758 J . Org. Clzem., Vol. 44, No. 5, 1979
Zoutendam and Kissinger
Novel Electrohydrodimerization of N-Substituted Maleimides in Aqueous Media Paul H. Zoutendam and Peter T. Kissinger” Department of Chemistry, Purdue University, West Lafayette, Indiana 47907 Received August 15,1978 The electroreduction of N-substituted maleimides in neutral aqueous media is shown to yield hydrodimers via electrohydrodimerization, EHD. Previous studies on the electroreduction of diactivated olefins have concluded that an aprotic environment is necessary for EHD to occur. This novel behavior of N-substituted maleimides is examined by polarography, coulometry, bulk electrolysis, and product analysis. The reduction products were identified on the basis of microanalysis, lH NMR, 13C NMR, mass spectrometry, and gas chromatography retention data. Several possible mechanisms are examined and a radical-radical coupling mechanism is proposed as the predomi(IC) were nant pathway. N-Ethylmaleimide (la),N-ethylcitraconimide ( l b ) ,and 3,4-dimethyl-N-ethylmaleimide selected as representative N-substituted maleimides for this study.
There have been a number of recent reports describing detailed studies of the formation of hydrodimers from the electrolytic reduction of diactivated olefins, in a process called electrohydrodimerization (EHD). The available evidence suggests that in most cases EHD involves the direct coupling of anion radicals followed by protonation of the resulting dianion.l4 To obtain a high yield of the dimer an aprotic solvent must be used. If the concentration of water (or other proton donors) is significant, the anion radical is rapidly protonated forming a neutral radical. Since the neutral radical is normally easier to reduce than 1he starting material, it rapidly accepts another electron and then a proton to form a dihydromonomer. Hence, if protons are readily available, no dimer is formed. Alternately, a good yield of dimer may be obtained by using a high concentration of a large organic ion, e.g., tetraethylammonium p -toluenrsulfonate, as a supporting electrolyte. It has been argued that these relatively hydrophobic ions produce a “water poor” region at the surface of the electrode, approximating aprotic conditi0ns.j Studies on the interaction of N-ethylmaleimide, la, with sulhydryl compounds led to our discovery that maleimides form hydrodimers in high yield in aqueous media at neutral pH. The unique behavior of N-substituted maleimides, compared with previously studied diactivated olefins, is the subject of this paper. There has been little previous work on the electrochemistry
of the maleimides. A classical, dc polarographic study noted the influence of different N-substituents on the reduction potential of maleimides, but no product analysis was carried out.6 The exhaustive electrolysis of maleimide itself has been d e ~ c r i b e dThis . ~ report noted that the reduction product a t low pH (below pH 5) was succinimide. At intermediate pH values (pH 5-8) an unidentified product was obtained. We report here the isolation of the reduction product of N-ethylmaleimide, la, as the hydrodimer of la, bis[3,3’-(N-ethylsuccinimide)], 3a. To aid in identifying the reduction products and elucidating the mechanism, two additional substrates were synthesized, 3-methyl-N-ethylmaleimide, 1b, (N-ethylcitraconimide), and 3,4-dimethyl-N-ethylmaleimide, IC. The electrochemical behavior of these compounds as a function of pH was explored. Half-wave potentials, apparent n values (number of electrons consumed per substrate molecule), gas chromatographic retention data, and spectroscopic information have been analyzed in terms of the reduction mechanism. Experimental Section
3a: R,=H 3b: R l = CH3
Sampled dc polarography was performed on a Princeton Applied Research Model 174 polarographic analyzer using 0.5 mM samples. The supporting electrolyte consisted of a 3:l (by volume) mixture of the appropriate McIlvaine buffer and 95% ethanol. A 1 s drop time, and 1 mV/s scan rate were used. The reference electrode for all electrochemical experiments was either a saturated sodium calomel (SSCE) or an aqueous AgiAgCl(3 M NaC1) electrode (Bioanalytical Systems Model RE-1). Coulometric experiments were carried out using a conventional operational amplifier potentiostat. The current was measured using an operational amplifier current-to-voltage converter and the resulting voltage was integrated via a voltage-to-frequency converter and a digital counter. A Pyrex cell (i.d. 34 mm; height, 8.0 cm) having a capacity of 50 mL was used with a mercury pool electrode of approximately 9.0 cm2. Contact to the mercury pool was made via a platinum wire which entered the cell through a small side arm. The reference electrode, a glass stirrer, a coarse frit for solution degassing (Ace Glass No. 9435-08), and a central auxiliary electrode compartment (terminated with a 10-mm diameter coarse glass frit) were inserted through a tightly fitting Teflon top. A 7-mm spectroscopicgrade graphite rod was used for the auxiliary electrode. A similar but larger cell was used for preparative electrolyses (i.d. 47 mm, height 10 cm, auxiliary electrode compartment-15 mm coarse frit, working electrode area approximately 17.0 cm2,capacity 100 mL). Electrolysis was conducted using a locally constructed 0.5-A potentiostat and the current measured by observing the potential drop across a small resistor in the auxiliary electrode circuit using a high impedance digital voltmeter. ‘H and 13C NMR spectra in CDC13were obtained using a PerkinElmer R32 90-MHz instrument and a Varian CFT-20, respectively. Electron impact (22.5 eV) mass spectrometry was performed on either an LKB-9000 with a gas chromatograph sample inlet system or a Varian MAT-CH5 with a direct probe inlet system. Microanalyses were carried out by the Microanalysis Laboratory, Department of Chemistry, Purdue University
0022-3263/79/1944-0758$01.00/0
1979 American Chemical Society
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J . Org. Chem., Vol. 41,No. 5,1979 759
Electrohydrodirnerization of N - S u b s t i t u t e d Maleimides
Table I. Half-Wave P o t e n t i a l as a Function of pH A Hewlett-Packard HP-5700 and a Varian Aerograph 2400 gas chromatograph were used with flame ionization detectors. A 6 ft X Ice l ac lbd in. stainless s k e l column of 3% SE-30 on Chromosorb W-AWpH 1st wave 2nd wave Xt wave 2nd wave 1st wave" DCMS (100/120 mesh) was used in the HP-5700. The operating conditions were as follows: He flow = 20 mL/min, Hz flow = 20 2.21 -0.51b -0.60 -0.69 mL/min, air flow = 200 mL/min, detector temperahre = 250 "C, in2.69 -0.56 -0.67 -0.77 jector temperature = 200 "C, temperature program (Ti) = 100 "C (4 3.06 -0.61 -0.72 -0.81 min), rate = 32 "Cimin, 1'1 = 230 "C (4 rnin). A 6 ft X /,3' in. stainless 3.51 -0.66 -0.77 -0.87 steel column of 1.5% OV-101 on Gas Chromosorb Q (100/120 mesh) 4.04 -0.71 -0.81 -0.90 was used in the Varian 2400 with He flow = 30 mL/min, Hz flow = 30 5.00 -0.75 -1.20 -0.86 -1.27 -0.96 mL/min, air flow -= 250 m l / m i n , detector temperature = 250 "C, in6.00 -0.77 -1.19 -0.90 - 1.26 -1.02 jector temperatuw = 200 "C. temperature program (Ti) = 100 "C (4 7.00 -0.77 -1.19 -0.91 -1.25 -1.04 minj, rate = 30 OC/min, jni = 220 "C (4min). 8.07 -0.78 -1.19 -0.91 -1.24 -1.06 Preparative gas chromatography was carried out using a Varian Aerograph 920. A 10 ft X in. aluminum column packed with 15% a A second wave was n o t observed for IC over t h e entire p H SE-52 on Chrtrmosorb G (70/80 mesh) was used. Up to 100 GL (-100 range studied. Potential vs. t h e sodium saturated calomel mg) of the crude product mixture was injected. Samples were collected electrode. Registry no., 128-53-0. Registry no., 31217-72-8. over liquid nitrogen. e Registry no., 34316-72-4. Coulometry. In a typical experiment 20 mL of solution was used to conserve materials and time. The cell was filled with the supporting electrolyte solution. This was deoxygenated and electrolyzed until 3,4-Dimethylsuccinimide (2c). Electrolysis of 3,4-dimethylthe background current was below the threshold of the integrator. The maleimide ( I C )a t any p H (from p H 2-8) and any potential more purpose of this step was tci help purify the mercury. The solution was negative than -1.0 V vs. AglAgCl results in the production of two then aspirated out of the cell with a glass capillary (Pasteur pipet). forms of 3,4-dimethy1-N-ethylsuccinimide, designated 2c and 2c'. The cell was rinsea twice with doubly distilled water and emptied by Both are liquids a t room temperature. The isomers were purified by aspiration. Twenty mil!iliters of supporting electrolyte solution preparative gas chromatography. (2c has the shorter retention time.) contaiiiing a knoun amount of the compound of interest was then For a mixture of 2c and 2c', mass spectrometry gives m / e (re1 intenadded to the cell. The fritted auxiliary electrode compartment was sity) 155 (18), 140 (100),82 (7),56 (32). refilled with fresh electrolyte. The cell was deoxygenated with 2c: IH NMR 6 3.52 (q, 2 H, J = 7.5 Hz),2.38 (m, 1 H), 1.32 (d, 3 H), bubbling nitrogen for 15 min prior to electrolysis and throughout the 1.15 (t,3 H , J = 7.5 Hz). Anal. Calcd for C8H1:$J:Oa: C, 61.91; H. 8.44; experiment. A typical electrolysis required 1 to 2 h, for the current N, 9.03. Found: C, 61.69: H , 8.47; N, 8.81. to decay to less than 5% or' its initial value, depending on the con2c': 'H NMR 6 3.52 (q, 2 H, J = 7.5 Hz), 2.90 (m.1 H), 1.21 (d, 3 H), centration of the reactant. Two electrolyses were carried out before 1.14 (t, 3 H, J = 7.5 Hz). Found: C, 61.70: H, 8.43: N. 8.83. the mercury was ri:placed and the preelectrolysis step repeated. Synthesis of N-Ethylcitraconimide ( 1b) a n d 3,4-DimethylP r e p a r a t i v e Electrolysis. For a typical electrolysis 100-400 mg N-ethylmaleimide (IC).The general procedures of Coleman, Bork, of compound was dissolved in 25 mL of 95% ethanol and added to 75 and Dunn8 and Miyadera and Kosowerg were used for the synthesis mL of McIlvaine buffer containing 0.3 M KN03 for additional ionic of l b and IC. Rather than use a reduced pressure distillation, a strength. The solution was deoxygenated for 15 min with Nz and the Dean-Stark condenser was used to collect the water that is driven off Nn bubbling contir~uedthroughout the electrolysis. The solution was during ring closure. st,irred by a magnetic stir bar (7/8 in. X 5/16 in.) floating on top of the N-Ethylcitraconimide ( 1 b) [or 2-Methyl-A'-ethylmaleimide]. Hg. Electrolysis was continued until the current decayed to less than Citraconic anhydride, 18.0 mL (0.2 mol) (Aldrich).was dissolved in 5% of the initial cdrrent. After an electrolysis was completed, the 2*50mL of xylene in a 500-mL three-neck round-bottom flask. Anelectrolyte solution was extracted three times with chloroform (1 X hydrous ethylamine (Eastman) (15.0 mL, 0.2 mol) w a ~ dissolved in 25 mL, 2 X 15 mI.). The combined chloroform extracts were back 100 mL of benzene. These were reacted :iccordiiig t o the published extracted twice wiih 25 mI, of doubly distilled water to remove rep r o c e d ~ r eAfter . ~ reducing the volume hy removing some xylene, the sidual supporting electroly te and then dried over anhydrous NaZSO1. reaction mixture was transferred to a IO0 m L Hantamware roundThe chloroform was then stripped off using a rotary evaporator. The (12 mm bottom flask. The product was vacuum distilled a t 86 -if0 isolated product mix was purified further or taken up again in a known Hg) (lit.y93 "C (13 mm Hg)i through a l5O-mni Vigreitx column using amount of chloroform for product distrihution studies by gas chroa short path distilling head and a cow receiver. T h e yield was ca. -i0~,: matography. ' H NMR 6 6.35 (d. 1 H, I > = 2 H 3 iq. 2 H. I J = 7.: Hzi. ?.OH (d. :I N-Ethylsuccinimide (2a). N-Ethylsuccinimide (2a) was proH. 1' = 2 Hz), 1.17 (t. 3 H. I < = 7.5 Hz): m / v (re1 intensityi I:EI (L8),11'4 duced via controlled potential electrolysis of N-ethylmaleimide ( l a ) 1100). 69 (e),68 (16), 65 ( 1 4 ) . 56 (15). at pH 2.2 and E = -11.8V v s AglAgC1. The product was recrystallized 3,1-Dimethyl-N-ethylmaleimide(IC). Dimethyl maleic anhyfrom ether in a 2-propanot/dry ice bath. 2a is a liquid at room temdride, 1.89 g (0.015mol) (Aldrich), was added to 25 mL of benzene in perature: 'HNMR i, 4.54 iq, 2 H, J = 7.5 Hz), 2.69 (s, 4 H), 1.14 (t, 3 a 100 mL three-neck round-bottom flask. Ethylamine, 1.0 mL (0.015 H , J = 7.5 Hzi: m/e ire1 intensity) 125 (100),113 (12), 112 ( l l ) 99 , (13), mol), was diluted with 15 mL of benzene and added to the reaction 84 (361,56 (56). mixture. The product was vacuum distilled at 93-95 "C ( 13.5 mrn Hg) :~-MethyI-N-etliylsuccimide(2b). 2b was produced by electrol(lit.9 105 "C (15 mm Hg)): 'H NMR 6 3.52 (q, 2 H. u = 7.5 Hz), 1.94 (s, i l b ) at pH 2.2 and E = -0.9 V vs. ysis of:i-methyl-Y-etIi~Im;~ieimide 6 H), 1.15 (t,3 H, u = 5.5 Hz); m/f 153 (46), 139 (51,138 i100), 110 i4.3), Agl AgCI. The product was recry-stallized from ether in a 2-propa
