Abstract:
A process includes substituting a substituent on a substrate. The process includes reacting a salt of an anionic form of the substituent with an electrophilic fluorination agent to provide an electrophile containing a cationic form of the substituent. The electrophile is then electrophilically substituted on the substrate. In some aspects of the process, the substrate can be an aromatic or a non-aromatic. The process can be used for a variety of reactions having electrophilic mechanisms, including halogenation, thiocyanation and nitration.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     Not applicable. 
     STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT 
     Not applicable. 
     BACKGROUND OF THE INVENTION 
     This invention relates to electrophilic reactions and reactants, and more particularly to a process for generating useful electrophiles, E + , from common anions, E − . 
     Electrophilic addition/substitution of aromatic systems is a field of chemistry that has been widely studied (1-4). Specific examples of reactions having electrophilic mechanisms include halogenation, thiocyanation and nitration. 
     Reagents for electrophilic halogenation are available in numerous forms ranging from the diatomic element to some fairly exotic halogen delivery reagents (1-5). Most of these reagents are necessarily prepared in advance of halogenation, but some are generated in situ. Reagents specific for electrophilic halogenation include but are not limited to N-chlorosuccinimide (6-12) (NCS), N-chloroammonium salts (13), tert-butylhypochlorite (14), sodium chlorite/(salen)Mn(III) complex (15), chlorine trifluoromethanesulfonate (16), and triethylammonium trichloride (17), for chlorination, N-bromosuccinimide (8-12) and alkylammonium tribromide (18) for bromination, N-iodosuccinimide (19), iodine(l) triflate (20), and dichlorohypoiodite salts (21) for iodination, and various −NF, −XeF, and −OF agents for fluorination (6, 22). 
     Reagents which are known to deliver electrophilic thiocyanogen include thiocyanogen (23, 24), cyanogen chloride (25-28), and metal thiocyanates mediated by aryliodite (29), NCS (30, 31), and NBS (31, 32). 
     Electrophilic nitration can be accomplished using a variety of techniques (1). In particular, reagents available include nitronium salts (33-37), methyl nitrate (38), and sodium nitrite mediated by trifluoroacetic acid (39). 
     Zupan et al. (40) discloses an electrophilic fluorination agent functioning as a mediator in affecting electrophilic reactions. In this reference, mixtures of anisole, Selectfluor™ (i.e., 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane-bis(tetrafluoroborate), hereinafter referred to as F-TEDA-BF 4 ) and I 2 , KI, Me 3 Sil, or Mel in solution were shown to produce iodo anisole derivatives regioselectively. This result is not surprising, however, since it has been established that F-TEDA-BF 4  readily and immediately oxidizes iodide to iodine in solution (39). 
     There is a general need for effective methodologies for introducing various functional groups into aromatic systems. In particular, electrophilic methodologies find widespread applications since these reactions are very well understood and the product distribution is generally predictable. Despite the importance of synthetic methods for introducing electrophiles into aromatic systems, relatively few reagents are available to accomplish such transformations, and moreover, the reagents themselves can be difficult to prepare and use. 
     Accordingly, it would be desirable to provide an easily employed and generally applicable method for introducing electrophilic groups, E + , into a variety of aromatic systems. 
     All references cited herein are incorporated herein by reference in their entireties. 
     BRIEF SUMMARY OF THE INVENTION 
     The present invention provides a process for substituting a substituent on a substrate. The process comprises reacting a salt of an anionic form of the substituent with an electrophilic fluorination agent to provide an electrophile comprising a cationic form of the substituent. The electrophile is then electrophilically substituted on the substrate. 
    
    
     BRIEF DESCRIPTION OF SEVERAL VIEWS OF THE DRAWINGS 
     Not applicable. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The present invention relates to a new process for achieving regioselective electrophilic aromatic substitution of an electrophile, E + , from mixtures of an electrophilic fluorination agent and a salt of the electrophile in a solvent. This process can be described in general terms by Equation 1, below, wherein F +  represents the electrophilic fluorination agent, M + X −  represents a salt (e.g., an ammonium or sodium salt) of chloride (Cl − ), bromide (Br − ), thiocyanate (SCN − ), nitrite (NO 2   − ), acetate (CH 3 COO − ), or trifluoroacetate (CF 3 COO − ), and R 1-6  each independently represent a strongly deactivating to strongly activating substituent selected from the group consisting of H, F, Cl, CH 3 , COOH, C(O)CH 3 , NO 2 , OR′ and NR′R″, where R′ and R″ are H, C(O)CH 3  or CH 3 .                           
     From this reaction, electrophiles Cl + , Br + ,SCN +  and NO 2   +  are generated from their respective sodium or ammonium salts by reaction with F-TEDA-BF 4  in acetonitrile solution at ambient temperature and pressure. The said generated electrophiles are then reacted directly in situ with various aromatic substrates, including anisole, toluene, p-xylene, phenol, benzene, acetanilide, dimethylaniline, 2-chloro-p-xylene, 2-fluoroanisole, 4-fluoroanisole, 1,3-dimethyluracil, nitrophenol, benzoic acid, or 4′-methoxyacetophenone to give the corresponding addition/substitution products in high yield and purity. In many cases, the yield is quantitative. 
     In embodiments, the said generated electrophiles can be reacted in situ with any electrophilic addition process, e.g., non-aromatic substrates. Examples of non-armoatic substrates useful in the present invention include 1,3-dimethyluracil and cis-cyclooctene. 
     The electrophilic fluorination agent is preferably 1-fluoro-4-hydroxy-1,4-diazoniabicyclo[2.2.2]octane-bis(tetrafluoroborate) (hereinafter NFTh). A particularly preferred form of NFTh is Accufluor™ (AlliedSignal Inc., Morristown, N.J.). A particularly preferred electrophilic fluorination agent is 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane-bis(tetrafluoroborate) (hereinafter F-TEDA-BF 4 ). A particularly preferred form of F-TEDA-BF 4  is Selectfluor™ (Air Products and Chemicals, Allentown, Pa.). 
     In embodiments, other bicyclo electrophilic fluorination agents that possess sufficient oxidizing power to effect the transformation of E −  to E +  are suitable for use in this process. For example, 1-fluoro-4-methyl-1,4-diazoniabicyclo[2.2.2]octane-bis(tetrafluoroborate), is a preferred bicyclo electrophilic fluorination agent. A particularly preferred form of 1-fluoro-4-methyl-1,4-diazoniabicyclo[2.2.2]octane-bis(tetrafluoroborate) is Selectfluor(II)™ (Air Products and Chemicals, Allentown, Pa.). 
     In further embodiments, other N-F fluorination agents are also suitable for use in the present process as electrophilic fluorination agents, for example, N-fluoro-bipyridyl salts, such as N,N′-difluoro-2,2′ bipyridinium bis(tetrafluoroborate). A particularly preferred form of N,N′-difluoro-2,2′ bipyridinium bis(tetrafluoroborate) is SynFluor™ (SynQuest Laboratories, Inc., Alachua, Fla.). 
     Although acetonitrile is the most preferred solvent for use in the invention, other nitrile-containing solvents are acceptable, such as, e.g., proprionitrile. Furthermore, amide containing solvents such as, e.g., dimethylformamide (herenafter DMF) could also be used. Solvent mixtures are also suitable, for example in certain embodiments, a mixture of acetonitrile and DMF, or a 50:50 (v/v) mixture of water and acetonitrile is used. 
     The invention will be illustrated in more detail with reference to the following examples, but it should be understood that the present invention is not deemed to be limited thereto. 
     EXAMPLE 1 
     Thiocyanation of Anisole 
     7.1 g (20 mmol) of F-TEDA-BF 4  fluorination agent, 1.6 g (20 mmol) of NaSCN, and 200 mL of acetonitrile were added to a 500-mL round bottom flask containing a magnetic stir bar and stirring was commenced. Anisole was then added in an amount of 2.2 g (20 mmol) and the contents of the flask were stirred under nitrogen and sampled periodically. After 20 hours of stirring at room temperature, analysis by gas chromatography (GC) and gas chromatography—mass spectrometry (GC-MS) indicated that about 67% conversion of the anisole starting material had been achieved with a product distribution of 1% and 62% 2- and 4-methoxyphenylthiocyanate, respectively. At this point, the solvent was removed under vacuum on a Rotavap. To the resulting residue was added to 200 mL of de-ionized water. This aqueous mixture was extracted with 2×100 mL portions of methylene chloride. The methylene chloride extracts were combined, dried with MgSO 4 , and evaporated to a product residue. The resulting residue was purified by chromatography on silica gel using a mixture of 5% ethyl acetate and 95% hexane. A product fraction was collected, evaporated to a residue, and then analyzed by NMR spectroscopy, GC-MS, and gas chromatography-infrared spectroscopy (GC-IR) and shown to be a mixture of 2- and 4-methoxyphenylthiocyanate, but predominately the 4-isomer. 
     4-methoxyphenylthiocyanate 
     NMR (CDCl 3 ) Results: δ( 1 H) 3.76 ppm (s, 3H), 6.89 ppm (d, 2H, J=8.9 Hz), 7.44 ppm (d, 2H, J=8.8 Hz); 
       13 C{ 1 H}: 55.26 ppm (s, 1C), 111.39 ppm (s, 1C), 113.41 ppm (s, 1C), 115.59 ppm (s, 2C), 133.49 ppm (s, 2C), 161.02 ppm (s, 1C). 
     MS (EI) Results: m/e (relative intensity): 165 (M + , 100), 150 (74), 122 (48), 63 (18). 
     EXAMPLE 2 
     Thiocyanation of p-xylene 
     3.5 g (10 mmol) of F-TEDA-BF 4  fluorination agent, 0.82 g (10 mmol) of NaSCN, and 100 mL of acetonitrile were added to a 250-mL round bottom flask containing a magnetic stir bar and stirring was commenced. Added to this was 1.1 g (10 mmol) of 1,4-dimethylbenzene (p-xylene) and the contents of the flask were stirred under nitrogen and sampled periodically. After 147 hours of stirring at room temperature, analysis by GC and GC-MS indicated that about 56% conversion of the p-xylene starting material had been achieved with a product distribution of 21% and 26% dimethylphenylthiocyanate derivatives. At this point, the solvent was removed under vacuum on a Rotavap. To the resulting residue was added 200 mL of de-ionized water. This aqueous mixture was extracted with 2×100 mL portions of methylene chloride. The methylene chloride extracts were combined, dried with MgSO 4 , and evaporated to a product residue. The resulting residue was purified by chromatography on silica gel using a mixture of 5% ethyl acetate and 95% hexane. Two product fractions were collected, evaporated to residues, and then analyzed separately by NMR spectroscopy and GC-MS. The analysis was consistent with 4-methylbenzylthiocyanate and 2,5-dimethylphenylthiocyanate. 
     4-methylbenzylthiocyanate 
     NMR (CDCl 3 ): ( 1 H) 2.34 ppm (s, 3H), 4.13 ppm (s, 2H), 7.20 ppm (m, 4H); 
       13 C{ 1 H}: 21.23 ppm (s, 1C), 38.29 ppm (s, 1C), 112.14 ppm (s, 1C), 128.91 ppm (s, 2C), 129.83 ppm (s, 2C), 131.25 ppm (s, 1C), 138.93 ppm (s, 1C); 
     MS (EI): m/e (relative intensity): 163 (M + , 3), 105 (100), 77 (13). 
     2,5-dimethylphenylthiocyanate 
     NMR (CDCl 3 ): ( 1 H) 2.32 ppm (s, 3H), 2.40 ppm (s, 3H), 7.13-7.41 ppm (m, 3H); 
       13 C{ 1 H}: 19.80 ppm (s, 1C), 20.72 ppm (s, 1C), 110.61 ppm (s, 1C), 123.05 ppm (s, 1C), 130.95 ppm (s, 1C), 131.16 ppm (s, 1C), 132.20 ppm (s, 1C), 135.99 ppm (s, 1C), 137.69 ppm (s, 1C); 
     MS m/e (relative intensity): 163 (M + , 100), 135 (85), 105 (21), 77 (33). 
     EXAMPLE 3 
     Nitration of Anisole 
     3.5 g (10 mmol) of F-TEDA-BF 4  fluorination agent, 0.69 g (10 mmol) of NaNO 2 , and 100 mL of acetonitrile were added to a 250-mL round bottom flask containing a magnetic stir bar and stirring was commenced. Added to this was 1.1 g (10 mmol) of anisole and the contents of the flask were stirred under nitrogen and sampled periodically. After 120 hours of stirring at room temperature, analysis by GC and GC-MS indicated that about 43% conversion of the anisole starting material had been achieved with a product distribution of 2% 2-nitroanisole and 4% 4-nitroanisole as nitrated products. The reaction products were purified from the solvent and analyzed as in Example 2. The analysis was consistent with 2-nitroanisole and 4-nitroanisole. 
     2-Nitroanisole 
     NMR (CDCl 3 ): ( 1 H) 3.94 ppm (s, 3H), 7.05 ppm (m, 2H), 7.52 ppm (m, 1H); 
       13 C{ 1 H}: 56.45 ppm (s, 1C), 113.44 ppm (s, 1C), 120.25 ppm (s, 1C), 125.71 ppm (s, 2C), 134.2 ppm (s, 1C), 139.7 ppm (s, 1C), 153.0 ppm (s, 1C); 
     MS (EI): m/e (relative intensity) 153 (M + , 57), 123 (32), 106 (93), 92 (67), 77 (100) 
     4-Nitroanisole. 
     NMR (CDCl 3 ): ( 1 H) 3.89 ppm (s, 3H), 6.94 ppm (d, 2H, J=9.2 Hz), 8.19 ppm (d, 2H, J=9.2 Hz); 
       13 C{ 1 H}: 55.94 ppm (s, 1C), 113.99 ppm (s, 2C), 125.91 ppm (s, 2C), 141.9 ppm (s, 1C), 164.56 ppm (s, 1C); 
     MS (EI): m/e (relative intensity) 153 (M + , 100), 123 (71), 92 (58), 77 (53). 
     EXAMPLE 4 
     Nitration of Phenol 
     3.5 g (10 mmol) of F-TEDA-BF 4  fluorination agent, 1.0 g (15 mmol) of NaNO 2 , and 80 mL of acetonitrile were added to a 100-mL round bottom flask containing a magnetic stir bar and stirring was commenced. Added to this was 1.0 g (10 mmol) of phenol and the contents of the flask were stirred under nitrogen and sampled periodically. After 68 hours of stirring at room temperature, analysis by GC and GC-MS indicated that about 98% conversion of the phenol starting material had been achieved with a product distribution which included 79% 4-nitrophenol as the major nitrated product. At this point, the solvent was removed under vacuum on a Rotavap. To the resulting residue was added 200 mL of de-ionized water. This aqueous mixture was extracted with 2×100 mL portions of methylene chloride. The methylene chloride extracts were combined, dried with MgSO 4 , and evaporated to a product residue. The resulting residue was purified by chromatography on silica gel using a mixture of 50% ethyl acetate and 50% hexane. A single product fraction was collected, evaporated to a residue, and then analyzed by NMR spectroscopy and GC-MS. The analysis was consistent with 4-nitrophenol. 
     4-Nitrophenol 
     NMR (CDCl 3 ): ( 1 H) 6.90 ppm (d, 2H, J=9.1 Hz), 8.14 ppm (d, 2H, J=9.1 Hz); 
       13 C{ 1 H}: 115.66 ppm (s, 2C), 126.23 ppm (s, 2C), 140.1 ppm (s, 1C), 161.9 ppm (s, 1C); 
     MS (EI): m/e (relative intensity) 139 (M + , 100), 122 (5), 93 (10), 81 (36). 
     EXAMPLE 5 
     Bromination of Phenol 
     3.5 g (10 mmol) of F-TEDA-BF 4  fluorination agent, 1.9 g (19 mmol) of NaBr, and 80 mL of acetonitrile were added to a 100-mL round bottom flask containing a magnetic stir bar and stirring was commenced. Added to this was 1.0 g (10 mmol) of phenol and the contents of the flask were stirred under nitrogen and sampled periodically. After 3 hours of stirring at room temperature, analysis by GC and GC-MS indicated that greater than 98% conversion of the phenol starting material had been achieved and with a product distribution which included mono- and dibromophenol as the major brominated products. At this point, the solvent was removed under vacuum on a Rotavap. To the resulting residue was added to 200 mL of de-ionized water. This aqueous mixture was extracted with 2×100 mL portions of methylene chloride. The methylene chloride extracts were combined, dried with MgSO 4 , and evaporated to a product residue. The resulting residue was purified by chromatography on silica gel using a mixture of 20% ethyl acetate and 80% hexane. Three product fractions were collected, evaporated to solid residues, and then analyzed separately by NMR spectroscopy and GC-MS. The analyses were consistent with 2- and 4-bromophenol and 2,6-dibromophenol. 
     2-bromophenol 
     NMR (CDCl 3 ): ( 1 H) 6.7 ppm (m, 1H), 7.0 ppm (m, 1H), 7.3 ppm (m, 1H), 7.5 ppm (m, 1H); 
       13 C{ 1 H}: 110.04 ppm (s, 1C), 117.16 ppm (s, 1C), 121.81 ppm (s, 1C), 128.95 ppm (s, 1C), 132.27 ppm (s, 1C), 154.49 ppm (s, 1C); 
     MS (EI): m/e (relative intensity) 174 (99), 172 (M + , 100), 93 (16). 
     4-bromophenol 
     NMR (CDCl 3 ): ( 1 H) 6.78 ppm (d, 2H), 7.31 ppm (d, 2H); 
       13 C{ 1 H}: 112.47 ppm (s, 1C), 117.13 ppm (s, 2C), 132.24 ppm (s, 2C), 154.56 ppm (s, 1C); 
     MS (EI): m/e (relative intensity) 174 (103), 172 (M + , 100), 93 (30). 
     2,6-dibromophenol. 
     NMR (CDCl 3 ): ( 1 H) 6.68 ppm (t, 1H, J=8.0 Hz), 7.43 ppm (d, 2H, J=8.0 Hz); 
       13 C{ 1 H}: 110.0 ppm (s, 2C), 122.0 ppm (s, 1C), 132.0 ppm (s, 2C); 
     MS (EI): m/e (relative intensity) 254 (100), 252 (189), 250 (M + , 100), 172 (18). 
     EXAMPLE 6 
     Bromination of Anisole 
     3.5 g (10 mmol) of F-TEDA-BF 4  fluorination agent, 1.1 g (11 mmol) of NaBr, and 100 mL of acetonitrile were added to a 100-mL round bottom flask containing a magnetic stir bar and stirring was commenced. To this was added 1.1 g (10 mmol) of anisole and the contents of the flask were stirred under nitrogen and sampled periodically. After 75 hours of stirring at room temperature, analysis by GC and GC-MS indicated that about 90% conversion of the anisole starting material had been achieved with a product distribution which included 4-bromoanisole as the major brominated product in about 90% yield. 
     No further analyses were done. 
     EXAMPLE 7 
     Thiocyanation of N,N-Dimethyaniline 
     3.5 g (10 mmol) of F-TEDA-BF 4  fluorination agent, 1.0 g (12 mmol) of NaSCN, and 40 mL of acetonitrile were added to a 100-mL round bottom flask containing a magnetic stir bar and stirring was commenced. To this was added 1.2 g (10 mmol) of N,N-dimethylaniline and the contents of the flask were stirred under nitrogen and sampled periodically. After 27.5 hours of stirring at room temperature, analysis by GC-MS indicated that about 98% conversion of the dimethylaniline starting material had been achieved and with a single dominant product. At this point, the solvent was removed under vacuum on a Rotavap. To the resulting residue was added 200 mL of de-ionized water. This aqueous mixture was extracted with 2×100 mL portions of methylene chloride; the methylene chloride extracts were combined, dried with MgSO 4 , and evaporated to a product residue. The resulting residue was purified by chromatography on silica gel using a mixture of 40% ethyl acetate and 60% hexane. A single product fraction was collected, evaporated to a yellow oily residue, and then analyzed separately by NMR spectroscopy and GC-MS. The analysis was consistent with N,N-dimethylaniline-4-thiocyanate. 
     N,N-dimethylaniline-4-thiocyanate 
     NMR (CDCl 3 ): ( 1 H) 3.00 ppm (s, 6H), 6.65 ppm (d, 2H), 7.41 ppm (d, 2H); 
       13 C{ 1 H}: 40.11 ppm (s, 2C), 106.40 ppm (s, 1C), 110.03 ppm (s, 1C), 113.07 ppm (s, 2C), 134.50 ppm (s, 2C), 151.25 ppm (s, 1C); 
     MS (EI): m/e (relative intensity): 178 (M + , 100), 163 (12), 152 (25), 134(9), 120(4). 
     EXAMPLE 8 
     Nitration of Acetanililde 
     3.5 g (10 mmol) of F-TEDA-BF 4  fluorination agent, 1.36 g (20 mmol) of NaNO 2 , and 40 mL of acetonitrile were added to a 100-mL round bottom flask containing a magnetic stir bar and stirring was commenced. To this was added 1.35 g (10 mmol) of acetanilide and the contents of the flask were stirred under nitrogen and sampled periodically. After 26.5 hours of stirring at room temperature, analysis by GC and GC-MS indicated that about 10% conversion of the acetanilide starting material had been achieved and with a product distribution which included 4-nitroacetanilide as the major nitrated product. At this point, the solvent was removed under vacuum on a Rotavap. To the resulting residue was added 200 mL of de-ionized water. This aqueous mixture was extracted with 2×100 mL portions of methylene chloride. The methylene chloride extracts were combined, dried with MgSO 4 , and evaporated to a product residue. The resulting residue was purified by chromatography on silica gel using a mixture of 50% ethyl acetate and 50% hexane. A mixed product fraction was collected, evaporated to a residue, and then analyzed by GC-MS. The fraction contained 2-fluoroacetanilide (26%), acetanilide (27%) and 4-nitro- acetanilide (47%). 
     4-Nitroacetanilide 
     MS (EI): m/e (relative intensity) 180 (M + , 14), 138 (100), 134 (11). 
     EXAMPLE 9 
     Bromination of Acetanilide 
     3.5 g (10 mmol) of F-TEDA-BF 4  fluorination agent, 1.95 g (19 mmol) of NaBr, and 40 mL of acetonitrile were added to a 100-mL round bottom flask containing a magnetic stir bar and stirring was commenced. To this was added 1.35 g (10 mmol) of acetanilide and the contents of the flask were stirred under nitrogen and sampled periodically. After 3.5 hours of stirring at room temperature, analysis by GC and GC-MS indicated that greater than 98% conversion of the acetanilide starting material had been achieved and with a product distribution which includes 2-monobrominated products. At this point, the solvent was removed under vacuum on a Rotavap. To the resulting residue was added 100 mL of de-ionized water. This aqueous mixture was extracted with 2×100 mL portions of methylene chloride. The methylene chloride extracts were combined, dried with MgSO 4 , and evaporated to a product residue. The resulting residue was purified by chromatography on silica gel using a mixture of 60% ethyl acetate and 40% hexane. A product fraction was collected and evaporated to a white solid residue. This residue was analyzed by NMR spectroscopy and GC-MS. The analysis of this white solid fraction was consistent with 4-bromoacetanilide. 
     4-bromoacetanilide 
     NMR (CDCl 3 ): ( 1 H) 2.14 ppm (s, 3H), 7.0-7.5 ppm (m, 4H); 
       13 C{ 1 H}: 14.3 ppm (s, 1C), 117.1 ppm (s, 1C), 121.3 ppm (s, 2C), 131.9 ppm (s, 2C), 138.5 ppm (s, 1C), 168.3 ppm (s, 1C); 
     MS (EI): m/e (relative intensity) 213 (M + , 20), 171 (100). 
     EXAMPLE 10 
     Bromination of Toluene 
     3.5 g (10 mmol) of F-TEDA-BF 4  fluorination agent, 1.03 g (10 mmol) of NaBr, and 100 mL of acetonitrile were added to a 100-mL round bottom flask containing a magnetic stir bar and stirring was commenced. To this was added 0.92 g (10 mmol) of toluene and the contents of the flask were stirred under nitrogen and sampled periodically. After 93.5 hours of stirring at room temperature, analysis by GC and GC-MS indicated that about 35% conversion of the toluene starting material had been achieved with a product distribution which included 2- and 4-bromotoluene and bromomethylbenzene. No further analyses were done. 
     EXAMPLE 11 
     Chlorination of Toluene 
     3.5 g (10 mmol) of F-TEDA-BF 4  fluorination agent, 0.60 g (10 mmol) of NaCl, and 100 mL of acetonitrile were added to a 100-mL round bottom flask containing a magnetic stir bar and stirring was commenced. To this was added 0.92 g (10 mmol) of toluene and the contents of the flask were stirred at reflux under nitrogen and sampled periodically. After 47 hours of stirring at reflux, analysis by GC and GC-MS indicated that about 75% conversion of the toluene starting material had been achieved with a product distribution which included 2-chlorotoluene (63%), 4-chlorotoluene (32%), chloromethylbenzene (1%), and fluorotoluene (4%) as the major species. No further analyses were done. 
     EXAMPLE 12 
     Chlorination of Acetanilide 
     3.5 g (10 mmol) of F-TEDA-BF 4  fluorination agent, 0.60 g (10 mmol) of NaCl, and 100 mL of acetonitrile were added to a 250-mL round bottom flask containing a magnetic stir bar and stirring was commenced. To this was added 1.35 g (10 mmol) of acetanilide and the contents of the flask are stirred under nitrogen and sampled periodically. After 22.5 hours of stirring at room temperature, analysis by GC and GC-MS indicated that approximately 53% conversion of the acetanilide starting material had been achieved and with a product distribution which include 2-chloroacetanilide (42.7%) and 4-chloroacetanilide (30.0%) as the major chlorinated products. Also observed was chlorofluoroacetanilide (4.9%), fluoroacetanilide (21.9%) and difluoroacetanilide (0.2%). 
     2-chloroacetanilide 
     MS (EI): m/e (relative intensity) 169 (M + , 11), 134 (33), 127(100). 
     chlorofluoroacetanilide 
     MS (EI): m/e (relative intensity) 187 (M + , 12), 145 (100), 127(3), 110(4). 
     fluoroacetanilide 
     MS (EI): m/e (relative intensity) 153 (M + , 17), 111 (100). 
     EXAMPLE 13 
     Chlorination of Acetanilide 
     This is a repeat of Example 12 with the exception of using an excess of F-TEDA-BF 4  in order to get complete conversion of the acetanilide starting material. In this experiment, 15.0 g (42 mmol) of F-TEDA-BF 4  fluorination agent, 1.17 g (20 mmol) of NaCl, and 200 mL of acetonitrile were added to a 500-mL round bottom flask containing a magnetic stir bar and stirring was commenced. To this was added 2.70 g (20 mmol) of acetanilide and the contents of the flask were stirred under nitrogen and sampled periodically. After 90 hours of stirring at room temperature, analysis by GC and GC-MS indicated that complete conversion of the acetanilide starting material had been achieved. At this point, the solvent was removed under vacuum on a Rotavap. To the resulting residue was added 100 mL of de-ionized water. This aqueous mixture was extracted with 3×100 mL portions of chloroform. The chloroform extracts were combined, dried with MgSO 4 , and evaporated to a product residue which weighed 3.49 g. A portion of this residue was dissolved in acetonitrile and analyzed by GC-MS. Analysis indicated a product distribution which included 2-chloroacetanilide (46.3%) and 4-chloroacetanilide (16.2%) as the major chlorinated products. Also observed was chlorofluoroacetanilide (6.6%), fluoroacetanilide (16.2%) and dichloroacetanilide (14.7%). 
     2-chloroacetanilide 
     MS (EI): m/e (relative intensity) 169 (M + , 15), 134 (35), 127(100). 
     chlorofluoroacetanilide 
     MS (EI): m/e (relative intensity) 187 (M + , 17), 145 (100). 
     fluoroacetanilide 
     MS (EI): m/e (relative intensity) 153 (M + , 17), 111 (100). 
     2,4-dichloroacetanilide 
     MS (EI): m/e (relative intensity) 203 (M + , 15), 168 (14), 161(100), 133(6). 
     EXAMPLE 14 
     Chlorination of p-xylene 
     15.0 g (42 mmol) of F-TEDA-BF 4  fluorination agent, 1.17 g (20 mmol) of NaCl, and 200 mL of acetonitrile were added to a 500-mL round bottom flask containing a magnetic stir bar and stirring was commenced. To this was added 2.13 g (20 mmol) of p-xylene and the contents of the flask are stirred under nitrogen. After 93 hours of stirring at room temperature, analysis by GC and GC-MS indicated that complete conversion of the p-xylene starting material had been achieved. At this point, the solvent was removed under vacuum on a Rotavap. To the resulting residue was added 100 mL of de-ionized water. This aqueous mixture was extracted with 3×100 mL portions of chloroform. The chloroform extracts were combined, dried with MgSO 4 , and evaporated to a product residue which weighed 2.02 g. A portion of this residue was dissolved in acetonitrile and analyzed by GC-MS and shown to contain primarily 2-chloro-1,4-dimethylbenzene as well as some dichlorinated and fluorinated products. The product residue was purified by chromatography on silica gel using hexane as the eluent. Two product fractions were collected, evaporated to residues, and then analyzed separately by NMR spectroscopy and GC-MS. The analysis were consistent with 2-chloro-1,4-dimethylbenzene as the primary product in each fraction. 
     2-chloro-1,4-dimethylbenzene 
     NMR (CDCl 3 ): ( 1 H) 2.31 ppm (s, 3H), 2.36 ppm (s, 3H), 6.94 -7.18 ppm (m, 3H); 
       13 C{ 1 H}: 19.41 ppm (s, 1C), 20.62 ppm (s, 1C), 127.32 ppm (s, 1C), 129.62 ppm (s, 1C), 130.66 ppm (s, 1C), 132.79 ppm (s, 1C), 134.25 ppm (s, 1C), 136.93(s, 1C); 
     MS (EI): m/e (relative intensity): 140 (M + , 42), 125 (10), 105 (100). 
     EXAMPLE 15 
     Chlorination of Anisole 
     15.0 g (42 mmol) of F-TEDA-BF 4  fluorination agent, 1.17g (20 mmol) of NaCl, and 200 mL of acetonitrile were added to a 500-mL round bottom flask containing a magnetic stir bar and stirring was commenced. To this was added 2.16 g (20 mmol) of anisole and the contents of the flask were stirred under nitrogen. After 98 hours of stirring at room temperature, analysis by GC and GC-MS indicated that complete conversion of the anisole starting material had been achieved. At this point, the solvent was removed under vacuum on a Rotavap. To the resulting residue was added 100 mL of de-ionized water. This aqueous mixture was extracted with 3×100 mL portions of chloroform. The chloroform extracts were combined, dried with MgSO 4 , and evaporated to a product residue which weighed 2.40 g. A portion of this residue was dissolved in acetonitrile and analyzed by GC-MS and shown to contain primarily 2-chloroanisole (27%) and 4-chloroanisole (18%) as the major chlorinated species, but also contained dichloroanisole (24%), fluoroanisole (18%), chlorofluoroanisole (12%), difluoroanisole (1%), and chlorodifluoroanisole (0.2%) as minor components. 
     2-chloroanisole 
     MS (EI): m/e (relative intensity) 142 (M + , 100), 127(51). 
     4-chloroanisole 
     MS (EI): m/e (relative intensity) 142 (M + , 100), 127(43). 
     2,4-dichloroanisole 
     MS (EI): m/e (relative intensity) 176 (M + , 100), 161(80), 126(4). 
     chlorofluoroacetanilide 
     MS (EI): m/e (relative intensity) 187 (M + , 12), 145 (100), 127(3), 110(4). 
     fluoroacetanilide 
     MS (EI): m/e (relative intensity) 153 (M + , 17), 111 (100). 
     EXAMPLE 16 
     Chlorination of 2-Fluoroanisole 
     15.0 g (42 mmol) of F-TEDA-BF 4  fluorination agent, 1.17 g (20 mmol) of NaCl, and 200 mL of acetonitrile were added to a 500-mL round bottom flask containing a magnetic stir bar and stirring was commenced. To this was added 2.52 g (20 mmol) of 2-fluoroanisole and the contents of the flask were stirred under nitrogen. After 26 hours of stirring at room temperature, analysis by (GC) indicated that approximately 52% conversion of the 2-fluoroanisole starting material had been achieved. At this point, the solvent was removed under vacuum on a Rotavap. To the resulting residue was added 100 mL of de-ionized water. This aqueous mixture was extracted with 3×100 mL portions of chloroform. The chloroform extracts were combined, dried with MgSO 4 , and evaporated to a product residue which weighed 2.31 g. A portion of this residue was dissolved in acetone and analyzed by GC-MS and shown to contain chloro-2-fluoroanisole (50%) as the primary chlorinated species, but also contained minor amounts of difluoroanisole (1%) and chloroanisole (1%). 
     chloro-2-fluoroanisole 
     MS (EI): m/e (relative intensity) 160 (M + , 100), 145(89). 
     difluoroanisole 
     MS (EI): m/e (relative intensity) 144 (M + , 100), 129 (90), 113 (6). 
     EXAMPLE 17 
     Chlorination of 4-Fluoroanisole 
     15.0 g (42 mmol) of F-TEDA-BF 4  fluorination agent, 1.18 g (20 mmol) of NaCl, and 200 mL of acetonitrile were added to a 500-mL round bottom flask containing a magnetic stir bar and stirring was commenced. To this was added 2.53 g (20 mmol) of 4-fluoroanisole and the contents of the flask were stirred under nitrogen. After 26 hours of stirring at room temperature, analysis by GC indicated that approximately 53% conversion of the 4-fluoroanisole starting material had been achieved. At this point, the solvent was removed under vacuum on a Rotavap. To the resulting residue was added 100 mL of de-ionized water. This aqueous mixture was extracted with 3×100 mL portions of chloroform. The chloroform extracts were combined, dried with MgSO 4 , and evaporated to a product residue which weighed 2.06 g. A portion of this residue was dissolved in acetone and analyzed by GC-MS and shown to contain 2-chloro-4-fluoroanisole (48%) as the primary chlorinated species, but also contained minor amounts of difluoroanisole (3.3%) and chlorofluorophenol derivatives. 
     2-chloro-4-fluoroanisole 
     MS (EI): m/e (relative intensity) 160 (M + , 100), 145 (95). 
     EXAMPLE 18 
     Chlorination of 2-Chloro-p-Xylene 
     15.0 g (42 mmol) of F-TEDA-BF 4  fluorination agent, 1.18 g (20 mmol) of NaCl, and 200 mL of acetonitrile were added to a 500-mL round bottom flask containing a magnetic stir bar and stirring was commenced. To this was added 2.81 g (20 mmol) of 2-chloro-p-xylene and the contents of the flask are stirred under nitrogen. After 24 hours of stirring at room temperature, analysis by GC indicated that approximately 58% conversion of the 2-chloro-p-xylene starting material had been achieved. At this point, the solvent was removed under vacuum on a Rotavap. To the resulting residue was added 100 mL of de-ionized water. This aqueous mixture was extracted with 3×100 mL portions of chloroform. The chloroform extracts were combined, dried with MgSO 4 , and evaporated to a product residue which weighed 2.20 g. A portion of this residue was dissolved in acetone and analyzed by GC-MS and shown to contain dichloro-p-xylene (55%) as the primary chlorinated species, but also contained minor amounts (&lt;1%) of chlorofluoro-p-xylene and fluorodichloro-p-xylene. 
     EXAMPLE 19 
     Chlorination of Phenol 
     3.5 g (10 mmol) of F-TEDA-BF 4  fluorination agent, 1.0 g (17 mmol) of NaCl, and 80 mL of acetonitrile were added to a 100-mL round bottom flask containing a magnetic stir bar and stirring was commenced. To this was added 1.0 g (10 mmol) of phenol and the contents of the flask are stirred under nitrogen and sampled periodically. Although the analysis did not change much after the initial sample taken at 21 hours of reaction time, the mixture was allowed to stir for an additional 120 hours. After 141 hours of stirring at room temperature, analysis by GC and GC-MS indicated that about 64% conversion of the phenol starting material had been achieved with a product distribution which included 2-chlorophenol (56%) as the major chlorinated product and 2-fluorophenol (44%) as the other major product. Very small amounts of 4-chloro and 4-fluorophenol were also observed. 
     2-chlorophenol 
     MS (EI): m/e (relative intensity) 128 (M + , 100), 92(13). 
     2-fluorophenol 
     MS (EI): m/e (relative intensity) 112 (M + , 100), 92 (22). 
     EXAMPLE 20 
     Thiocyanation of Phenol 
     3.5 g (10 mmol) of F-TEDA-BF 4  fluorination agent, 1.22 g (15 mmol) of NaSCN, and 80 mL of acetonitrile were added to a 100-mL round bottom flask containing a magnetic stir bar and stirring was commenced. To this was added 1.0 g (10 mmol) of phenol and the contents of the flask were stirred under nitrogen and sampled periodically. After 93 hours of stirring at room temperature, analysis by GC-MS indicated that about 21% conversion of the phenol starting material had been achieved. GC-MS analysis showed that ortho-phenolthiocyanate (1%) and para-phenolthiocyanate (20%) were the predominant products. 
     2-phenolthiocyanate 
     MS (EI): m/e (relative intensity) 151 (M + , 100), 124 (7). 
     4-phenolthiocyanate 
     MS (EI): m/e (relative intensity) 151 (M + , 100), 123 (19). 
     EXAMPLE 21 
     Acetylation of p-Xylene 
     3.5 g (10 mmol) of F-TEDA-BF 4  fluorination agent, 0.77 g (10 mmol) of ammonium acetate, NH 4   + CH 3 COO − , and 80 mL of acetonitrile were added to a 100-mL round bottom flask containing a magnetic stir bar and stirring was commenced. To this was added 1.1 g (10 mmol) of p-xylene and the contents of the flask were stirred under nitrogen and sampled periodically. After 70 hours of stirring at room temperature, analysis by GC-MS indicated that about 3% conversion of the p-xylene starting material had been achieved. GC-MS analysis showed a trace amount of the expected ortho substituted product, 2,5-dimethylphenyl acetate. 
     2,5-dimethylphenyl acetate 
     MS (EI): m/e (relative intensity) 164 (M + , 12), 122 (100). 
     EXAMPLE 22 
     Chlorination of Benzene 
     3.54 g (10 mmol) of F-TEDA-BF 4  fluorination agent, 0.5891 g (10 mmol) of NaCl, and 80 mL of acetonitrile were added to a 100-mL round bottom flask containing a magnetic stir bar and stirring was commenced. To this was added 0.78 g (10 mmol) of benzene and the contents of the flask were stirred under nitrogen and sampled periodically. After 72 hours of stirring at room temperature, analysis by GC-MS indicated that complete conversion of the benzene starting material had been achieved. GC-MS analysis showed a single product which was identified as chlorobenzene. 
     chlorobenzene 
     MS (EI): m/e (relative intensity) 112 (M + , 100), 77 (51). 
     EXAMPLE 23 
     Bromination of Benzene 
     3.54 g (10 mmol) of F-TEDA-BF 4  fluorination agent, 1.0834 g (11 mmol) of NaBr, and 80 mL of acetonitrile were added to a 100-mL round bottom flask containing a magnetic stir bar and stirring was commenced. To this was added 0.78 g (10 mmol) of benzene and the contents of the flask were stirred under nitrogen and sampled periodically. After 72 hours of stirring at room temperature, analysis by GC-MS indicated that complete conversion of the benzene starting material had been achieved. GC-MS analysis showed a single product which was identified as bromobenzene. 
     bromobenzene 
     MS (EI): m/e (relative intensity) 156 (M + , 59), 77 (100). 
     EXAMPLE 24 
     Nitration of Benzene 
     In a typical experiment 3.54 g (10 mmol) of F-TEDA-BF 4  fluorination agent, 0.7248 g (11 mmol) of NaNO 2 , and 80 mL of acetonitrile were added to a 100-mL round bottom flask containing a magnetic stir bar and stirring was commenced. To this was added 0.78 g (10 mmol) of benzene and the contents of the flask were stirred under nitrogen and sampled periodically. After 72 hours of stirring at room temperature, analysis by GC-MS indicated that complete conversion of the benzene starting material had been achieved. GC-MS analysis showed a single product which was identified as nitrobenzene. 
     nitrobenzene 
     MS (EI): m/e (relative intensity) 123 (M + , 46), 77 (100). 
     EXAMPLE 25 
     Chlorination of 1,3-Dimethyluracil 
     3.54 g (10 mmol) of F-TEDA-BF 4  fluorination agent, 0.58 g (10 mmol) of NaCl, and 80 mL of acetonitrile were added to a 100-mL round bottom flask containing a magnetic stir bar and stirring was commenced. To this was added 0.82 g (6 mmol) of 1,3-dimethyluracil and the contents of the flask were stirred under nitrogen and sampled periodically. After 94 hours of stirring at room temperature, analysis by GC-MS indicated that complete conversion of the 1,3-dimethyluracil starting material had been achieved. GC-MS analysis showed a product distribution which included 5-chloro-6-fluoro-1,3-dimethyluracil (41%) and 5-chloro-1,3-dimethyluracil (24%) as major products. 
     5-chloro-6-fluoro-1,3-dimethyluracil 
     MS (EI): m/e (relative intensity) 193 (M + , 100), 174 (1), 158 (8). 
     5-chloro-1,3-dimethyluracil 
     MS (EI): m/e (relative intensity) 174 (M + , 100). 
     EXAMPLE 26 
     Chlorination of Anisole with Varying Amounts of F-TEDA-BF 4    
     In this experiment, 20, 10, 5, and 1 mmol of F-TEDA-BF 4  fluorination agent were weighed, respectively, into 4 individual 250-mL flasks, and to each flask was added 1.17 g (20 mmol) of NaCl, 200 mL of acetonitrile, and 2.2 g (20 mmol) of anisole. A magnetic stir bar was added to each and the contents of the flasks were stirred under nitrogen. Samples from each flask were taken after 46.5 hours and analyzed by GC. The main chlorinated products were 2- and 4-chloroanisole. The results are summarized in Table EG-26 below. 
     
       
         
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE EG-26 
               
               
                   
               
               
                 Amount 
                 Anisole 
                   
                   
               
               
                 F-TEDA-BF 4   
                 Conversion 
                 % 2-chloroanisole 
                 % 4-chloroanisole 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1 
                 mmol 
                 0% 
                  0% 
                  0% 
               
               
                 5 
                 mmol 
                 1% 
                   0.4% 
                   0.1% 
               
               
                 10 
                 mmol 
                 42% 
                 24% 
                 10% 
               
               
                 20 
                 mmol 
                 75% 
                 41% 
                 15% 
               
               
                   
               
             
          
         
       
     
     EXAMPLE 27 
     Chlorination of Anisole Using NFTh Fluorination Agent 
     In this experiment, the ability of NFTh fluorination agent to accomplish the novel generation of electrophilic chlorine from chloride ion was assessed and was compared directly to the same reaction using an equivalent amount of F-TEDA-BF 4 . Thus, in two separate flasks was weighed 0.58 g NaCl (10 mmol), 1.1 g anisole (10 mmol), and 100 mL acetonitrile. To flask 1 was added 3.5 g (10 mmol) of F-TEDA-BF 4  and to the second flask were added 3.2 g (10 mmol) of NFTh. Stirring was commenced and the contents were monitored periodically by GC. After 117 hours the reactions were deemed complete and in Table EG-27 below is an assay of each reaction mixture. 
     
       
         
               
               
               
               
             
               
               
               
               
             
           
               
                   
                 TABLE EG-27 
               
               
                   
                   
               
               
                   
                 Anisole 
                   
                   
               
               
                   
                 Conversion 
                 % 2-chloroanisole 
                 % 4-chloroanisole 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                 F-TEDA-BF 4   
                 ≈84% 
                 60% 
                 20% 
               
               
                 NFTh 
                 ≈76% 
                 48% 
                 15% 
               
               
                   
               
             
          
         
       
     
     EXAMPLE 28 
     Chlorination of p-Xylene Using NFTh Fluorination Agent 
     In this experiment, the ability of NFTh fluorination agent to accomplish the novel generation of electrophilic chlorine from chloride ion was assessed and was compared directly to the same reaction using an equivalent amount of F-TEDA-BF 4 . Thus, in two separate flasks were weighed 0.58 g NaCl (10 mmol), 1.1 g p-xylene (10 mmol), and 100 mL acetonitrile. To flask 1 was added 3.5 g (10 mmol) of F-TEDA-BF 4  and to the second flask was added 3.2 g (10 mmol) of NFTh. Stirring was commenced and the contents were monitored periodically by GC. After 121 hours the reactions were deemed complete the results are shown in Table EG-28 below. 
     
       
         
               
               
               
               
             
               
               
               
               
             
           
               
                   
                 TABLE EG-28 
               
               
                   
                   
               
               
                   
                 p-xylene 
                   
                   
               
               
                   
                 Conversion 
                 % 2-chloro-p-xylene 
                 % dichloro-p-xylene 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                 F-TEDA-BF 4   
                 ≈74% 
                 78% 
                 14% 
               
               
                 NFTh 
                 ≈54% 
                 90% 
                 6% 
               
               
                   
               
             
          
         
       
     
     EXAMPLE 29 
     Chlorination of Toluene Using NFTh Fluorination Agent 
     In this experiment, the ability of NFTh fluorination agent to accomplish the novel generation of electrophilic chlorine from chloride ion was assessed and was compared directly to the same reaction using an equivalent amount of F-TEDA-BF 4 . Thus, in two separate flasks were weighed 0.58 g NaCl (10 mmol), 0.92 g toluene (10 mmol), and 100 mL acetonitrile. To flask 1 was added 3.5 g (10 mmol) of F-TEDA-BF 4  and to the second flask was added 3.2 g (10 mmol) of NFTh. Stirring was commenced and the contents were monitored periodically by GC. After 47.5 hours the reactions were deemed complete. The results are shown in Table EG-29 below. 
     
       
         
               
               
               
               
             
               
               
               
               
             
           
               
                   
                 TABLE EG-29 
               
               
                   
                   
               
               
                   
                 toluene 
                   
                   
               
               
                   
                 Conversion 
                 % 2-chlorotoluene 
                 % 4-chlorotoluene 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                 F-TEDA-BF 4   
                 ≈75% 
                 56% 
                 43% 
               
               
                 NFTh 
                 ≈5% 
                 58% 
                 42% 
               
               
                   
               
             
          
         
       
     
     EXAMPLE 30 
     Chlorination of p-Xylene Using F-TEDA-BF 4  in Different Solvents 
     In this experiment, the ability of F-TEDA-BF 4  fluorination agent to accomplish the novel generation of electrophilic chlorine from chloride ion was assessed in solvents other than acetonitrile. Thus, in three separate flasks were weighed 0.58 g NaCl (10 mmol), 1.1 g p-xylene (10 mmol), and 3.5 g (10 mmol) of F-TEDA-BF 4 . To the first flask was added 100 mL methanol, to the second 100 mL dimethyformamide (DMF), and to the third flask was added 50 mL water and 50 mL acetonitrile. Stirring was commenced and the contents were monitored periodically by GC. After 47.5 hours the reactions were terminated. The results are shown in Table EG-30 below. 
     
       
         
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE EG-30 
               
               
                   
               
               
                   
                 p-xylene 
                 % 2-chloro- 
                   
               
               
                 solvent 
                 Conversion 
                 p-xylene 
                 % dichloro-p-xylene 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 methanol 
                 0% 
                 0% 
                 0% 
               
               
                 DMF 
                 ≈25% 
                 100% 
                 0% 
               
               
                 50:50 water/ACN 
                 ≈5% 
                 100% 
                 0% 
               
               
                   
               
             
          
         
       
     
     EXAMPLE 31 
     Chlorination of Anisole Using F-TEDA-BF 4  in Different Solvents 
     In this experiment, the ability of F-TEDA-BF 4  fluorination agent to accomplish the novel generation of electrophilic chlorine from chloride ion was assessed in solvents other than acetonitrile. Thus, in three separate flasks was weighed 0.58 g NaCl (10 mmol), 1.1 9 anisole (10 mmol), and 3.5 g (10 mmol) of F-TEDA-BF 4 . To the first flask was added 100 mL methanol, to the second 100 mL dimethyformamide (DMF), and to the third flask was added 50 mL water and 50 mL acetonitrile. Stirring was commenced and the contents were monitored periodically by GC. After 46 hours the reactions were terminated. The results are shown in Table EG-31 below. 
     
       
         
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE EG-31 
               
               
                   
               
               
                   
                 anisole 
                   
                   
               
               
                 solvent 
                 Conversion 
                 % chloroanisole 
                 % fluoroanisole 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 methanol 
                 0% 
                 0% 
                 0% 
               
               
                 DMF 
                 ≈94% 
                 100% 
                 0% 
               
               
                 50:50 water/ACN 
                 ≈69% 
                 ≈17% 
                 ≈53% 
               
               
                   
               
             
          
         
       
     
     EXAMPLE 32 
     Thiocyanation of Various Substrates Using F-TEDA-BF 4  in DMF 
     In this experiment, the ability of F-TEDA-BF 4  fluorination agent to accomplish the novel generation of electrophilic SCN +  from thiocyanate ion was assessed for various aromatic substrates in DMF solvent. Thus, in three separate flasks were weighed 0.82 g NaSCN (10 mmol), 3.5 g (10 mmol) of F-TEDA-BF 4 , and 100 mL dimethyformamide (DMF). To the first flask was added 1.1 g (10 mmol) of anisole, to the second flask was added 0.92 g (10 mmol) toluene, and to the third flask was added 1.1 g (10 mmol) p-xylene. Stirring was commenced and the contents were monitored periodically by GC. After 70 hours the reactions were terminated. The results are shown in Table EG-32 below. 
     
       
         
               
               
               
             
               
               
               
             
           
               
                 TABLE EG-32 
               
               
                   
               
               
                 substrate 
                 substrate Conversion 
                 % SCN product 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 anisole 
                 ≈6% 
                 100% 
               
               
                 toluene 
                 0% 
                 0% 
               
               
                 p-xylene 
                 0% 
                 0% 
               
               
                   
               
             
          
         
       
     
     EXAMPLE 33 
     Nitration of Various Substrates Using F-TEDA-BF 4  in DMF 
     In this experiment, the ability of F-TEDA-BF 4  fluorination agent to accomplish the novel generation of electrophilic NO 2   +  from nitrite ion was assessed for various aromatic substrates in DMF solvent. Thus, in three separate flasks were weighed 0.69 g NaNO 2  (10 mmol), 3.5 g (10 mmol) of F-TEDA-BF 4 , and 100 mL dimethyformamide (DMF). To the first flask was added 1.1 g (10 mmol) of anisole, to the second flask was added 0.92 g (10 mmol) toluene, and to the third flask was added 1.1 g (10 mmol) p-xylene. Stirring was commenced and the contents were monitored periodically by GC. After 95 hours the reactions were terminated and in the Table below is an assay of each reaction mixture. 
     
       
         
               
               
               
             
           
               
                 TABLE EG-33 
               
               
                   
               
               
                 substrate 
                 substrate conversion 
                 % NO 2  product 
               
               
                   
               
             
             
               
                 anisole 
                 0% 
                 0% 
               
               
                 toluene 
                 0% 
                 0% 
               
               
                 p-xylene 
                 0% 
                 0% 
               
               
                   
               
             
          
         
       
     
     EXAMPLE 34 
     Bromination of Various Substrates Using F-TEDA-BF 4  in DMF 
     In this experiment, the ability of F-TEDA-BF 4  fluorination agent to accomplish the novel generation of electrophilic Br +  from bromide ion was assessed for various aromatic substrates in DMF solvent. Thus, in three separate flasks were weighed 1.02 g NaBr (10 mmol), 3.5 g (10 mmol) of F-TEDA-BF 4 , and 100 mL dimethyformamide (DMF). To the first flask was added 1.1 g (10 mmol) of anisole, to the second flask was added 0.92 g (10 mmol) toluene, and to the third flask was added 1.1 g (10 mmol) p-xylene. Stirring was commenced and the contents were monitored periodically by GC. After 45 hours the reactions were terminated. The results are shown in Table EG-34 below. 
     
       
         
               
               
               
             
               
               
               
             
           
               
                 TABLE EG-34 
               
               
                   
               
               
                 substrate 
                 substrate conversion 
                 % Bromo product 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 anisole 
                 95% 
                 100% 
               
               
                 toluene 
                 100% 
                 100% 
               
               
                 p-xylene 
                 100% 
                 95% 
               
               
                   
               
             
          
         
       
     
     EXAMPLE 35 
     Bromination of 4′-Methoxyacetophenone 
     3.5 g (10 mmol) of F-TEDA-BF 4  fluorination agent, 1.03 g (10 mmol) of NaBr, and 80 mL of acetonitrile were added to a 100-mL round-bottomed flask containing a magnetic stir bar and stirring was commenced. To this was added 1.50 g (10 mmol) of 4′-methoxyacetophenone and the contents of the flask were stirred under nitrogen and sampled periodically. After 95 hours of stirring at room temperature, analysis by GC-MS indicated that about 89% conversion of the 4′-methoxyacetophenone starting material had been achieved, with a product distribution of 3′-bromo-4′-methoxyacetophenone (97%), 2,4-dibromo-1-methoxybenzene (2%), and 1-bromo-4-methoxybenzene (1%) as the brominated products. At this point, the solvent was removed under vacuum on a Rotavap. The resulting crude product was treated with 50 mL each of distilled water and saturated sodium bicarbonate. This aqueous mixture was extracted with 2×200 mL portions of dichloromethane. The dichloromethane extracts were combined, dried with MgSO 4 , and evaporated to a product residue. This residue was subsequently treated with hexane and ethyl acetate and placed in a freezer to facilitate crystal formation. The resulting crystals were analyzed by NMR spectroscopy and GC-MS. The analyses were consistent with 3′-bromo-4′-methoxyacetophenone. 
     3′-bromo-4′-methoxyacetophenone 
     NMR (CDCl 3 ): ( 1 H) 2.53 ppm (s, 3H), 3.95 ppm (s, 3H), 6.91 ppm (d, 1H, J=8.6 Hz), 7.89 ppm (m, 1H,  1 J=8.5 Hz,  2 J=2.1 Hz), 8.14 ppm (d, 1H, J=2.1 Hz); 
       13 C{ 1 H}: 26.30 ppm (s, 1C), 56.46 ppm (s, 1C), 111.04 ppm (s, 1C), 111.82 ppm (s, 1C), 129.46 ppm (s, 1C), 131.20 ppm (s, 1C), 133.83 ppm (s, 1C), 159.54 ppm (s, 1C), 195.61 ppm (s, 1C); 
     MS (EI): m/z (relative intensity) 230 (39), 228 (M + , 43), 215 (99), 213 (100), 187 (10) 185 (11). 
     EXAMPLE 36 
     Thiocyanation of 4′-Methoxyacetophenone 
     3.5 g (10 mmol) of F-TEDA-BF 4  fluorination agent, 0.81 g (10 mmol) of NaSCN, and 80 mL of acetonitrile were added to a 100-mL round-bottomed flask containing a magnetic stir bar and stirring was commenced. To this was added 1.50 g (10 mmol) of 4′-methoxyacetophenone and the contents of the flask were stirred under nitrogen and sampled periodically. After 95 hours of stirring at room temperature, analysis by GC-MS indicated that about 47% conversion of the 4′-methoxyacetophenone starting material had been achieved, with 4′-methoxy-3′-thiocyanatoacetophenone as the single product. At this point, the solvent was removed under vacuum on a Rotavap. The crude product was treated with 50 mL each of distilled water and saturated sodium bicarbonate. This aqueous mixture was extracted with 2×200 mL portions of dichloromethane. The dichloromethane extracts were combined, dried with MgSO 4 , and evaporated to a product residue. The resulting residue was purified by chromatography on silica gel using a mixture of 40% ethyl acetate and 60% hexane. Eight product fractions were collected and combined. The solvent was evaporated and the resulting product was analyzed by NMR spectroscopy and GC-MS. The analyses were consistent with 4′-methoxy-3′-thiocyanatoacetophenone. 
     4′-methoxy-3′-thiocyanatoacetophenone 
     NMR (CDCl 3 ): ( 1 H) 2.57 ppm (s, 3H), 3.99 ppm (s, 3H), 6.98 ppm (d, 1H, J=8.7 Hz), 8.00 ppm (m, 1H,  1 J=8.6 Hz,  2 J=2.1 Hz), 8.15 ppm (d, 1H, J=2.1 Hz); 
       13 C{ 1 H}: 26.36 ppm (s, 1C), 56.66 ppm (s, 1C), 109.70 ppm (s, 1C), 110.94 ppm (s, 1C), 113.93 ppm (s, 1C), 130.87 ppm (s, 1C), 131.44 ppm (s, 1C), 131.48 ppm (s, 1C), 159.98 ppm (s, 1C), 195.34 ppm (s, 1C); 
     MS (EI): m/z (relative intensity) 209 (2), 208 (5), 207 (M + , 37), 193 (12), 192 (100), 151 (1), 149 (2). 
     EXAMPLE 37 
     Chlorination of 4′-Methoxyacetophenone 
     3.5 g (10 mmol) of F-TEDA-BF 4  fluorination agent, 0.58 g (10 mmol) of NaCl, and 80 mL of acetonitrile were added to a 100-mL round-bottomed flask containing a magnetic stir bar and stirring was commenced. To this was added 1.50 g (10 mmol) of 4′-methoxyacetophenone and the contents of the flask were stirred under nitrogen and sampled periodically. After 95 hours of stirring at room temperature, analysis by GC-MS indicated that about 73% conversion of the 4′-methoxyacetophenone starting material had been achieved, with a product distribution which included 3′-chloro4′-methoxyacetophenone (97%), 1-chloro-4-methoxybenzene (1%), and 1,3-dichloro-2-methoxybenzene (1%) as chlorinated products. At this point, the solvent was removed under vacuum on a Rotavap. The crude product was treated with 50 mL each of distilled water and saturated sodium bicarbonate. This aqueous mixture was extracted with 2×200 mL portions of dichloromethane. The dichloromethane extracts were combined, dried with MgSO 4 , and evaporated to a product residue. The resulting residue was dissolved in a mixture of ethyl acetate and hexane and placed in a freezer to promote crystallization. The resulting crystals were analyzed by NMR spectroscopy and GC-MS and the results were consistent with 4′-methoxy-3′-thiocyanatoacetophenone as the product. 
     3′-chloro-4′-methoxyacetophenone 
     NMR (CDCl 3 ): ( 1 H) 2.54 ppm (s, 3H), 3.95 ppm (s, 3H), 6.95 ppm (d, 1H, J=8.6 Hz), 7.85 ppm (m, 1H,  1 J=8.5 Hz,  2 J=2.2 Hz), 7.97 ppm (d, 1H, J=2.2 Hz); 
       13 C{ 1 H}: 26.31 ppm (s, 1C), 56.36 ppm (s, 1C), 111.21 ppm (s, 1C), 112.00 ppm (s, 1C), 128.75 ppm (s, 1C), 130.65 ppm (s, 1C), 130.77 ppm (s, 1C), 158.73 ppm (s, 1C), 195.75 ppm (s, 1C); 
     MS (EI): m/z (relative intensity) 186 (13), 184 (M + , 39), 171 (31), 169 (100), 154 (1(13). 
     EXAMPLE 38 
     Nitration of 4-Nitrophenol 
     3.5 g (10 mmol) of F-TEDA-BF 4  fluorination agent, 0.69 g (10 mmol) of NaNO 2 , and 80 mL of acetonitrile were added to a 100-mL round-bottomed flask containing a magnetic stir bar and stirring was commenced. To this was added 1.40 g (10 mmol) of 4-nitrophenol and the contents of the flask were stirred under nitrogen and sampled periodically. After 20 hours of stirring at room temperature, analysis by GC-MS indicated near complete conversion of the 4-nitrophenol starting material had been achieved, with 2,4-dinitrophenol as the single product. The reaction solution was treated with distilled water and filtered to remove solids. NMR and GC-MS analysis of the resulting solution were consistent with 2,4-dinitrophenol as the product. 
     2,4-dinitrophenol 
     MS (EI): m/z (relative intensity) 184 (M + , 100), 154 (38), 138 (2). 
     EXAMPLE 39 
     Bromination of Benzoic Acid 
     3.6 g (10 mmol) of F-TEDA-BF 4  fluorination agent, 1.01 g (10 mmol) of NaBr, and 80 mL of acetonitrile were added to a 100-mL round-bottomed flask containing a magnetic stir bar and stirring was commenced. To this was added 1.20 g (10 mmol) of benzoic acid and the contents of the flask were stirred under nitrogen and sampled periodically. After 142 hours of stirring at room temperature, analysis by GC-MS indicated about 8% conversion of the benzoic acid starting material had been achieved, with bromobenzene as the single brominated product. 
     bromobenzene 
     MS (EI): m/z (relative intensity) 158 (54), 156 (M + , 57), 77 (100). 
     EXAMPLE 40 
     Chlorination of Anisole Using SynFluor™ 
     3.7 g (10 mmol) of SynFluor™ fluorination agent, 0.59 g (10 mmol) of NaCl, and 80 mL of acetonitrile were added to a 100-mL round-bottomed flask containing a magnetic stir bar and stirring was commenced. To this was added 1.08 g (10 mmol) of anisole and the contents of the flask were stirred under nitrogen and sampled periodically. After 163 hours of stirring at room temperature, analysis by GC-MS indicated that about 71% conversion of the anisole starting material had been achieved, yielding a product distribution including 1-chloro-4-methoxybenzene (53%) and 1-chloro-2-methoxybenzene (&lt;1%) as chlorinated products. 
     EXAMPLE 41 
     Bromination of Anisole Using SynFluor™ 
     3.7 g (10 mmol) of SynFluor™ fluorination agent, 1.03 g (10 mmol) of NaBr, and 80 mL of acetonitrile were added to a 100-mL round-bottomed flask containing a magnetic stir bar and stirring was commenced. To this was added 1.07 g (10 mmol) of anisole and the contents of the flask were stirred under nitrogen and sampled periodically. After 24 hours of stirring at room temperature, analysis by GC-MS indicated that near complete conversion of the anisole starting material had been achieved, yielding a product distribution including 1-bromo-4-methoxybenzene (70%), 1-bromo-2-methoxybenzene (6%), and 2,4-dibromo-1-methoxybenzene (6%), as brominated products. 
     EXAMPLE 42 
     Nitration of Anisole Using SynFluor™ 
     3.7 g (10 mmol) of SynFluor™ fluorination agent, 0.69 g (10 mmol) of NaNO 2 , and 80 mL of acetonitrile were added to a 100-mL round-bottomed flask containing a magnetic stir bar and stirring was commenced. To this was added 1.09 g (10 mmol) of anisole and the contents of the flask were stirred under nitrogen and sampled periodically. After 164 hours of stirring at room temperature, analysis by GC-MS indicated that a small amount of the anisole starting material had been converted to a mixture of 1-methoxy-2-nitrobenzene and 1-methoxy-4-nitrobenzene. 
     EXAMPLE 43 
     Thiocyanation of Anisole Using SynFluor™ 
     3.7 g (10 mmol) of SynFluor™ fluorination agent, 0.81 g (10 mmol) of NaSCN, and 80 mL of acetonitrile were added to a 100-mL round-bottomed flask containing a magnetic stir bar and stirring was commenced. To this was added 1.10 g (10 mmol) of anisole and the contents of the flask were stirred under nitrogen and sampled periodically. After 119 hours of stirring at room temperature, analysis by GC-MS indicated that about 47% conversion of the anisole starting material had been achieved, yielding a product distribution which included 4-methoxyphenylthiocyanate (37%) as the only thiocyanated product. 
     EXAMPLE 44 
     Chlorination of p-Xylene Using SynFluor™ 
     3.7 g (10 mmol) of SynFluor™ fluorination agent, 0.58 g (10 mmol) of NaCl, and 80 mL of acetonitrile were added to a 100-mL round-bottomed flask containing a magnetic stir bar and stirring was commenced. To this was added 1.06 g (10 mmol) of p-xylene and the contents of the flask were stirred under nitrogen and sampled periodically. After 113 hours of stirring at room temperature, analysis by GC-MS indicated that about 28% conversion of the p-xylene starting material had been achieved, yielding a product distribution which included 2-chloro-1,4-dimethylbenzene (37%) as the only chlorinated product. 
     EXAMPLE 45 
     Bromination of p-Xylene Using SynFluor™ 
     3.7 g (10 mmol) of SynFluor™ fluorination agent, 1.02 g (10 mmol) of NaBr, and 80 mL of acetonitrile were added to a 100-mL round-bottomed flask containing a magnetic stir bar and stirring was commenced. To this was added 1.06 g (10 mmol) of p-xylene and the contents of the flask were stirred under nitrogen and sampled periodically. After 45 hours of stirring at room temperature, analysis by GC-MS indicated that about 95% conversion of the p-xylene starting material had been achieved, yielding a product distribution which included 2-bromo-1,4-dimethylbenzene (39%) and 1-(bromomethyl)-4-methylbenzene (28%) as the main brominated products. 
     EXAMPLE 46 
     Trifluoroacetylation of p-Xylene 
     3.5 g (10 mmol) of F-TEDA-BF 4  fluorination agent, 1.4 g (10 mmol) of Na +   − OC(O)CF 3 , and 80 mL of acetonitrile were added to a 100-mL round-bottomed flask containing a magnetic stir bar and stirring was commenced. To this was added 1.1 g (10 mmol) of p-xylene and the contents of the flask were stirred under nitrogen and sampled periodically. After 67 hours of stirring at room temperature, analysis by GC-MS indicated that a small amount of the p-xylene starting material had been converted, yielding a product distribution which included 1,4-dimethyl-2-phenyltrifluoroacetate (1%) single trifluoroacetylated product. 
     1,4-dimethyl-2-phenyltrifluoroacetate 
     MS (EI): m/z (relative intensity) 218 (M + , 19), 203 (1), 105 (100). 
     EXAMPLE 47 
     Chlorination of Anisole in Proprionitrile Solvent 
     3.5 g (10 mmol) of F-TEDA-BF 4  fluorination agent, 0.6 g (10 mmol) of NaCl, and 100 mL of proprionitrile were added to a 100-mL round-bottomed flask containing a magnetic stir bar and stirring was commenced. To this was added 1.1 g (10 mmol) of anisole and the contents of the flask were stirred under nitrogen and sampled periodically. After 115 hours of stirring at room temperature, analysis by GC-MS indicated that a small amount of the anisole starting material had been converted, yielding a product distribution which included 1-chloro-2-methoxybenzene (2%) and 1-chloro-4-methoxybenzene (1%) as the main chlorinated products. 
     EXAMPLE 48 
     Chlorination of cis-Cyclooctene 
     3.5 g (10 mmol) of F-TEDA-BF 4  fluorination agent, 0.6 g (10 mmol) of NaCl, and 80 mL of acetonitrile were added to a 100-mL round-bottomed flask containing a magnetic stir bar and stirring was commenced. To this was added 1.1 g (10 mmol) of cis-cyclooctene and the contents of the flask were stirred under nitrogen and sampled periodically. After 94 hours of stirring at room temperature, analysis by GC-MS indicated nearly complete conversion of the cis-cyclooctene starting material, yielding a product distribution which included chlorocyclooctene (1%) as the main chlorine addition product. 
     chlorocyclooctene 
     MS (EI): m/z (relative intensity) 146 (3), 144 (M + , 10), 109 (19). 
     While the invention has been described in detail and with reference to specific examples thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof. 
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