Oxidative cleavage of gabapentin with N-bromosuccinimide in ... - NOPR

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Indian Journal of Chemistry. Vol. 48A, August ... Department of Studies in Chemistry, University of Mysore,. Manasagangotri .... indicating the absence of free radical species in the reaction .... transfer, the rate increases in D2O medium, since. D3O+ and .... 35 Isaacs N S, Physical Organic Chemistry (Wiley, New York). 1987.
Indian Journal of Chemistry Vol. 48A, August 2009, pp. 1107-1112

IPC Code: Int. Cl.9 C07B33/00

of neuroleptic drug). In view of its importance several analytical methods including high performance liquid chromatography (HPLC)8, gas chromatography coupled with mass spectrometry 9 as well as capillary electrophoresis10,11 have been reported for the determination of the drug in biological fluids. Kinetic study of oxidation of gabapentin by chloramine-T in HClO4 medium has also been reported12. N-bromosuccinimide (NBS) is a source of positive halogen and this reagent has been exploited as an oxidant for a variety of substrates13-17 in both acidic and alkaline solutions. The use of NBS as an oxidant is extensive in the determination of a number of organic compounds18-21. However, little information exists in the literature on NBS reactions, with respect to the oxidation kinetics of pharmaceuticals22,23 which may throw some light on the mechanism24 of metabolic conversions in biological systems. In view of these facts, there is a considerable scope for the study of reactions with NBS to get better insight of the speciation of NBS reaction models and to understand its redox chemistry in solutions. We report herein the detailed kinetics of oxidation of GBP with NBS in HClO4 medium. This study was carried out with a view to elucidate the mechanism of the reaction, put forward appropriate rate law, identify the oxidation products of the reaction and ascertain the reactive species of oxidant.

Gabapentin (neurontin) (GBP) is a neuroleptic drug and is important because of its biological significance and selectivity towards the oxidant. GBP has been introduced as an anti-convulsant agent that is useful as an add-on therapy in the treatment of epileptic seizures1. It has also been shown to be a potential drug for treatment of neurogenic pain2-4. Gabapentin was originally designed as a lipophilic γ-amino butyric acid (GABA) analogue5, but has subsequently been shown not to interact with any of the enzymes on the GABA metabolic pathway nor does it interact directly with the GABAA or GABAB receptors6. However, it is able to efficiently cross the blood brain barrier via an L-system amino acid transporter7. GBP has been prescribed off-label for the treatment of some mood disorders, anxiety and tardive dyskinesia (a neurological syndrome caused by the long-term use

Experimental An aqueous solution of NBS was prepared afresh each day from a GR Merck sample of the reagent and its strength was checked by the iodometric method. Solution of gabapentin (obtained as a gift sample from Hikal Ltd., India) was prepared by dissolving appropriate amount of the recrystallised sample in doubly distilled water. The purity of GBP was checked by comparing its IR spectrum with literature data. The required concentration of GBP was used from its aqueous stock solution. All other reagents used were of analytical grade. Doubly distilled water was used throughout the investigation. All kinetic measurements were performed in glass stoppered Pyrex boiling tubes coated black to eliminate photochemical effects. The reactions were carried out under pseudo-first order conditions by

Oxidative cleavage of gabapentin with N-bromosuccinimide in acid medium: A kinetic and mechanistic study P M Ramdas Bhandarkar & K N Mohana* Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570 006, India Email: [email protected] Received 13 April 2009; revised and accepted 2 July 2009 The kinetics of oxidative degradation of gabapentin with N-bromosuccinimide in HClO4 medium has been studied at 308 K. The experimental rate law obtained is − d [NBS] = [NBS][GBP]x [H + ]y , where x and y are less than unity. dt

The reaction was subjected to changes in concentration of succinimide, the reduction product of NBS, concentration of the added neutral salt, dielectric permittivity and ionic strength of the medium. Solvent isotope effect has been studied using D2O. The stoichiometry of the reaction has been found to be 1:1, and oxidation products have been identified and characterized by FTIR and 1H NMR spectral studies. Activation parameters for the overall reactions have been computed from Arrhenius plot. (CH2CO)2N+HBr has been postulated as the reactive oxidizing species. The oxidation reaction fails to induce polymerization of the added acrylonitrile. The proposed mechanism and the derived rate law are consistent with the observed kinetic data. Keywords:

Kinetics, Reaction Gabapentin

mechanisms,

Oxidations,

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INDIAN J CHEM, SEC A, AUGUST 2009

taking a known excess of [GBP]o over [NBS]o at 308 K. Appropriate amounts of GBP, HClO4 solution, mercuric acetate, sodium perchlorate and water to keep the total volume constant at 50 ml, were equilibrated at constant temperature (± 0.1 oC). A measured amount of NBS solution also preequilibrated at the same temperature was rapidly added to the mixture. The progress of the reaction was monitored by estimating the amount of unconsumed NBS at regular time intervals iodometrically. The course of the reaction was studied for at least two half-lives. The pseudo-first-order rate constants (kobs) calculated from the linear plots of log [NBS] versus time were reproducible within ± 4%. Regression analysis of the experimental data to obtain regression coefficient, r, was performed using MS Excel. IR spectra were recorded on a Jasco FT-IR spectrometer using KBr pellets. 1H NMR spectra was recorded on a Bruker 400 MHz NMR spectrometer using CDCl3 as solvent and TMS as internal reference. Reaction mixtures containing varying ratios of NBS and GBP in the presence of 0.005 mol dm-3 HClO4 at 308 K was kept aside for 48 h, so that the substrate was completely converted into products. Estimation of the unreacted NBS showed that one mole of substrate utilized one mole of oxidant, confirming the following stoichiometry (Eq. 1): C9H17O2N + (CH2CO)2 NBr C7H12 + CH3N + CO2 + (CH2CO)2NH + HBr … (1) The products in the reaction mixture were extracted several times with ether. The combined ether extract was evaporated and subjected to column chromatography on silica gel (60 - 200 mesh) using gradient elusion (chloroform). After initial separation, the solid product was further purified by recrystallization. The reduction product of NBS, succinimide (CH2CO)2NH, and oxidation product of GBP methylene cyclohexane, were detected by spot tests25, and confirmed by FTIR and 1H NMR spectral data. IR data: (CH2CO)2NH - A broad band at 3450 cm-1 for NH stretching mode and a sharp band at 1698 cm-1 for C = O stretching mode. Methylene cyclohexane-1640 cm-1 (C = C stretch) and 2870 cm-1 (C-H stretch in methylene). 1H NMR data: Methylene cyclohexane - 1.38 (m, 10H, cyclohexyl methylenes group), 4.75 (s, 2H, CH2).

Results and discussion The oxidation of GBP with NBS was kinetically investigated at several initial concentrations of the reactants in HClO4 medium at 308 K. Under pseudo-first-order conditions ([GBP] >> [NBS]) at constant [HClO4] and temperature, plots of log [NBS] versus time were linear (r ≥ 0.998) indicating a first-order dependence of rate on [NBS]o. The pseudo-first order rate constants (kobs) calculated is given in Table 1. Further, the values of kobs calculated from these plots are unaltered with variation of [NBS]o confirming the first order dependence on [NBS]o. The rate increased with increase in [GBP]o (Table 1). A plot of log kobs versus log [GBP] was linear (r = 0.999) with a slope of 0.52, indicating fractional order dependence of rate on [GBP]o. The rate increased with increase in [HClO4] (Table 1). A plot of log kobs versus log [HClO4] was linear (r = 0.998) with a slope of 0.58 indicating fractional order dependence of the rate on [HClO4]. The effect of initially added product, succinimide, was studied in the concentration range from 0.0002 to 0.001 mol dm-3, keeping all other concentrations constant. It was found that the added product had no significant effect on the reaction rate. Addition of mercuric acetate (0.001-0.005 mol dm-3) to the reaction mixture also had no significant effect on the rate. At constant [H+], addition of chloride ions in the form of NaCl did not change the rate of reaction. The effect of dielectric permittivity (D) on the reaction rate was studied by adding various Table 1―Effect of varying concentrations of oxidant, substrate and HClO4 on the reaction rate at 308 K. {µ = 0.1 mol dm-3; [Hg(OAC)2] = 1×10-3 mol dm-3}

a

104[NBS] (mol dm-3)

103[GBP] (mol dm-3)

103[HClO4] (mol dm-3)

kobs ×104 (s-1)

1.0 3.0 5.0 7.0 9.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0a 5.0b

8.0 8.0 8.0 8.0 8.0 4.0 6.0 10.0 12.0 8.0 8.0 8.0 8.0 8.0 8.0

5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 3.0 4.0 6.0 7.0 5.0 5.0

3.40 3.45 3.42 3.47 3.46 2.29 2.88 3.79 4.16 2.60 3.02 3.80 4.13 3.48 3.43

µ = 0.15 mol dm-3 ; b µ = 0.25 mol dm-3

NOTES

proportions of CH3CN (0 - 20% v/v) to the reacting system. The rate decreased with increasing CH3CN content and the results are shown in Table 2. Plot of log kobs versus 1/D was linear (r = 0.997) with a negative slope. The values of permittivity (D) for CH3CN-H2O mixtures were calculated from the equation, D = DwVw + DAVA, where Dw and DA are the dielectric permittivities of pure water and acetonitrile and Vw and VA are the volume fractions of components, water and acetonitrile in the total mixture. Blank experiments indicated that CH3CN was not oxidized with NBS under the experimental conditions employed. Variation of ionic strength of the medium (0.1-0.3 mol dm-3) using NaClO4 solution had no significant effect on the rate. Solvent isotope study in D2O medium was also carried out. The value of kobs (H2O) is 3.42 and that of kobs (D2O) is 2.61 leading to solvent isotope effect, kobs (H2O)/kobs (D2O) = 1.30. Proton inventory studies were made in H2O-D2O mixtures, and it was observed that the reaction rate decreased (3.34 × 10-4 – 2.61 × 10-4 s-1) with increasing atom fraction (n) of D2O (0.25-0.95). Kinetic and thermodynamic parameters were calculated by studying the reaction at various temperatures (303-321 K). A plot of log kobs versus 1/T was linear (r = 0.999) and the results are given in Table 3. Addition of aqueous acrylonitrile monomer solution to the reaction mixture in an inert atmosphere did not initiate polymerization, indicating the absence of free radical species in the reaction sequence. NBS is a two equivalent oxidant which oxidizes many substrates through NBS itself or by Br+, RN+HBr or hypobromite anion. The reactive species responsible for the oxidizing character may depend on the pH of the medium. Depending on the pH of the medium, NBS furnishes different types of reactive species in solutions26-28 as shown in Eqs (2) – (7), Table 2―Effect of varying dielectric permittivity of the medium on the reaction rate at 308 K. {[NBS] = 5 ×10-4 mol dm-3; [GBP] = 8 ×10-3 mol dm-3 ; [HClO4] = 5 ×10-3 mol dm-3; [Hg(OAC)2] = 1×10-3 mol dm-3 ; µ = 0.1 mol dm-3} CH3CN (%, v/v)

D

kobs ×104(s-1)

0 5 10 15 20

73.6 71.8 70.0 68.2 66.5

3.42 2.82 2.38 1.92 1.30

1109 RN+HBr RNH + HOBr OBr- + H2O RNH + Br+ (H2OBr)+ RNH + OBr-

RNBr + H+ RNBr + H2O HOBr + OHRNBr + H+ Br+ + H2O RNBr + OH-

… (2) … (3) … (4) … (5) … (6) … (7)

where R is (CH2CO)2. In acid medium, the probable reactive species of NBS are NBS itself or Br+ or protonated NBS (RN+HBr), and the reactive species in alkaline solutions are NBS itself or HOBr or OBr-. It may be pointed out that, all kinetic studies have been made in presence of mercury(II) acetate in order to avoid any possible bromine oxidation which may be produced as shown in Eq (8). O NBr

O

HBr

O

Br2

NH O

… (8) Mercuric acetate acts as a capture agent for any Brformed in the reaction. It exists as HgBr42- or unionized HgBr2 and ensures that oxidation takes place purely through NBS29 . Most investigations of NBS oxidations of organic substrates have assumed that the molecular NBS acts only through its positive polar end30. In the present investigation, acceleration of the rate by increasing concentration of H+ assumes that protonated species of NBS, i.e., RN+HBr, is the most likely oxidizing species. Further, the insignificant effect of initially added product succinimide (RNH) allows us to Table 3―Effect of varying temperature on the reaction rate and activation parameters for the oxidation of GBP. {[NBS] =5 ×10-4 mol dm-3 ; [GBP] = 8 ×10-3 mol dm-3; [HClO4] = 5 ×10-3 mol dm-3 [Hg(OAC)2] = 1×10-3 mol dm-3; µ = 0.1 mol dm-3} Temp. (K)

kobs ×104(s-1)

303 308 313 318 321 Ea(kJ mol-1) ∆H≠ (kJ mol-1) ∆G≠ (kJ mol-1) ∆S≠ (JK-1 mol-1)

1.97 3.42 5.72 9.55 13.18 83.15 80.55 96.16 -49.95

INDIAN J CHEM, SEC A, AUGUST 2009

1110

assume RN+HBr as the active oxidizing species. The protonated NBS reacts with GBP to form a complex which further undergoes intramolecular rearrangement to form the products. K1 +

RN HBr

fast

... (i)

fast

... (ii)

K2

RN+HBr + GBP kk33

From step (i) of Scheme 1 +

+

RNBr + H

If [RNBr]t represents the total effective concentration of NBS in solution, then [RNBr]t = [RNBr] + [RN+HBr] + [X] ... (10)

X +

X → X′ + H

slow and rds … (iii)

k

k44 X′  → Products

fast

… (iv)

Scheme 1

In Scheme 1, X and X′ are the intermediate species whose structures are shown in Scheme 2, where a detailed mechanistic interpretation of GBP oxidation with NBS is proposed. Step (iii) of Scheme 1 determines the overall rate, −d [RNBr] = k3 [X] rate = dt

… (9)

[R N HBr] [RNBr] = K1[H + ] From step (ii) of Scheme 1

… (11)

+

[X] … (12) K 2 [GBP] Substituting Eqs (11) and (12) in Eq. (10) one obtains

[R N HBr] =

[X]=

K1 K 2 [RNBr]t [GBP][H + ] 1+K1[H + ]+K1 K 2 [GBP][H + ]

… (13)

By substituting for [X] from Eq. (13) in Eq. (9), the following rate law (Eq.14) can be obtained:

rate=

K1K 2 k3 [RNBr]t [GBP][H+ ] 1+K1[H + ]+K1K 2 [GBP][H + ]

… (14)

NOTES

Since rate = kobs[RNBr]t, Eq. (14) can be transformed into Eqs (15) and (16), kobs =

1 kobs 1 kobs

K1 K 2 k3 [GBP][H + ] 1 + K1[H + ][1 + K 2 [GBP]]

... (15)

=

1 1 1 + + + K1 K 2 k3 [GBP][H ] K 2 k3 [GBP] k3

=

 1  1 1 + 1 +  + K 2 k3 [GBP]  K1[H ]  k3

1

… (16)

1 at kobs [GBP] the constant [H+] and temperature has been found to be linear (r = 0.999). From the intercept of the plot, the value of k3 was found to be 6.862 × 10-4 s-1. The change in solvent composition by varying the CH3CN content in CH3CN – H2O affects the reaction rate. For the limiting case of zero angle of approach between two dipoles or an ion-dipole system, Amis31 has shown that a plot of log kobs versus 1/D gives a straight line, with a positive slope for a reaction involving a positive ion and a dipole and a negative slope for a negative ion-dipole or dipole-dipole interactions. In the present investigation, a plot of log kobs versus 1/D was linear with a negative slope. This observation indicates the ion-dipole nature of the rate determining step in the reaction sequence and also points to extending of charge to the transition state. The observed solvent isotope effect supports the proposed mechanism and the derived rate law. For a reaction involving a fast equilibrium H+ or OH- ion transfer, the rate increases in D2O medium, since D3O+ and OD- are stronger acid and stronger base respectively as compared to H3O+ and OH- ions32,33. In the present case, the observed solvent isotope effect of kobs(H2O)/kobs(D2O) >1 is due to the protonation step followed by hydrolysis involving the OH bond scission. The retardation of rate in D2O is due to the hydrolysis step which tends to show the normal kinetic isotope effect. The proton inventory studies made in H2O-D2O mixture may throw light on the nature of the transition state. The dependence of the rate constant, kobs, on the deuterium atom fraction, ‘n’, in the solvent mixture is given by the following form of Gross-Butler equation34,

Based on Eq. (16), plot of

k01 π TS (1 − n + nϕi ) = kn1 π RS (1 − n + nϕ J )

versus

where φi and φJ are isotope fractionation factor for isotopically exchangeable hydrogen sites in the transition state (TS) and in the ground/reactant state (RS), respectively. The Gross-Butler equation permits the evaluation of φi when the value of φJ is known. However, the curvature of proton inventory plot may reflect the number of exchangeable proton in the reaction34. In the present case, plot of kobs versus n is a curve and this in comparison with the standard curves, indicates the involvement of a single proton or H-D exchange in the reaction sequence35. This proton exchange is indicative of the participation of hydrogen in the formation of transition state. The negligible influence of added succinimide and halide ions on the rate are in agreement with the proposed mechanism. The proposed mechanism is also supported by the high values of energy of activation and other thermodynamic parameters. The fairly high positive value of ∆H≠ indicates that, the transition state is highly solvated. Acknowledgement The authors are thankful to University of Mysore, Mysore for financial support in the form of minor research project (DV3 /389). References 1

2 3 4 5 6 7 8 9 10 11 12 13 14 15

... (17)

1111

16

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