Nucleophilic Substitution Reactions of 2 , 4-Dinitrobenzene Derivatives with Hydrazine : Leaving Group and Solvent Effects

The hydrazinolysis of 2,4-dinitrophenyl acetate in methanol proceed exclusively through acyl-oxygen scission by a concerted mechanism. The reaction of 1-chloro-2,4-dinitrobenzene with hydrazine in methanol, acetonitrile and dimethyl sulfoxide undergo uncatalyzed substitution and the formation of the zwitterionic intermediate is the rate-determining step. While 2,4-dinitrobenzene derivatives 1, 2, 3, 4, 5a-i, 6 with hydrazine in DMSO undergo uncatalyzed substitution and the departure of the leaving group is the rate-determining step. The process depends on the basicity of the leaving group and its steric hindrance as well as the possible intramolecular hydrogen bond in the transition state. The reactivity of compounds 5a-i depends on the substituent of the thioaryl ring while the small ρY value is due to the sulfides existing preferentially in the skew conformation. The small βlg value (-0.18, r = 0.99) indicated that the reaction of sulfides with hydrazine proceeds with advanced bond formation to the nucleophile and the bond cleavage proceed in a slow extent in the transition state.


Introduction
The generally accepted mechanism for nucleophilic aromatic substitution (the S N Ar mechanism) is an addition-elimination mechanism and involves the formation of a Meisenheimer type of intermediate (Terrier, 1991).The rate-limiting step is the formation of the intermediate, the expulsion of the leaving group, or the proton transfer process.Several properties of the nucleophiles (basicity, polarisability, degree of solvation, etc) or leaving groups more or less influence reactivity depending on the kind of interaction between nucleophile, leaving group, substrate and solvent (Isanbor & Babatunde, 2009;Crampton et al., 2006;Crampton, Emokape, Isanbor, & Mondal, 2005;Emokape & Atasie, 2005;Macini, Fortunato, & Vottero, 2004;Macini, Fortunato, Adam, Vottero, & Terenzani, 2002;Bartoli & Toddesco, 1977).In reactions in which bonds are broken, part of one reactant, the leaving group, becomes detached.Actually, one might expect that a good leaving group gives an increased rate of substitution, whatever substrate or nucleophile is involved.Therefore, the leaving group can determine reactivity in nucleophilic substitution in aromatic system.This has fostered the illusion that the leaving group ability depends upon the pK a of the conjugate acid of the leaving group and will affect the rate of reaction if the leaving group is involved in the rate-determining step (Paghaleh, Harifi-Mood, & Gholami, 2011;Crampton, Emokape, & Isanbor, 2007;Crampton, Emokape, Howard, Isanbor, & Mondal, 2004;Crampton, Emokpae, Howard, & Isanbor, 2004;Annulli, Mencareli, & Stegel, 1983;Stirling, 1979).In fact, several years ago, Bunnett, Garbisch, and Pruitt (1957) strongly supported the hypothesis of a two-step pathway for nucleophilic aromatic substitution, using as a criterion the so-called "element-effect" i.e., the variation in the rate of substitution as a leaving group is varied.To gain further understanding of the mechanism for nucleophilic aromatic substitution, and in order to explain the mobility of the leaving groups and substituent containing leaving group, kinetic studies of hydrazinolysis of 2,4-dinitrobenzene derivatives 1, 2, 3, 4, 5a-i, 6 in DMSO are examined.
The corresponding sulphone 6 was prepared by oxidizing the sulphides 5a with slight excess of the theoretically required amount of H 2 O 2 in glacial acetic acid.The product was crystallized from methanol as pale .yellowneedles in yield 88%.

Product Analysis
A mixture of the desired compound 1 (X = OCOCH 3 ) (0.05 mole) and hydrazine (0.5 mole) in methanol were stirred at room temperature.The formed precipitate was filtered, washed with cold methanol and recrystallised from methanol.Analysis of the products gave a mixture of 2,4-dinitrophenol and acetyl hydrazide.When a mixture of compounds 2-6 (0.05 mole) and hydrazine (0.5 mole) in methanol were stirred at room temperature, work up gave 2,4-dinitrophenylhydrazine (Ahmad, Qureshi, & Andrabi, 1995) as a sole product.

Kinetic Measurements
The reaction mixture was prepared by the transfer of 1 ml of the substrate solution that gives a final concentration of 1 × 10 -4 M to a 10 ml measuring flask and the volume was completed by a given volume of absolute solvent (methanol and acetonitrile or dimethyl sulfoxide).The measuring flask and the stock solution of the amine were allowed to reach thermal equilibrium in a well stirred and thermostatic bath at the desired temperature ± 0.5 o C. The reaction time started when the amines was mixed with the reaction mixture (final concentration of amine ranges from 2x10 -2 to 72x10 -2 M) and transfer quickly to a well thermostatic chamber containing the UV cell.The absorbance A t at the desired  was recorded at several time intervals depending on the reaction rate.The resultant change of absorbance with time was recorded by kinetic mode or time scan mode on UV-VIS Shimadzu 160-A spectrophotometer.Measurements were usually carried by following the increase of the reaction products absorbance with time at λ = 410 nm for the reaction of 1 with hydrazine, and at λ = 365-440 nm for the reactions of 2-6 with hydrazine in DMSO.
We studied the mechanism for the reaction of 2,4-dinitrophenyl acetate 1 with hydrazine in MeOH to examine the mode of scission whether through the CO-O or/and Ar-O bond scission pathways.The reaction in methanol proceed exclusively through acyl-oxygen scission rather than aryl-oxygen scission as indicated from the isolation and identification of acetate hydrazide, 2,4-dinitrophenoxide, Scheme 1. Furthermore, the exclusive acyl-oxygen fission is attributed to the fact that the departure of 2,4-dinitro-phenoxide is better than the acetate as a leaving group.This is consistent with the fact that acetic acid is a relatively stronger acid with pK a = 9.57 (MeOH) (Edwards & Pearson, 1973), where 2,4-dinitophenol pK a value is equal 7.83 (MeOH) (Dawson et al., 1986).
The reactions of 1 with hydrazine obeyed pseudo-first-order rate constants (k obs ).The linear plot of k obs vs. amine concentration indicated that there is no base-catalysis and the overall reactions follow the route given by Scheme 1.The large negative S # value indicates a rigid transition state or great participation of methanol molecules in the activated complex, Table 1.
Table 1.Second-order rate constants, k N (l mol -1 s -1 ), for the reaction of 2,4-dinitrophenyl acetate 1 with hydrazine in methanol at different temperatures Hydrazine 11.50 12.11 12.69 13.28 13.81 228.89 6.44 Menger and Smith (1972) suggested that the leaving group departs slowly in either a concerted mechanism, Scheme 1, pathway (a) or a stepwise mechanism, Scheme 1, pathway (b).They chose to favor a stepwise mechanism.However, our results could favor a concerted mechanism rather than a stepwise mechanism because i) intramolecular hydrogen bond is not preferred in polar solvents and the large negative ΔS # value are in the line with concerted mechanism or the break-down of the addition intermediate to the products is the rate determining step, (ii) the pK a of the conjugate acid of the leaving group (2,4-dinitrophenoxide ion) is 7.83 while the pK a value of hydrazine is 8.10 respectively (Hall, 1957).It is apparent that the basicity of the incoming amines and the basicity of the leaving group are approximately the same, Scheme 1, pathway (a).Therefore, we can propose that the hydrazinolysis of 1 in MeOH proceeds through a concerted mechanism with a transition state TS. ) is known to be a moderately strong nucleophilic reagent toward 1-chloro-2,4-dinitrobenzene (Bunnett & Davi, 1954, 1960).The reactions were followed spectrophotometrically by monitoring the appearance of the product 2,4-dinitrophenyl hydrazine at  = (365-440 nm) depending on the solvent used, Scheme 2. The runs were designed to facilitate observation of pseudo-first-order kinetics (excess of hydrazine concentration).

Effect of Solvent
The reactivity sequence for the reactions of 2 with hydrazine is DMSO > MeCN > MeOH.In DMSO, the intramolecular hydrogen bonding to the o-nitro group is less significant since the -NH 2 + proton will be strongly hydrogen bonded to the DMSO solvent, Figure 1.In addition, MeCN molecules can stabilize the zwitterionic intermediate I by intermolecular hydrogen bonding as shown in Figure 2. In methanol, intramolecular hydrogen bond is relatively weak and the zwitterionic intermediate I is extensively solvated by intermolecular hydrogen bonding.Accordingly, the relative rates indicate that the intermolecular hydrogen bond may be the predominant effect in stabilizing the transition state consisting with the order mentioned before.

Reactions of 2,4-dinitrobenzene Derivatives with Hydrazine in DMSO (2, 3, 4, 5a, 6)
Compounds 1-methoxy-2,4-dinitrobenzene 3; 2,4-dinitrophenyl phenyl ether 4; 2,4-dinitrophenyl phenyl sulfide 5a; and 2,4-dinitrophenyl phenyl sulfone 6 undergo attack of hydrazine molecule on the ipso carbon followed by the elimination of the leaving group anion (X = -OMe, -OPh, -SPh, -SO 2 Ph) as indicated from the isolation and identification of the known 2,4-dinitrophenyl hydrazine 7.All these reactions confirmed the pseudo-first order kinetics.The k obs values were determined from the slope of the plot of ln (A ∞ -At) vs. time.Generally five different concentrations of hydrazine were used to determine second-order rate constants.The linear plot of k obs vs hydrazine concentration passing through the origin, indicates that the general base catalysis by a second hydrazine molecule is absent.The apparent second-order rate constants k A determined in this way and the values of H # and S # for the reaction of hydrazine with 2-6 are summarized in Table 3.The plot of S # versus H # values give straight line, except X = Cl.This indicates a common mechanism for all X-substituent, except for the chlorine leaving group.
Actually, the second order kinetic is compatible with, Scheme 4. Therefore, the rate determining step is either the formation of Meisenhiemer intermediate I or the departure of the leaving group.While the first step seems to be affected by the electronic nature of the leaving group which may stabilize the ground state of the reacting compounds 2-6, the second step depends on the basicity of the leaving group X.The basicities of the leaving groups are designated by their pK a values in DMSO (Bordwel & Hughes, 1982;Clare, Cook, Ko, Mac, & Parker, 1966).Other effects are the steric hindrance of the bulky leaving group, the difference in the stabilization of the corresponding transition states TS and the charge polarization of the leaving group X.
The k A values for the reactions of different X-substituent with hydrazine in DMSO gave good correlation with the leaving group basicities (not shown), except compound 2, X = Cl.Although the pK a of X = -SO 2 Ph (7.10) is smaller than that of X = SPh (10.30), the rate constants for both are of comparable value, Table 3.This is apparently due to (i) the steric effect which inhibits the reaction in case X = -SO 2 Ph, (ii) the intramolecular hydrogen bond in the transition state developed from the reaction of 7 (X = SO 2 Ph, ΔS # = -187.22)which is less pronounced than that for the reaction of 5a (X = SPh, ΔS # = -231.66)with hydrazine.Therefore, the intramolecular hydrogen bonding in the corresponding transition states, Figure 3, is responsible for the low differences in rate constants at all temperatures, although SO 2 Ph is better leaving group than SPh.On the other hand, the GS stabilization of 2-6 is not responsible for increasing the rate for X = -SPh rather than X = OPh.This is explained by the fact that the sulfur atom in compound 5a can resonate more than the more electronegative oxygen atom with the dinitrophenyl ring, Figure 4. Another factor which can explain the difference in rates is the charge polarization nature of the leaving group which strengths the intramolecular hydrogen bonding interaction.

Figure Resonance structure of 3, 4 and 5a
Accordingly the reaction proceeds by the mechanism shown in Scheme 4 in which the departure of the leaving group in reactions of compounds 3, 4, 5a, 6 with hydrazine in DMSO at all temperatures is the rate determining step.This is clearly observed from low reactivity of compounds 3 and 4 that have the higher basicities of their leaving group anions ¯OCH 3 , ¯OPh.While, compound 2 proceeds by the same mechanism by the formation of Meisenhiemer complex II, at the rate limiting step.
Scheme 4. The reactions of 2,4-dinitrophenyl aryl sulfides 5a-i with hydrazine in DMSO All the reactions of 3'-and 4'-substituted phenyl 2,4-dinitrophenyl sulfides 5a-i with excess hydrazine obeyed pseudo-first-order kinetics.All the plots of k obsd values vs. hydrazine concentrations were linear, passing through the origin, indicating that the general base catalysis by a second hydrazine molecule is absent.The apparent second-order rate constants (k A ) were determined from the slope of the linear plots vs. the hydrazine concentration.The k A values determined in this way are summarized in Table 4.The reactivity of 6a-i increases as the substituent Y on the leaving group becomes a stronger electron-withdrawing group, Table 4.The k A value for the reactions of 5a-i with hydrazine in DMSO increases from 6.05 x 10 -3 to 61.40 x 10 -3 as the substituent Y changes from 4-OCH 3 to 4-NO 2 .This is consistent with a typical nucleophilic substitution reaction (Crampton et al., 2006;Smith, 2001) provided there is a positive charge developed at the nucleophilic nitrogen atom and a negative charge at the thiophenoxy sulfur atom in the transition state.
The Hammett plots have long been considered to be the most commonly employed linear free energy relationship (LFER) to examine structure-reactivity relationships for aromatic substrates and in investigation of reaction mechanism.It is found that σ⎯-constants give good Hammett correlation against log k A with ρ = 0.65 (r = 0.99).
It implies that the sulfur atom in thioaryloxide bears a partial negative charge which can be delocalized on substituent Y in the transition state.This suggests that the leaving group departure occurs at the rate-determining step.
The reaction constant value (ρ Y = 0.65), seems to indicate that the substituent effect is not high.The low value of ρ in this study is in contrast to the previously reported value (ca +4) for substituted halogenonitrobenzene because their substituents affect directly the reaction center (Chaw, Fischer, & Happer, 1971), while, the present substituents exist in the leaving group moiety.Therefore, our results clearly suggest that the reaction of compounds 5a-i proceed through an S N Ar mechanism in which the leaving group departure from the zwiterionic complex intermediate occurs in the rate-determining step, Scheme 4.

Bronsted Relationship
Bronsted relationship has been used as a probe for determining the mechanistic pathway (Mohanty & Nayak, 1975).The magnitude of the Bronsted coefficient has usually been related to the extent of bond formation in the transition state (Senator, Ciuffarin, & Fava, 1970).The sign of β depends on the pK a either for the attacking nucleophile or the leaving group.As the pK a of the nucleophile varies at constant leaving group a positive Bronsted coefficient is observed (Ananthakrishnanadar & Kannan, 1982).This can be explained by the direct proportionality between the logarithmic of the rate and the pK a of the nucleophile (i.e., the higher the pK a value of the nucleophile, the higher the rate of the reaction).Generally, Bronsted coefficients between 0.6 and 1.5 have been taken as indicative of extensive bond formation whereas those between 0.0 and 0.3 are indicative of the little bond formation when the pK a of the nucleophiles are variable (Ananthakrishnanadar & Kannan, 1982).On the other hand, the change of the pK a values of the leaving group at constant nucleophile would result in a negative Bronsted coefficient (Khattab et al., 2011) due to the inverse proportionality between pK a of the leaving group and the rate (i.e., the higher the pK a of the leaving group, the lower the rate).
Table 4 shows that the reactivity of 2,4-dinitrophenyl phenyl sulfide derivatives 5a-i and hydrazine increases with the decrease in pK a of the thioaryl leaving group (Dean, 2003).The correlation of the rate constants against pK a values of the corresponding conjugate acids in DMSO gives small β lg value (-0.18, r = 0.99).This is consistent with the good Hammett correlation using σ⎯-constants.Accordingly, the reaction of 5a-i proceeds through zwitterionic intermediate in which bond formation to the nucleophile is well advanced and bond rapture to the leaving group has proceeded in a slow extent in the transition state.

Conclusion
The reaction of 2,4-dinitrophenyl acetate with hydrazine in MeOH proceeds exclusively through acyl-oxygen scission.The reaction obeyed pseudo-first-order rate constants (k obs ) and the large negative S # value indicates a rigid transition state or great participation of methanol molecules in the activated complex.The leaving group departs slowly in a concerted mechanism due the large negative ΔS # value, the lower value of the pK a of the conjugate acid of the leaving group than that of the hydrazine, and the basicity of the incoming amines and the leaving groups are the same.
The reactions of 1-chloro-2,4-dinitrobenzene with hydrazine in MeOH, MeCN and DMSO at different temperatures were followed spectrophotometrically.Kinetic results suggest that the reaction proceeds by uncatalysed process with the rate determining formation of the zwitterionic intermediate.The plot of H # against log -S # indicates a common mechanism for the reaction in these solvents.The reactivity sequence for the reactions of 1-chloro-2,4-dinitrobenzene with hydrazine is the order DMSO > MeCN > MeOH.This order depends on the intramolecular and intermolecular hydrogen bonding interactions.Reactions of 1-methoxy-2,4-dinitrobenzene, 2,4-dinitrophenyl phenyl ether, 2,4-dinitrophenyl phenyl sulfide and 2,4-dinitrophenyl phenyl sulfone with hydrazine in DMSO show absence of general base catalysis by a second hydrazine molecule.The plot of S # versus H # values give straight line, except for X = Cl, which indicates a common mechanism for all X-substituent, except for the chlorine leaving group.The reaction proceeds by the mechanism in which the departure of the leaving group at all temperatures is the rate determining step.The mechanism is compatible with the second order kinetic, the electronic nature of the leaving group, the basicities of the leaving groups and the steric effects of the bulky leaving group, the difference in the stabilization of the corresponding transition states TS and the charge polarization of the leaving group X.
Reactions of 2,4-dinitrophenyl aryl sulfides with hydrazine in DMSO at 25 °C were followed specrtophotometrically and proceeds by a typical nucleophilic substitution reaction uncatalysed process.The reactivity increases as the substituent on the leaving group becomes a stronger electron-withdrawing group.The linear plot of σ⎯-constants gives good Hammett correlation against log k A with ρ = 0.65 suggesting that the leaving group departure occurs at the rate-determining step and the substituent effect is not high.The correlation of the rate constants against pK a values of the corresponding conjugate acids in DMSO gives small β lg value (-0.18) which indicates that the reaction proceeds through zwitterionic intermediate in which bond rapture to the leaving group has proceeded in a slow extent in the transition state.

Figure 1
Figure 1.A) Strong hydrogen bonding of the -NH 2 + proton to DMSO.B) MeCN molecules stabilize the zwitterionic intermediate by intermolecular hydrogen bonding

Figure 3 .
Figure 3. Intramolecular hydrogen bonding in the transition states

Table 2 .
Summary of second-order rate constants and activation parameters values for the hydrazinolysis of 2 in MeOH,

Table 3 .
Summary of second-order rate constants and activation parameters for hydrazinolysis of 2

Table 4 .
Summary of second-order rate constants reaction constant ρ Y and Bronsted coefficient β Y for hydrazinolysis of sulfides 5a-i in DMSO at 25 °C