J. Chem Soc. Nigeria, Vol. 44, No. 1, pp 115 -124 [2019] Nucleophilic Aromatic Substitution Reactions in Dipolar Aprotic Solvents: The Remarkable Effect of Trifluoromethyl Group on the Reactivity of Nitrophenyl Ethers with Nucleophiles. C. Isanbor,* and A.I. Babatunde Chemistry Department, University of Lagos, Lagos, Nigeria. *Correspondence author: Email: [email protected] Received 12 November 2018; accepted 22 December 2018, published online 17 January 2019 ABSTRACT Rate constants are reported for the reactions of 4-phenoxy-3-nitrobenzotrifluoride 3c, 2-phenoxy-5- nitrobenzotrifluoride 4c and 1-phenoxy-2,4-dinitrobenzene 5c activated by trifluoromethyl (CF3) or nitro (NO2) groups with n-butylamine, pyrrolidine and piperidine in DMSO. The results are compared with results reported previously for same reactants and with the more strongly ring-activated compounds 4-phenoxy-3,5-dinitrobenzotrifluoride 1c and 2-phenoxy-3,5-dinitrobenzotrifluoride 2c in acetonitrile. A change in reaction medium from acetonitrile to DMSO leads to a reduction in values of kAm/k-1 as the proton-transfer from zwitterionic intermediates to catalysing amine becomes less thermodynamically favourable. Overall, the reactivity order is 5c > 3c> 4c and decreasing ring- activation in the 1-phenoxy compounds 1c - 5c leads to lower values of kAm/k–1 resulting in greater susceptibility to base catalysis. Specific steric effects leading to rate-retardation, is noted for the ortho- CF3 group. The higher reactivity of para-CF3 group in compounds 3c compared to 4c has been attributed partly to the more effective polar hyperconjugative activation by the CF3 group in 3c and to a possible participation of unfavourable electrostatic repulsion for the ortho-CF3 group between the electronegative fluorine atoms in 4c and the incoming nucleophiles. Keywords: Trifluoromethyl group, Proton transfer mechanism, Stereoelectronic effects, Nucleophilic aromatic substitution. X NRR' X NHRR' k1 k2 + RR'NH + HX k-1 1.0 INTRODUCTION kB[B] EWG EWG EWG ZH Mechanisms and reactivity of aromatic nucleoplilic substitution (SNAr) reactions EWG = electron withdrawing groups continue to attract attention [1-4] and recent studies show the continued synthetic utility of Scheme 1 SNAr strategies in the development of pharmaceuticals and other functional materials. Early studies [8] were concerned with SNAr reactions of activated aromatic discerning the mechanism of the general base compounds with amines usually involves the catalysed step, kB[B]. It is now recognised that Bunnett-type mechanism [5-7] shown in in dipolar aprotic solvents, such as dimethyl Scheme 1. When the second step is rate limiting sulfoxide (DMSO) and acetonitrile (MeCN), the then general base catalysis may be observed. rate limiting proton transfer may be from the zwitterionic intermediate ZH to base, the rate- limiting proton transfer (RLPT) mechanism; or, it may involve general acid catalysis, by BH+, of the expulsion of the leaving group from the J. Chem Soc. Nigeria, Vol. 44, No. 1, pp 115 -124 [2019] deprotonated form of ZH, the specific base – the phenoxy derivatives 3c and 4c, on the of general acid (SB-GA) mechanism [9]. The base-catalyzed (k3[B]) and uncatalyzed (k2) latter mechanism has been shown to apply to pathways in Scheme 1 and to elucidate further substrates such as alkyl ethers carrying poor the mechanism of base catalysis in these leaving groups [10, 11]. However there is good chemical systems. Herein rate data for the evidence that for substrates containing good substitutions of compounds, 3c, 4c and 5c with leaving groups, such as phenyl ethers the RLPT the amine n-butylamine, pyrrolidine and mechanism applies [12-15]. The absence of piperidine in DMSO are reported. The effect of base catalysis implies that the initial changing the solvent medium from MeCN to nucleophilic attack, k1 step, is rate limiting [5- DMSO and the comparison of the relative 7]. activation and stereoelectronic effects due to Steric and electronic effects due to ortho-nitro and ortho-trifluoromethyl groups in substituent groups on the kinetics of organic these compounds are examined. reactions in solution are very useful tools for probing reaction mechanism [16]. In previous 2.0 EXPERIMENTAL publications [17-20] we have shown that in the field of nucleophilic aromatic substitution, The phenoxy compounds 3c, 4c and 5c were kinetic data obtained by varying the steric and prepared by reaction at 45ºC for two hours of electronic properties of the electrophilic the appropriate 1-chloro compound (1 equiv.) substrates 1-5 can provide valuable information with potassium hydroxide (1 equiv.) in an on the mechanism of SNAr processes in aprotic excess of phenol in aqueous ethanol. On and dipolar aprotic solvent. Our results showed completion water was added and the solid that in the reaction carried out in toluene and formed was recrystallised from ethanol. MeCN as solvent, the decreased ring-activation Analytical data for 3c-5c have been reported in compounds 3-5, compared to compounds 1, previously [17-19]. 2, leads to reductions in values of kAm/k–1 Amines and DMSO were the purest resulting in greater susceptibility to base available commercial samples. Kinetic catalysis. Rate constants k for nucleophilic measurements were made 1 spectrophotometrically at the absorption attacks are also reduced but steric effects due to maxima of the products using Shimadzu UV PC repulsion between the incoming nucleophile and spectrometer. Rate constants were measured at ortho-substituents are less evident in 3-5. These 25ºC under first-order conditions with substrate studies also revealed remarkable rate-retarding concentrations of ca. 1 10–4 mol dm–3 and effects of an ortho-CF3 group in compound 2 were evaluated by standard methods. Values [17,19]. are precise to 3%. X X X X X O N O2N CF3 CF 3.0 RESULTS AND DISCUSSION 2 NO2 NO2 3 NO2 NO 3.1. Kinetic data CF3 2 CF3 NO2 NO2 1 2 3 4 5 UV-vis measurements of the reaction of a X = Cl 5 3 b X = F substrates 3c 5.0x10 mol dm in DMSO c X = OPh 3 Fluoroorganic compounds are known to containing (0.001-0.2 mol dm ) amine showed have unique chemical, physicochemical and in each case a single process. Spectra at the biological properties continue to attract completion of the reactions were identical to attention [21,22]. Hence, we have extended our those of the authentic samples of the products interest in the SNAr reactions of these dissolved in the reaction medium. At the compounds to obtain additional information concentration of the amines used, the rapid about the effects of changing reaction medium reversible reactions leading to the formation of and the relative position of CF3 substituent in adducts at the 3-position were not observed. The J. Chem Soc. Nigeria, Vol. 44, No. 1, pp 115 -124 [2019] results are therefore interpreted in terms of Equation (4) when the uncatalysed pathway Scheme 2. In all cases, substitution of the may be neglected, kAm[Am] >> k2. phenoxy group by amine to give the corresponding amine substituted derivatives kA = K1k2 + K1kAm[Am] (3) occurred without the appearance in spectroscopically observable concentration, of K1 k Am [Am] intermediate 7 on the reaction pathway. Failure k= (4) A k [Am] to observe such an intermediate is attributed to 1 Am k its rapid cleavage by loss of phenoxide ion [23, 1 24]. Rate data for the reactions of 3c with n- Making the assumption that the zwitterionic butylamine and with piperidine are displayed in adduct 6 may be treated as a steady-state Table I. For the reaction of 3c with n- intermediate leads, when the amine acts both as butylamine, values of the second order rate the nucleophile and as the catalysing base, to constant, kA, in Table I were independent of the equation (1). amine concentration. This corresponds to the condition k2 + kAm[Am] >> k–1 so that k k (k +k [Am]) equation 2 applies. k =obs = 1 2 Am (1) A [Am] k +k +k [Am] Rate data for the corresponding reaction of -1 2 Am 3c with piperidine are also displayed in Table 1 but the corresponding reactions with pyrrolidine If nucleophilic attack is rate-limiting, are in Table 2. In both cases, the plots of kA corresponding to the condition k2 + versus amine concentration shown in Figures 1 k [Am] >> k then Equation (1) reduces to Am –1 (a and b) had a distinct intercept. Hence Equation (2) equation (3) applies, indicating that the contribution of both the base-catalysed and the kA = k1 (2) uncatalysed pathway is significant to the overall reaction flux. Other limiting forms of Equation (1) are Equation (3) when k–1 >> k2 + kAm[Am], and O NHRR' O NRR' NO2(CF3) NO2(CF3) O k1 kAm NO2(CF3) + 2NHRR' + NHRR' k -1 kAmH + NH2RR' CF3(NO2) CF3(NO2) CF3(NO2) 3 or 4 6 7 k4 k2 NRR' NO2(CF3) + PhOH + NHRR' CF3(NO2) 8 Scheme 2 J. Chem Soc. Nigeria, Vol. 44, No. 1, pp 115 -124 [2019] Table 1. Kinetic resultsa for reaction of 3c with n-butylamine and with piperidine in DMSO at 25C. [Amine]/ n-Butylamine Piperidine –2 –3 –5 –1 –4 –4 –4 10 mol dm kobs/10 s kA/10 kA/10 kAcalc10 3 –1 –1 3 –1 –1 3 –1 –1 dm mol s dm mol s dm mol s 1.2 0.65 5.41 - - 1.6 0.71 4.44 - - 4.0 1.90 4.75 - - 6.0 - 0.72 0.71 8.0 4.07 5.09 0.78 0.77 10.0 4.68 4.68 0.83 0.83 20.0 8.81 4.41 1.17 1.15 40.0 - 1.85 1.80 50.0 - - 2.12 2.10 a) kAcalc (Values calculated using equation 3 with the values given in Table 3) Table 2.