Amine Mediated Photoreduction of Aryl Ketones in N-Heterocyclic

Chapter 30

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Amine Mediated Photoreduction of Aryl Ketones in N-Heterocyclic Ionic Liquids: Novel Solvent Effects Leading to Altered Product Distribution Paul B. Jones*, John L. Reynolds, Robert G. Brinson, and Ryan L. Butke Department of Chemistry, Wake Forest University, Winston-Salem, NC 27109

Amine mediated photoreduction of benzophenones in N -heterocyclic ionic liquids produces the corresponding benzhydrols as the major product instead of the expected benzpinacols. The ratio of benzhydrol to benzpinacol is a function of the reduction potential of the intermediate ketyl radical. Results consistent with a mechanism involving a dark electron transfer between the ketyl radical and α-amino radical are presented. Other important factors contributing to the observed benzhydrol/benzpinacol ratio are solvent viscosity and reduction potential ofthecation.

370

© 2003 American Chemical Society In Ionic Liquids as Green Solvents; Rogers, R., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2003.


371 Room temperature ionic liquids (RTILs) are salts that remain molten at, or below, 25 °C. Salts of this kind have been known for many years and have been the subject of intensive study.(i,2) For much of the history of ionic liquids, the most comprehensive investigations have related to their use in electrochemical applications.(J ) More recently, the possibility of using RTILs as "green" alternatives to conventional solvents has ignited new interest in these unique compounds.(Z) Because RTILs are non-volatile, and because many have limited solubility in water and hydrocarbons, solutes may be easily removed via extraction or distillation allowing the RTIL to be recycled. The use of RTILs, therefore, may greatly reduce volatile waste in chemical processes. The RTILs developed in the lastfifteenyears are stable to air and water and are significantly less corrosive than "first generation" RTILs.(2) Ionic liquids show promise as "green" solvents and a number of research groups have already produced clever and exciting results in this regard.(7-^) However, to fully realize the green potential of RTILs, much remains to be done. Recognition of the potential for the use of RTILs in green chemical processes resulted in the investigation of a number of reactions in new, waterstable RTILs. These include Diels-Alder cycloadditions,(5) alkene halogenations,(d) Stille couplings,(7) and even enzymatically catalyzed reactions(5) among many others. Furthermore, the need to tailor solvent to reaction has prompted several groups to develop "custom" ionic liquids. A good example is the preparation of an amino-substituted RTIL designed specifically for the removal of carbon dioxidefromgas streams.(P) Given the environmentally benign nature of photochemistry, we believe that carrying out photochemical reactions in a reusable solvent system could form the basis of a clean method for functional group transformation (Figure 1). Photochemical investigations in chloroaluminate salts showed that the radical cation and radical anion of 9-methylanthracene were produced, in the same experiment, upon irradiation of solutions of anthracene in the RTIL.(iO)

substrate

product

Figure 1. Resusable synthetic photochemistry system.

In Ionic Liquids as Green Solvents; Rogers, R., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2003.


372 Later, photoinduced electron transfer in ionic liquids and the abstraction of hydrogen atomsfromdialkylimidazolium cations by excited benzophenone were studied byflashphotolysis.(/1,12) Investigations of RTILs under pulse radiolysis conditions confirmed that ionic liquids are ideal media in which to conduct radical ion chemistry.(Z3,i¥) Both alkylpyridinium and dialkylimidazolium cations were reduced by solvated electrons to yield neutral radicals. These radicals exhibit quite different behavior. The imidazolium radicals were oxidized only by powerful oxidants and at unexpectedly slow rates. In contrast, reduced alkylpyridinium ions were oxidized by a variety of oxidizing agents at a rate near diffusion-controlled. These observations prompted our consideration of radical pair/ion pair equilibria in RTILs. Radical pairs exist in equilibrium with their corresponding ion pairs and this equilibrium can be affected by external conditions, such as solvent polarity. Given the ionic nature of RTILs, we hypothesized that reactions that normally proceed through a radical pair will instead produce ion pairs when carried out in RTILs {Figure 2). We have since tested this hypothesis and report the results of our investigation to date below.(ii) Ionic Liquid

Α·

Β"

Α®

ΒΘ

Conventional Organic Solvent Figure 2. Ion-Pair/Radical Pair Equlibrium Hypothesis.

A simplified mechanism for amine mediated photoreduction is shown in Figure 3.(16) Charge transfer following excitation of 1 gave a solvent separated radical-ion pair, which diffused to a contact radical-ion pair. Proton transfer produced 2 and 3, which reduced a second ketone. Coupling of the resulting ketyl radicals gave pinacol (4) and imine (5). Other evidence suggested an ionic pathway. Photoreduction of 4-benzoylbenzoic acid in aqueous amine gave the benzhydrol.(7 7) Later studies showed that this was general; when benzophenones bearing electron-withdrawing groups were photoreduced, products (6 and 5) consistent with the formation of ions (7 and 8) were produced as the primary products.(iS) Our hypothesis predicted that the reaction pathway of the photoreduction would be altered to favor ion pair 7/8 over radical pair 2/3. This prediction led to the expectation that photoreduction of benzophenones in RTILs


373

Ar^Ar 1

RCH2NH2

^ A r · 2 3 I SET ?

H

Ar^Ar

R

NH

® 8


neutralconventional solvents

Ά

^

2

fojifc-

Α / Λ 4

5

Γ ^ Λ ^

Jims

Figure 3. Mechanism of amine mediated aryl ketone photoreduction (reproducedfromreference 16. Copyright 2002 American Chemical Society.)

would result in the corresponding benzhydrol rather than the usual benzpinacols. Our results to date are presented in the following section.

Results and Discussion Product Ratios in Benzophenone Photoreduction Initial investigation demonstrated that amine-mediated benzophenone photoreduction in RTILs provided products (the corresponding benzhydrol, (6) that support the existence of an ionic pathway in the reaction. Control experiments confirmed that reduction did not occur in the absence of either light or amine and that base-catalyzed disproportionation of the pinacol did not account for the formation of benzhydrol. Benzophenone was photoreduced by .sec-butylamine in l-butyl-3-methylimidazolium tetrafluoroborate (BMIBF4) to benzhydrol, which was isolated in 90% yield (Table I, entry 3). Benzophenones with electron withdrawing groups on the ring(s) were also photoreduced to the benzhydrol, as expected from the literature (entries 5 and 6).(18) Only benzophenones with strong electron donating groups yielded any benzpinacol; 4-methoxybenzophenone was photoreduced under these conditions to give an 75:25 mixture of benzhydrol to benzpinacol (entry 8), while 4,4-dimethoxybenzophenone gave a 45:55 mixture of the corresponding benzpinacol and 4,4dimethoxybenzhydrol (entry 9). Acetophenone was photoreduced to give the pinacol as the sole product. Therefore, the major product is, apparently, dependent on the reduction potential of the intermediate ketyl radical (2), which supports the mechanism proposed in Figure 3.


374 Table I. Product Distribution in sgc-Butylamine Mediated Photoreduction entry benzhydrol benzpinacol compound RTIL 1 >95 s-butylammonium 0 benzophenone trifluoroacetate 2 >95 0 benzophenone EMI(OTf) 3 benzophenone >95 (90) 0 BMI(BF ) 4 BMM1(BF ) >95 0 benzophenone — — 5 benzophenone BuPic(BF ) 5 methyl 2-benzoyl BMI(BF ) >95 0 benzoate 0 6 >95 methyl 3-benzoyl BMI(BF ) benzoate 0 7 >95 (90) 4,4'-dichloro BMI(BF ) benzophenone 8 4-methoxy BMI(BF ) 75 25 benzophenone 9 4,4'-dimethoxy BMI(BF ) 45 (22) 55 benzophenone 10 4,4'-dimethoxy 30 70 EMI(OTf) benzophenone 11 4,4'-dimethoxy BMMI(BF ) 50 50 benzophenone 12 acetophenone BMI(BF ) 0 >95 13 acetophenone EMI(OTf) 0 >95 NOTE: Data represent ratios determined by Ή NMR. Isolated yields are shown in parentheses. SOURCE: Some data are takenfromreference 16. Copyright 2002 American Chemical Society. 4

4

4


4

4

4

4

4

4

4

Solvent Effects and Role of the Cation Because 4,4-Dimethoxybenzophenone (9) provides both benzhydrol (10) and benzpinacol (11) products when photoreduced in most RTILs, die compound provides a measure of the ionic liquid effect on ketone photoreduction. Photoreduction of (9) in a variety of RTILs revealed that the nature of the RTIL affected the product ratio (Table II)· There appears to be some correlation of the product ratio to the basicity of the anion in the RTIL, though this is far from an exhaustive list. A similar study involving a larger series of RTILs is underway. Ketone photoreductions in JV-butylpicolinyl tetrafluoroborate (BuPic(BF )) did not provide either the benzhydrol or benzpinacol (Table Π, entry 10). After 24 hours of irradiation, no consumption of ketone was observed. Because the lowest triplet state of pyridinium salts is approximately 4


375 25 kcal/mole higher than that for the benzophenone triplet, it is unlikely that the solvent is quenching the reaction through energy transfer.(iP) Instead, the cation appeared to be reduced by the ketyl radical (and, possibly, the amino radical) resulting in dimer formation (Figure 4). Although we had not isolated high yields of the BuPic dimer, we did positively identify it in the H NMR spectrum of the crude photolysis mixture. The dimer appeared to be prone to decomposition under the reaction conditions. This observation was a general trend; all aryl ketones studied failed to undergo photoreduction in BuPic(BF ). !


4

f

Table Π. Photoreduction of 4,4 -Dimethoxybenzophenone in RTILs. St^

RTIL

Mi

OMe

10

entry 1 2 3 4 S 6 7 8 9 10

RTIL BMI (OTf) EMI (OTf) EMt(BF ) BMI (OTs) BMI (BF ) EMI (N0 ) BMI(PF ) BMI (N0 ) BMMI(BF ) BuPic(BF ) 4

4

3

6

3

4

4

11

10 30 30 35 40 45 50 55 75 50

11 70 70 65 60 55 50 45 25 50

—

—

NOTE: Data represent ratios. Determined by H NMR. SOURCE: Some data takenfromReference 16. !

Given the observation that benzhydrols form only when the photoreduction was carried out in imidazolium based RTILs, we performed a series of reductions with varying amounts of imidazolium present. These results are shown in Table III. The results in Table III demonstrate that small amounts of the BMI cation do not result in a shift of product toward benzhydrol. While this observation did not rule out the possibility that the cation played an active role in the reaction, it did indicate that small amounts of cation are not enough to



376

Ν

ι Bu Figure 4. Photoreduction in

BuPicfôFJ.

Table III. Photoreduction of benzophenone in the presence of varying amount of BMI cation. entry

solvent

benzhydrol

benzpinacol

1 2 3 4 5 6 7

sBA-TFA secbutylamine secbutylamine + 1 equiv. BMI(BF ) secbutylamine + 5% (w/w) BMI(BF ) secbutylamine + 10% (w/w) BMI(BF ) BMI (BF ) + IM secbutylamine BMMI (BF ) + IM secbutylamine

95 >95 >95

Amine Mediated Photoreduction of Aryl Ketones in N-Heterocyclic

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