A Thesis Presented to The Faculty of Alfred University Reactions Mediated by the Conducting Polymer Poly-(3,4-ethylenedioxythiophene) (PEDOT) Danica Ostrander In Partial Fulfillment of the Requirements for The Alfred University Honors Program Date: May 14, 2013 Under the Supervision of: Chair: Dr. John G. D’Angelo Committee Members: Dr. Jeremy Cody Dr. Geoffrey Bowers TABLE OF CONTENTS INTRODUCTION 3-13 The Ritter Reaction 3-6 General Uses of Conducting Polymers 6 Reactions of Conducting Polymers 7 Poly-(3,4-ethylenedioxy thiophene) (PEDOT) 7-9 The Ritter Reaction and PEDOT 9-13 RESULTS 14-26 PEDOT-Mediated Ritter Reactions with Various Alcohols 14-17 Stoichiometric Attempts 18-20 PEDOT-Mediated Ritter Reactions with Various Nitriles 20-21 Mechanisitic Studies 21-24 Other Reactions Mediated by PEDOT 24-26 EXPERIMENTAL 27-30 CONCLUSIONS AND FUTURE WORK 31-32 APPENDIX A: LIST OF COMPOUNDS 33-36 REFERENCES 37-38 2 INTRODUCTION The Ritter Reaction: The reaction involving formation of n-carboxamides (1) from aliphatic or aromatic nitriles (2) and carbocations (3) is known as the Ritter reaction and was first reported by J. J. Ritter and P. P. Minieri in 1948 (Scheme 1).1 Scheme 1: General Ritter Reaction The Ritter reaction has been widely used for the preparation of acyclic amides as well as heterocycles, including lactams (4), oxazolines (5), and dihydroisoquinolines (6).1 In addition, the reaction has been used in the synthesis of certain natural product derivatives, such as in the completion of the first total synthesis of (-)-4-epiaxinyssamine (7), an epimer of axinyssamine (8), the latter of which shows cytotoxic acitivty against tumor cell lines. The Ritter reaction was used in this synthesis by way of treatment of a key olefinic intermediate (9) with chloroacetonitrile to furnish the chloroacetamide (10). A series of reactions followed to furnish the (-)-4-epiaxinyssamine (Scheme 2).2 3 Scheme 2: Ritter Reaction in the Synthesis of (-)-4-epiaxinyssamine Because of its synthetic utility, the mechanism of the Ritter reaction has been widely studied. When tertiary-, secondary-, or benzylic alcohols (11), are treated with a strong protic (12) or Lewis acid, a carbocation is formed after the elimination of water (13). When the acid is used to treat alkyl halides (14), an SN1 reaction occurs during which the carbocation is furnished, with alkenes (15), the carbocation is formed after protonation of the carbon-carbon double bond. A nitrile then attacks the cation and the intermediate nitrilium ion (16) is then attacked by the conjugate base of the mediating acid resulting in formation of an imidate (17). Subsequent hydration furnishes the hydrated intermediate (18), which rearranges to the desired amide (19). In cases where the reaction occurs intramolecularly, a lactam product is formed (Scheme 3).1 4 Scheme 3: Mechanism of the Ritter Reaction 5 The use of the aforementioned strong protic or Lewis acids results in the exclusion from or protection of certain acid-sensitive functional groups on the substrate. Utilization of more selective reagents may result in the ability to use these acid-sensitive functional groups, thereby potentially eliminating protection steps. Conducting Polymers: General Uses Conducting polymers are typically used for applications in gas sensors, pH sensors, pLEDs, electrolyte-gate transistors, and energy storage.3 A newer study has reported potential methods of overcoming challenges facing applications of conducting polymers in drug delivery, including bilayered conducting polymers, nanostructured conducting polymers, biotinylated conducting polymers, and conducting hydrogels.4 An additional study has shown the polymerization of PEDOT around living neural cells (Figure 1), which could be potentially beneficial in nerve repair. This was done safely as far as cell viability is concerned as the cells lived for at least 120 hours after polymerization.5 Figure 1: Polymerization of PEDOT around living neural cells 6 Reactions Recently, it has been shown that certain polymer-bound acids can mediate reactions such as: polyaniline salts loaded with H2SO4 or HNO3 to furnish tetrahydropyranylation products (20) from 3,4-dihydro-2H-pyran (21) and alcohols,6 polyaniline salts loaded with H2SO4, HCl or HNO3 to form transesterification products (22) from certain esters (23) and alcohols,7 polypyrrole with Pd(0) or Pd(II) to hydrogenate nitrobenzene (24) to aniline (25),8 and polypyrrole-based heteropoly acid catalysts for eliminations and oxidations (26) on alcohols with hydrogen peroxide (27) (Scheme 4).9 Scheme 4: Reactions of Polymer-Bound Acids Poly-(3,4-ethylenedioxythiophene) (PEDOT): The accepted structure of the conducting polymer, poly-(3,4-ethylenedioxythiophene) (PEDOT) (Figure 2), used in our study is a repeating trimer with a triflate counter ion.10 7 PEDOT has been shown to mediate formation of homoethers (28) from alcohols with small amounts of oxidation to the corresponding ketone or aldehyde (29) (Scheme 9);11 Friedel- Crafts alkylations (30) of benzene and toluene with alcohols (Scheme 10);12 and cyclodehydrations (31) of acyclic sugars (32) (Scheme 11).13 The advantages of using PEDOT include that it is a Figure 2: Poly-(3,4- heterogeneous catalyst, allowing for ease of product ethylenedioxythiophene) separation and reuse of the polymer. The disadvantages of PEDOT include that it is very expensive at a current cost of approximately 220 dollars for a dispersion of the polymer in 25 milliliters of water. The production process of PEDOT involves running a current through a mixture of EDOT, the monomer of PEDOT, in acetonitrile before scraping the collected polymer off the anode. This process is tedious and is not particularly high yielding. Finally, PEDOT is very statically charged and is easily lost during transfer to the reaction flask meaning that the exact amount of PEDOT used in each reaction may be incorrect. 8 Scheme 11: PEDOT-Mediated Reactions The Ritter Reaction and PEDOT: Our studies have shown that PEDOT can mediate the Ritter reaction in place of the Lewis or protic acid to furnish the acetamide product. This, combined with the supposition 9 that triflic acid is not responsible for the progress of the reaction, suggests that PEDOT can mediate the Ritter reaction under mild conditions and it may now be possible to use unprotected, acid-sensitive functional groups. In an attempt to determine the scope of the PEDOT-mediated Ritter reaction, a number of alcohols were reacted with acetonitrile. Given that these reactions used acetonitrile as both the solvent and substrate, a new solvent was required in order to perform these reactions with a stoichiometric ratio of alcohol and nitrile. In previous studies, it was found that PEDOT could mediate certain reactions in toluene. However, a Friedel-Crafts alkylation takes place between toluene and the carbocation, which is putatively generated from the interaction between the PEDOT and the alcohol, making it an undesirable solvent.14 After testing a number of solvents, nitromethane was identified as an acceptable solvent. In addition to probing the scope of the reaction with a variety of alcohols, nitrile versatility in the PEDOT-mediated Ritter reaction was also examined. In an effort to minimize by-products, attempts to optimize the ratio of nitrile to alcohol have been made utilizing diphenylmethanol (33) and benzonitrile (34). The selection alcohol 33 and nitrile 34 as substrates was a result of diphenylmethanol having been the most successful alcohol in Ritter reactions mediated by PEDOT in acetonitrile and the belief that benzonitrile should be deactivated because of the electron-withdrawing nature of the benzene ring. Because of this, it should follow that any optimizations useful to benzonitrile would be useful to other nitriles. The results obtained using PEDOT were compared with sulfuric acid, a more traditional initiator of Ritter reactions (Table 2). While work on these stoichiometric reactions is ongoing, this was the first instance in which we were able to show that PEDOT can be used as a mediator in Ritter reactions of alcohols and nitriles in non-nitrile solvents. 10 From here, we were able to confidently pursue the previously mentioned reactions between benzyl alcohol (35) and diphenylmethanol with a variety of nitriles. As previously mentioned, understanding the mechanism of PEDOT-mediated reactions is not only synthetically important, but may also lead to the production of novel polymer reagents at lower costs than PEDOT. The reactions of triphenylmethanol (36) and adamantanol (37) both suggest that the PEDOT is being approached directly by the alcohol. This finding was concluded from the difficulty associated with performing these reactions. With triphenylmethanol, PEDOT showed no reaction, but sulfuric acid and Amberlite, which function by way of an H+, both furnished high yields. The diphenylmethanol had a relatively good yield with PEDOT, but took approximately 32 hours to reach completion. 11 Our studies suggest that PEDOT behaves as an alcohol-selective Lewis acid, and that it is not the presence of a polymer-bound acid that is catalyzing the reaction. Given that the Ritter reaction can take place between alcohols, alkenes, and halides, reactions utilizing styrene (Figure 3) and benzyl chloride (Figure 4) were done in refluxing acetonitrile. Benzyl chloride would ordinarily react with other Lewis Figure 4: Benzyl acids and the fact that both it and styrene showed no Figure 3: chloride Styrene observable reaction via GCMS