2,2-trifluoroacetamide and 5-bromomethyl-(2-methyl)-2,2,2-trifluoroacetamide, brominated methyl groups, now CH^Br, are now secondary carbons. This experiment is very helpful as it can show the progress of the reaction by simply observing for the opposite phasing of this secondary carbon. Though, merely a mixture of 2-bromomethyl-(5-methyl)-2,2,2-trifluoroacetamide and 5-bromomethyl-(2- methyl)-2,2,2-trifluoroacetamide compounds, further reaction of the monobrominated products may be used to produce 2,5-bis(bromomethyl)anilines.

In an embodiment, the dibrominate 2,5-dimethyl-2,2,2-trifluoroacetamide may be formed by increasing the N-bromosuccinimide to substrate ratios to (4: 1), perhaps even (5: 1) to observe the effects of N-bromosuccinimde concentration. Reaction times have may also be extended to allow sufficient time to complete the reaction.

In another embodiment, the dibrominated products may be formed by bromination of both monobrominated products, 2-bromomethyl-(5-methyl)-2,2,2-trifluoroacetamide and 5- bromomethyl-(2-methyl)-2,2,2-trifluoroacetamide, keeping N-bromosuccinimide concentrations low at first to inhibit dibromination of a single methyl group. Other simple changes such as different solvents and higher temperatures may also be used.

Poly(p-Phenylene Vinylene)s (PPPVs) are used extensively in various industries for their light emitting, semi conducting properties as in Light Emitting Diodes, solar cells, and even in lasers. PPPVs are also used with certain nanorods to emit near ultraviolet luminescence.

Functionalization of PPPVs alters the properties of the PPPV, making the modified PPPV more useful for various applications. For example, processability for some polymers requires dispersion techniques for desired introduction of the polymer. A water soluble PPPV would greatly diminish the limitations of the polymer. An amino group available for hydrogen bonding on a PPPV would greatly enhance its solubility properties as well as introducing a different functional group available for further functionalizaiton.

In one embodiment, a bromomethylated derivative, such as compound (I) may be used to make conjugated molecules, such as compound (IX):

(IX) where Y is NH₂, NH-C(0)CX₃, OH, 0-C(0)CX₃, SH, S-C(0)CX₃;

R¹ is an alkyl group; and

X is F, CI, or Br. Compound (IX) has many applications, particularly in electronics. An advantage of compound (IX) is that the molecule can be rendered soluble in water by changing the degree of protonation. Compound (IX) may also interact with biological molecules (e.g., proteins) and can be used as a dye for detection and analysis of biomolecules.

In an embodiment, compound (IX) may be formed via a Wittig-type coupling of an ylide derived from compound (I) and a suitable dialdehyde (e.g., 1,4-benzenedialdehyde). In one embodiment, compound (IX) is made by reacting a compound having the structure (III):

(III)

X is F, CI, or Br;

with a phosphorus compound to produce the intermediate (X)

(X)

where R² is PPh₃ or P(0)(OR¹)₂.

Compound (X) is reacted with a dialdehyde having the structure (XI)

(XI) to produce the compound (IX).

Dibromomethylated derivatives, such as compound ((II), may be used to make conjugated polymers, such as compounds having the structure (XII):

(XII) where Y is NH₂, NH-C(0)CX₃, OH, 0-C(0)CX₃, SH, S-C(0)CX₃;

R¹ is an alkyl group;

X is F, CI, or Br; and

n is 2-1000.

PPPV derivatives have extensive use in solar cells and light emitting diodes. One major drawback for most PPPV polymers is that the solvents used in their processing are highly toxic (toluene, chloroform, tetrahydrofuran, etc.). Therefore, a water soluble derivative has a tremendous potential for even industrial application. Additionally, the presence of the NH₂ group allows for further chemical modifications that may result in the synthesis of new materials which increase the number of applications of the PPPVs.

In one embodiment, compounds having the structure (XII) may be formed by reacting a compound having the structure (II):

(Π)

with a phosphorus compound to produce the intermediate (XIII)

(XIII) where R² is PPI1₃ or P(0)(OR¹)2. The compound (XIII) may be reacted with a dialdehyde having the structure (XI)

(xi)

to produce the compound (XII). The length of the polymer (i.e., the value of n) may be controlled by altering the reaction conditions (e.g., ration of reactants, temperature,

concentration, solvent, etc.)

The use of trihaloacetyl protected aromatic groups allows the synthesis of electrophilic substituted products that are not readily synthesized using other protecting groups. It should be noted that while the examples presented herein depict the formation of aniline derivatives, the same protecting group may be applied to the synthesis of similar derivatives containing OH, and SH functional groups. This methodology allows a rapid, efficient, and easier alterative to the synthesis of momo- and bis-bromomethylated compounds, which may be used in the synthesis of electronically active polymers.

Further modifications and alternative embodiments of various aspects of the invention will be apparent to those skilled in the art in view of this description. Accordingly, this description is to be construed as illustrative only and is for the purpose of teaching those skilled in the art the general manner of carrying out the invention. It is to be understood that the forms of the invention shown and described herein are to be taken as examples of embodiments.

Elements and materials may be substituted for those illustrated and described herein, parts and processes may be reversed, and certain features of the invention may be utilized independently, all as would be apparent to one skilled in the art after having the benefit of this description of the invention. Changes may be made in the elements described herein without departing from the spirit and scope of the invention as described in the following claims.

Claims

WHAT IS CLAIMED IS:

1. A compound having the structure (I):

(I) where Y is NH₂, NH-C(0)C¾, OH, 0-C(0)C¾, SH, S-C(0)CX₃; R¹ is an alkyl group; and

X is F, CI, or Br.

2. The compound of claim 1, wherein Y is NH-C(0)CF₃.

3. The compound of claim 1, wherein Y is NH-C(0)CCi3.

4. The compound of claim 1, wherein Y is NH-C(0)CCi₃ and R¹ is methyl.

5. The compound of claim 1, wherein Y is Ν¾.

6. The compound of claim 1, wherein Y is ¾ and R¹ is methyl.

7. A compound having the structure (II):

(Π) where Y is NH₂, NH-C(0)CX₃, OH, 0-C(0)CX₃, SH, S-C(0)CX₃;

R is an alkyl group; and X is F, CI, or Br.

8. The compound of claim 7, wherein Y is NH-C(0)CF₃.

9. The compound of claim 7, wherein Y is NH-C(0)CCi₃.

10. The compound of claim 7, wherein Y is NH-C(0)CCl3 and R¹ is methyl.

11. The compound of claim 7, wherein Y is Ν¾.

12. The compound of claim 7, wherein Y is NH₂ and R¹ is methyl.

13. A method of making a compound having the structure (III):

(III) where Y is NH₂, NH-C(0)CX₃, OH, 0-C(0)CX₃, SH, S-C(0)CX₃; R¹ is an alkyl group; and

X is F, CI, or Br; the method comprising: reacting a compound having the structure (IV):

(IV)

where X is F, CI, or Br, and Z is NH, O, or S; with a formaldehyde source in the presence of bromine ions.

14. The method of claim 13, wherein reacting a compound having the structure (IV) comprises reacting the compound (IV) with paraformaldehyde and HBr in acetic acid.

15. The method of claim 13, wherein the reaction of (IV)with a formaldehyde source in the presence of bromine ions produces the compound (V):

(V) and wherein the method further comprises reacting the compound (V) under acidic or basic hydrolysis conditions to produce the compound (III), where Y is NH₂, OH, or -SH.

16. The method of claim 13, further comprising producing the compound (IV) by reacting p- anisidine with the compound (CXsCO^O.

17. The method of claim 13, wherein Y is NH-C(0)CF₃.

18. The method of claim 13, wherein Y is NH-C(0)CC1₃.

19. The method of claim 13, wherein Y is NH-C(0)CC1₃ and R¹ is methyl.

20. The method of claim 13, wherein Y is NH₂.

21. The method of claim 13, wherein Y is H2 and R¹ is methyl.

22. A method of making a compound having the structure (VI):

(VI) where Y is NH₂, NH-C(0)CX₃, OH, 0-C(0)C¾, SH, S-C(0)CX₃

R¹ is an alkyl group; and

X is F, CI, or Br; the method comprising: reacting a compound having the structure (VII):

(VII)

where X is F, CI, or Br, and Z is NH, O, or S; with bromine radicals.

23. The method of claim 22, wherein reacting a compound having the structure (VII) comprises reacting the compound (VII) with N-bromosuccinimide and a radical initiator.

24. The method of claim 22, wherein reacting a compound having the structure (VII) comprises reacting the compound (VII) with N-bromosuccinimide and benzoyl peroxide.

25. The method of claim 22, wherein the reaction of (VII) with bromine radicals produces the compound (VIII):

(VIII) and wherein the method further comprises reacting the compound (VIII) under acidic or basic hydrolysis conditions to produce the compound (III), where Y is NH₂, OH, or -SH.

26. The method of claim 22, further comprising producing the compound (IV) by reacting p- anisidine with the compound (0¾(Ι )2θ.

27. The method of claim 22, wherein Y is NH-C(0)CF₃.

28. The method of claim 22, wherein Y is NH-C(0)CC1₃.

29. The method of claim 22, wherein Y is NH-C(0)CC1₃ and R¹ is methyl.

30. The method of claim 22, wherein Y is Ν¾.

31. The method of claim 22, wherein Y is NH₂ and R¹ is methyl.

32. A compound having the structure (IX)

X is F, CI, or Br.

33 The compound of claim 32, wherein Y is NH-C(0)CF₃.

34. The compound of claim 32, wherein Y is NH-C(0)CC1₃.

35. The compound of claim 32, wherein Y is NH-C(0)CC1₃ and R¹ is methyl.

36. The compound of claim 32, wherein Y is Ν¾.

37. The compound of claim 32, wherein Y is NH₂ and R¹ is methyl.

38. A method of making a compound having the structure (IX):

X is F, CI, or Br; the method comprising: reacting a compound having the structure (III):

(III)

with a phosphorus compound to produce the intermediate (X)

where R² is PPh₃ or P(0)(OR¹)₂; and

reacting the compound (X) with a dialdehyde having the structure (XI)

(XI)

to produce the compound (IX).

39. The method of claim 38, wherein R² is P(0)(OEt)₂.

40. The method of claim 38, wherein Y is NH-C(0)CF₃.

41. The method of claim 38, wherein Y is NH-C(0)CC1₃.

42. The method of claim 38, wherein Y is NH-C(0)CC1₃ and R¹ is methyl.

43. The method of claim 38, wherein Y is NH₂.

44. The method of claim 38, wherein Y is NH₂ and R is methyl.

45. A compound having the structure (XII):

(XII) where Y is NH₂, NH-C(0)CX₃, OH, 0-C(0)CX_?, SH, S-C(0)CX₃;

R¹ is an alkyl group;

X is F, CI, or Br; and

n is 2-1000.

46. The compound of claim 45, wherein Y is NH-C(0)CF₃.

47. The compound of claim 45, wherein Y is NH-C(0)CCi₃.

48. The compound of claim 45, wherein Y is NH-C(0)CC1₃ and R¹ is methyl.

49. The compound of claim 45, wherein Y is NH₂.

50. The compound of claim 45, wherein Y is NH₂ and R¹ is methyl.

51. A method of making a compound having the structure (XII):

X is F, CI, or Br; and

n is 2-1000. the method comprising: reacting a compound having the structure (II):

(II)

with a phosphorus compound to produce the intermediate (XIII)

(xiii) where R² is PPh₃ or P(0)(OR¹)₂; and reacting the compound (XIII) with a dialdehyde having the structure (XI)

(XI) to produce the compound (XII).

52. The method of claim 51, wherein R² is P(0)(OEt)₂.

53. The method of claim 51, wherein Y is NH-C(0)CF₃.

54. The method of claim 51, wherein Y is NH-C(0)CC1₃.

55. The method of claim 51, wherein Y is NH-C(0)CC1₃ and R¹ is methyl.

56. The method of claim 51, wherein Y is NI¾.

57. The method of claim 51, wherein Y is NI¾ and R¹ is methyl.

58. A compound having the structure (XIV):

R¹ is an alkyl group or a CX₃ group;

R³ is hydrogen or -CH₂Br; and

X is a halogen.

59. A compound having the structure (IX):

R¹ is an alkyl group or a CX₃ group; and

X is a halogen.