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SN Applied Sciences

, 1:1004 | Cite as

Trichloroisocyanuric acid and NaNO2 mediated nitration of indoles under acid-free and Vilsmeier–Haack conditions: synthesis and kinetic study

  • D. Govardhan
  • M. Bhooshan
  • P. K. Saiprakash
  • K. C. RajannaEmail author
Research Article
  • 41 Downloads
Part of the following topical collections:
  1. 1. Chemistry (general)

Abstract

This study deals with the synthetic and kinetic aspects of trichloroisocyanuric acid (TCCA) and NaNO2 mediated nitration of indoles in aqueous acetonitrile media under acid-free and Vilsmeier–Haack conditions (using N,N′-dimethyl amides) conditions. Nitration of indoles revealed second order kinetics, with a first order dependence on [indole] and [nitrating agent] ([TCCA]/[NaNO2], [(TCCA–DMF)]/[NaNO2] or [(TCCA–DMA)]/[NaNO2], in which [NaNO2] far excess over other reagents). Reactions followed overall second order kinetics with first order in [reagent] and [indole] under the experimental conditions. Isokinetic temperature (β) values were obtained from Leffler’s equation for different kinetic protocols (β = 303 K (TCCA–NaNO2); 303 K (TCCA–DMF)/NaNO2; and 244 K (TCCA–DMA)/NaNO2). These values are the experimental temperature range (303–323 K) indicating that the entropy factors are probably more important in controlling the reaction.

Keywords

Nitration kinetics Trichloroisocyanuric acid (TCCA) N,N′ dimethyl formamide (DMF) N,N′ dimethyl acetamide (DMA) (TCCA–DMF) and (TCCA–DMA) adducts Indoles NaNO2 

1 Introduction

Indole is a bicyclic heteroaromatic molecule (C8H7N) containing a five-membered pyrrole ring fused to six-membered benzene ring. Indole is produced in nature by several bacteria; therefore, it is widely spread in the environment. It is isolated from coal tar distillate and one of the widely studied heterocyclic molecules, which regulates several aspects of bacterial physiology [1]. Tryptophan (one of the useful amino acids) is a derivative of indole, which acts as a precursor of the neurotransmitter serotonin [2]. Indole is an electron‐rich heteroaromatic nitrogen heterocycle, which is undergoes electrophilic substitution reactions primarily at the 3‐position. Different types of nitro indole derivatives were synthesized during the past several years, which include noteworthy syntheses of Majima and Kotake [3], and Wayland Noland’s research group [4, 5, 6, 7, 8], and several others [9, 10, 11, 12]. Sundberg’s monograph reviewed several aspects on the chemistry of indoles [12], including electrophilic substitution reactions including nitration of indole.

Electrophilic aromatic substitution (EAS) reactions in general and aromatic nitration reactions in particular played key role in the development of organic chemistry. These leading to the synthesis of many precursors and intermediates useful for the design and execution of drugs, dyes, explosive, pharmaceuticals and several other industrially important compounds [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11]. Eilhardt Mitscherlich was the first to prepare nitrobenzene using benzene and fuming HNO3 in 1834 [8], followed by the use of acid mixture (HNO3 + H2SO4) to achieve aromatic nitration. Hughes, Ingold and Reed [9] stated that Martinsen [10] was the first to accomplish definite second-order kinetics for the nitration of aromatic substances in sulphuric acid medium in 1904, and it is believed that nitration occurs through the formation of active nitronium ion (NO2+) species in acid-mixture during the course of reaction [9]. Participation of the nitronium ion has been evidenced from the Raman spectroscopic studies of Kecki [11], which depicted a line at 1400 cm−1 in the Raman spectrum. In recent past quite a good number of workers focused their attention on quantum chemical studies to explore mechanism of nitration of aromatic compounds [12, 13, 14, 15]. Review article published by Katrizky et al. [16] provided excellent bibliography on the direct mono nitration of wide varieties of heterocyclic compounds like furans, pyrroles, thiophenes, pyrazoles, imidazoles, isoxazoles and thiazoles using nitric acid/trifluoroacetic anhydride as nitrating agent. Adegoke et al. [17] accomplished spectrophotometric determination of metronidazole and tinidazole via charge transfer complexation using chloranilic acid. Mukherjee and Boshaff [18] explored that nitroimidazoles could be effectively used for the treatment of TB. During the past two decades our research group is also actively involved to achieve nitration using eco-friendly reagents and catalysts [19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29].

Trichloroisocyanuric acid (TCCA) was first reported by Chattaway and Wadmore [30], which has been explored as cost effective, less toxic, less corrosive, efficient, and versatile laboratory reagent for oxidation and chlorination reactions [31, 32, 33]. Recent reports from our group revealed that the TCCA/dimethyl formamide (DMF) is an efficient reagent for chloro dehydration of alcohols [34], (TCCA–DMF)/NaNO2 reagent for decarboxylative nitration of α, β unsaturated carboxylic acids and nitration of aromatic compounds (under mineral acid free conditions) [35, 36, 37]. Recently, we have explored (TCCA/(DMF) and (TCCA/(DMA) as green Vilsmeier–Haack (VH) type reagents for effective synthesis of 2-chloro 3-formyl and 2-chloro 3-acetyl quinolines from acetanilides [38] respectively. Enthused by the greenery nature of TCCA, we have embarked on the synthesis and kinetic study of nitration of indole compounds mediated by trichloroisocyanuric acid/and NaNO2 in absence and of N,N′-dimethyl amides: (i) (TCCA/NaNO2) and (ii) (TCCA/DMF)/NaNO2 and (TCCA/DMA)/NaNO2 under mineral acid free conditions (Scheme 1).
Scheme 1

Nitration of Indole compounds using TCCA and [TCCA/DAA] adduct and NaNO2

2 Experimental details

Chemicals used were obtained from either Avra (India) or SD-Fine Chemicals (India). Freshly prepared reagents and solutions were used for all the reactions.

2.1 Synthesis of [TCCA–DMF] and [TCCA–DMA] adducts

Trichloroisocyanuric acid/dimethyl formamide (TCCA–DMF), and (TCCA–DMA) reagents were always prepared fresh as detailed in our papers [34, 35, 36]. About 0.10 mol TCCA, and 0.13 mol of N,N′-dialkyl amides such as DMF or DMA were suspended into an RB flask containing about 50 ml of CH2Cl2 solvent. The contents were stirred continuously at room temperature till (for about 3 h) a while precipitate occurred. The resultant mass was separated as ([TCCA–DMF] (or) [TCCA–DMA]) reagent.

2.2 Method to follow the kinetics of TCCA–nitrite triggered nitration reactions

Known amounts of substrate (Indole), sodium nitrite (NaNO2), and suitable amount of aqueous acetonitrile (MeCN) in one reaction flask (Flask-A), and trichloroisocyanuric acid (TCCA) were taken in another flask (Flask-B). Both the flasks were clamped in a thermostatic bath at a desired temperature for about 20 min. Required amount of TCCA was transferred to flask-A, mixed thoroughly to trigger the reaction. About one to two mL portions of the reaction mixture were transferred into a cuvette, placed in the thermostatic cell compartment (comprising inlet–outlet devices for the circulation of thermostatic liquid to maintain desired temperature). Absorbance (A) values of the nitro product was recorded at various time intervals (At) at 430 nm till 60–70% of the reaction is completed, which were reproducible with ± 5% accuracy.

2.3 Method to follow the kinetics of nitration reactions triggered by (TCCA/DMF) and (TCCA/DMA) adducts and nitrite

Similar procedure is used to study the kinetics of nitration, when TCCA is replaced with (TCCA/DMF) and (TCCA/DMA) adducts, which were always prepared fresh every day.

2.4 Determination of the order of reaction

In the present kinetic protocols, we have defined At = absorbance of nitrate species produced during the course of reaction at a given time, A is the absorbance at infinite time (at the end of the reaction) and A0, the absorbance (if any) before the on-take of reaction, then (A − At) is proportional to (a–x) and (A − A0) proportional to (a). To determine order of the reaction, we have used graphical method of approach based on the integrated rate expressions of second order and first order kinetics, according to standard procedures.

Under the conditions, viz., (i) [Indole]0 ≫ [TCCA)]0 and [NaNO2]0 ≫ [TCCA]0, (ii) [Indole]0 ≫ [TCCA–DMF)]0 and [NaNO2]0 ≫ [TCCA–DMF]0, (iii) [Indole]0 ≫ [TCCA–DMA)]0 and [NaNO2]0 ≫ [TCCA–DMA]0, the pseudo first order plots of \(\ln [(A_{\infty } - A_{0} )/(A_{\infty } - A_{t} )]\) versus time were linear passing through origin with positive slope according to the following equation:
$$\ln \left[ {\frac{{\left( {A_{\infty } - A_{0} } \right)}}{{\left( {A_{\infty } - A_{t} } \right)}}} \right] = k^{{\prime }} t$$
(1)
These observations indicated first order kinetics in (i) [TCCA] (ii) [TCCA–DMF] (iii) [TCCA–DMA] in all the systems (Various Indoles) studied. Pseudo first order rate constant (k′) could be obtained from the slopes of these linear plots (Figs. 1, 2, 3). First order kinetics in [Indole] was further confirmed from the observed linear plot of (k′) versus [Substrate]), which passed through the origin (Figs. 4, 5, 6). When (i) TCCA, (ii) [TCCA–DMF], (iii) [TCCA–DMA] and [Substrate] (i.e., Indole) are taken in equal concentrations (i.e., (i) [TCCA)]0 = [Indole]0), [NaNO2]0 ≫ [TCCA]0 (ii) [TCCA–DMF]0 = [Indole]0), [NaNO2]0 ≫ [TCCA–DMF]0 (iii) [TCCA–DMA]0 = [Indole]0), and [NaNO2]0 ≫ [TCCA–DMA]0 plots of [1/(A − At)] versus time, have been found to be linear with a positive gradient and definite intercept on vertical axis indicating over all second order kinetics (Figs. 7, 8, 9), according to the following expression:
Fig. 1

Pseudo first order plot for TCCA/NaNO2 triggered nitration of indoles. 103[Substrate] = 5.0 mol/dm3−, 104[TCCA] = 5.0 mol/dm3−, Me-CN (% V/V) = 25, 102[NaNO2] = 2.5 mol/dm3−

Fig. 2

Pseudo first order plot for (TCCA–DMF)/NaNO2 triggered nitration of indoles. 103[2-Methyl Indole] = 2.5 mol/dm3−,104[VHR’F] = 2.5 mol/dm3−, 103[5-Bromo Indole] = 5.0 mol/dm3−, 104[VHR’F] = 5.0 mol/dm3−, 103[Indole] = 5.0 mol/dm3−, 104[VHR’F] = 5.0 mol/dm3−, Me-CN (% V/V) = 25, 102[NaNO2] = 2.5 mol/dm3−

Fig. 3

Pseudo first order plot for (TCCA–DMA)/NaNO2 triggered nitration of indoles. 103[Substrate] = 5.0 mol/dm3−, 104[VHR’A] = 5.0 mol/dm3−, Me-CN (% V/V) = 25, 102[NaNO2] = 2.5 mol/dm3−

Fig. 4

Second order plots for TCCA/NaNO2 triggered nitration of indoles. 104[2-Methyl Indole] = 2.5 mol/dm3−, 104[TCCA] = 2.5 mol/dm3−. 104[5-Bromo Indole] = 5.0 mol/dm3−, 104[TCCA] = 5.0 mol/dm3−, 104[Indole] = 5.0 mol/dm3−,104[TCCA] = 5.0 mol/dm3−, Me-CN (% V/V) = 25, 102[NaNO2] = 2.5 mol/dm3−. Temp = #03 K

Fig. 5

Second order plots for (TCCA–DMF)/NaNO2 triggered nitration of indoles. 104[2-Methyl Indole] = 2.5 mol/dm3−, 104[VHR’F] = 2.5 mol/dm3−, 104[5-Bromo Indole] = 5.0 mol/dm3−, 104[VHR’F] = 5.0 mol/dm3−, 104[Indole] = 5 mol/dm3−, 104[VHR’F] = 5.0 mol/dm3−, Me-CN (% V/V) = 25, 102[NaNO2] = 2.5 mol/dm3−. Temp = 323 K

Fig. 6

Second order plots for (TCCA–DMA)/NaNO2 triggered nitration of indoles. 104[Substrate] = 5.0 mol/dm3−, 104[VHR’A] = 5.0 mol/dm3−, Me-CN (% V/V) = 25, 102[NaNO2] = 2.5 mol/dm3−. Temp = 323 K

Fig. 7

Plots of (k′) versus [Sub] in TCCA/NaNO2 triggered nitration reactions of indoles at 313 K

Fig. 8

Plots of (k′) versus [Sub] in TCCA/NaNO2 triggered nitration reactions of indoles at 313 K

Fig. 9

Plots of (k′) versus [Sub] in (TCCA–DMF)/NaNO2 triggered nitration reactions of indoles at 313 K

Fig. 10

Plots of (k′) versus [Sub] in (TCCA–DMF)/NaNO2 triggered nitration reactions of indoles at 313 K

Fig. 11

Plots of (k′) versus [Sub] in (TCCA–DMA)/NaNO2 triggered nitration reactions of indoles at 313 K

Fig. 12

Plots of (k′) versus [Sub] in (TCCA–DMA)/NaNO2 triggered nitration reactions of indoles at 313 K

$$\frac{1}{{\left( {{\text{A}}_{\infty } - {\text{A}}_{\text{t}} } \right)}} = \frac{\text{k}}{{\left(\upvarepsilon \right)}}\left( {\text{t}} \right) + \frac{1}{{\left( {{\text{A}}_{\infty } - {\text{A}}_{0} } \right)}}\quad ({\text{Where}}\;\varepsilon = [{\text{Reagent}}]_{0} /({\text{A}}_{\infty } - {\text{A}}_{0} )$$
(2)
Proper substitution of (ε) into the above equation leads to
$$\frac{1}{{\left( {{\text{A}}_{\infty } - {\text{A}}_{\text{t}} } \right)}} = \frac{{{\text{k}}\left[ {\text{Reagent}} \right]_{0} }}{{\left( {{\text{A}}_{\infty } - {\text{A}}_{0} } \right)}}\left( {\text{t}} \right) + \frac{1}{{\left( {{\text{A}}_{\infty } - {\text{A}}_{0} } \right)}}$$
(3)
Kinetic features, observed in Trichloroisocyanuric acid (TCCA) triggered nitration of indoles under acid free and Vilsmeier–Haack conditions, when [NaNO2] ≫ [Other reactants] are compiled in Table 1.
Table 1

Kinetic observations in trichloroisocyanuric acid (TCCA) mediated nitration of Indoles under acid free and Vilsmeier–Haack conditions

Kinetic plots

Reagent/system

Figures

Result

First order in [TCCA reagent]: the \(\ln [\left( {{\text{A}}_{\infty } - {\text{A}}_{0} } \right)/\left( {{\text{A}}_{\infty } - {\text{A}}_{\text{t}} } \right) ]\) versus time plots were linear

Order in [TCCA]

Figure 1

One

Order in [TCCA/DMF]

Figure 2

One

Order in [TCCA/DMA]

Figure 3

One

Plots of 1/(A − At) versus time plots were linear with positive slope and intercept as shown in Figs. 4, 5 and 6

TCCA system

Figure 4

Plots here in show over all second order kinetics

[TCCA/DMF] system

Figure 5

[TCCA/DMA] system

Figure 6

First order in [substrate]:

Plots of (k′) versus [substrate] were liner with positive slope

TCCA system

Figures 7 and 8

One

[TCCA/DMF] system

Figures 9 and 10

One

[TCCA/DMA] system

Figures 11 and 12

One

2.5 Effect of added olefinic monomer to determine the participation of free radicals

We have tried to gain insight participation of free radicals using olefinic monomers (acrylamide and acrylonitrile) as additives in the reaction mixture. For this purpose, we have added freshly prepared and deareated acrylamide or deareated acrylonitrile to the reaction mixture containing TCCA, NaNO2, Indole under inert (nitrogen) atmosphere. Participation of free radicals is generally indicated by the formation of dense polyacrylamide (or viscous poly acrylonitrile if acrylonitrile is used as monomer). If free radicals are generated in situ in the reaction, the generated free radicals induce the formation of olefinic monomer radical (acrylamide and acrylonitrile radical), which in turn propagate the reaction and finally polymer is formed. But added olefinic monomers did not undergo polymerization even after 24 h, suggesting that free radicals are not formed in the present study.

2.6 Product analysis under kinetic conditions

After ensuring completion of the reaction kinetics, the reaction mixture is washed with aqueous NaHCO3 and ethylacetate. Organic layer was separated, dried over MgSO4. This product was further purified over column chromatography using ethylacetate: hexane as eluent. Isolated yields of products of nitration under acid free and Vilsmeier–Haack conditions are compiled in Table 2.
Table 2

Isolated yields of products in trichloroisocyanuric acid (TCCA) triggered nitration of Indoles under acid free and Vilsmeier–Haack conditions

Indoles

Reagent

Product

Yield (%)

M.P (°C)

2-Methyl indole

TCCA

2-Methyl-5-nitroindole

79

73

75

172–175

 

(TCCA–DMF) adduct

   
 

(TCCA–DMA) adduct

   

5-Bromo indole

TCCA

5-Bromo-3-nitroindole

80

70

81

285–288

 

(TCCA–DMF) adduct

   
 

(TCCA–DMA) adduct

   

Indole

TCCA

3-Nitroindole

86

80

83

215–218

 

(TCCA + DMF) adduct

   
 

(TCCA + DMA) adduct

   

Indole-3-Acetic acid

TCCA

5-Nitroindole-3-acetic acid

79

79

75

289–291

 

(TCCA + DMF) adduct

   
 

(TCCA + DMA) adduct

   

Indole-3-carbaldehyde

TCCA

5-Nitroindole-3-carbaldehyde

82

79

81

311–314

 

(TCCA + DMF) adduct

   
 

(TCCA + DMA) adduct

   

Indole-3-ethylamine

TCCA

5-Nitroinole-3-ethylamine

69

81

73

198–201

 

(TCCA + DMF) adduct

   
 

(TCCA + DMA) adduct

   
  1. (a)

    3-nitroindole: Pale yellow solid, Melting Point: 215–218 °C. 1H NMR (CDCl3, 500 MHz) δ 11.86 (s, 1H), 8.72 (s, 1H), 8.05–8.09 (m, 1H), 7.58–7.61 (m, 1H), 7.31–7.38 (m, 2H). 13C NMR (126 MHz, DMSO-d6) δ: 142.2, 141.5, 128.9, 126.6, 122.7, 120.8, 119.8, 111.8. EI-MS m z−1 (%): 162.04 (M+) (100). Anal.Data: Calcd. for C8H6N2O2 (in %): C-59.26; H-3.73; N-17.28. Found: C-59.19; H-3.51; N-17.02.

     
  2. (b)

    2-methyl-5-nitroindole: Yellow solid, Melting Point: 311–314 °C. 1H NMR (CDCl3, 500 MHz): δ 10.1 (s, 1H), 8.91 (s, 1H), 8.52 (s, 1H), 8.16 (d, J = 8.9 Hz, 1H), 7.72 (d, J = 8.6 Hz, 1H). 13C NMR (126 MHz, DMSO-d6) δ: 185.6, 143.9, 138.6, 131.2, 127.8, 125.9, 118.7, 114.5, 112.3. EI-MS m z−1 (%): 190.04 (M+) (100). Anal.Data: Calcd. for C9H6N2O3 (in %): C-56.85; H-3.18; N-14.73. Found: C-56.58; H-3.09; N-14.59.

     
  3. (c)

    5-bromo-3-nitroindole: Brown solid, Melting Point: 285–288 °C. 1H NMR (CDCl3, 500 MHz, CDCl3) δ 10.09 (s, 1H), 8.29 (s, 1H), 7.78 (s, 1H), 7.41 (d, J = 2.9 Hz, 1H). 13C NMR (126 MHz, DMSO-d6) δ: 141.9, 139.6, 126.4, 125.5, 124.2, 121.6, 114.8, 113.5. EI-MS m z−1 (%): 239.95 (M+) (100). Anal.Data: Calcd. for C8H5BrN2O2 (in %): C-39.86; H-2.09; N-11.62. Found: C-39.58; H-2.25; N-11.51.

     
  4. (d)

    5-Nitro-3-indolecarbaldehyde: Yellow solid, Melting Point: 311–314 °C. 1H NMR (CDCl3, 500 MHz): δ 10.1 (s, 1H), 8.91 (s, 1H), 8.52 (s, 1H), 8.16 (d, J = 8.9 Hz, 1H), 7.72 (d, J = 8.6 Hz, 1H). 13C NMR (126 MHz, DMSO-d6) δ: 185.6, 143.9, 138.6, 131.2, 127.8, 125.9, 118.7, 114.5, 112.3. EI-MS m z−1 (%): 190.04 (M+) (100). Anal.Data: Calcd. for C9H6N2O3 (in %): C-56.85; H-3.18; N-14.73. Found: C-56.58; H-3.09; N-14.59.

     
  5. (e)

    5-Nitro-3-indoleaceticacid: Solid, Melting Point: 215–218 °C. 1H NMR (CDCl3, 500 MHz) δ 10.07 (s, 1H), 8.36–8.28 (m, 1H), 7.86 (d, J = 3.0 Hz, 1H), 7.48–7.41 (m, 1H), 7.36–7.31 (m, 2H). 13C NMR (126 MHz, DMSO-d6) δ: 174.8, 143.3, 132.8, 128.9, 127.1, 123.3, 114.7, 112.2, 107.6, 31.8. EI-MS m z−1 (%): 220.05 (M+) (100). Anal.Data: Calcd. for C10H8N2O4 (in %): C-54.55; H-3.66; N-12.72. Found: C-54.62; H-3.28; N-12.51.

     
  6. (f)

    5-Nitro-3-indolethylamine: Solid, Melting Point: 215–218 °C. 1H NMR (CDCl3, 500 MHz, CDCl3) δ 10.07 (s, 1H), 8.36–8.28 (m, 1H), 7.86 (d, J = 3.0 Hz, 1H), 7.48–7.41 (m, 1H), 7.36–7.31 (m, H). 13C NMR (126 MHz, DMSO-d6) δ: 174.8, 143.3, 132.8, 128.9, 127.1, 123.3, 114.7, 112.2, 107.6, 31.8. EI-MS m z−1 (%): 205.09 (M+) (100). Anal.Data: Calcd. for C10H11N3O2 (in %): C-58.53; H-5.40; N-20.48. Found: C-58.21; H-5.39; N-20.13.

     

3 Results and discussion

3.1 Kinetics and mechanism of the TCCA/NaNO2 triggered nitration reaction

The structure of indole shows that it is a bicyclic heteroaromatic compound (C8H7N) containing a five-membered pyrrole ring fused to six-membered benzene ring.

Pyrrole ring is the most reactive portion of indole, and electrophilic substitution occurs preferably at C-3. Substitution of the carbocyclic (benzene) ring can be expected only after N-1, C-2, and C-3 of indole are substituted [39]. But, electrophilic attack of indoles in position 3 is in accord with the fact that this is the carbon atom with the highest electron density [40, 41, 42]. During the synthesis of Indole-3-aldehyde, James and Snyder observed that that the most reactive position on indole for electrophilic aromatic substitution is C-3, which is 1013 times more reactive than benzene [43]. However, a noteworthy exception took place when Noland, Smith, and Rush, carried out nitration of 2-Phenylindole under acidic conditions [44, 45, 46, 47, 48, 49, 50, 51, 52]. Electrophilic nitration took place at C-5 (carbocyclic ring), because C-3 of pyrrole ring is protonated. This aspect could also be seen form the work of Da Settimo and Saettone [53], which carried out nitration of some methyl substituted indole-3-aldehydes in sulphuric acid medium. The nitration of 1-methylindole-3-aldehyde, 2-methylindole-3-aldehyde and 1, 2-dimethylindole-3-aldehyde in sulphuric acid afforded mixtures of the corresponding C-5, and C-6-nitro derivatives, containing little excess of the 5-nitro derivatives. This aspect could also be seen from another work of Sundberg [38] on nitration of methyl derivatives of indole-3-aldehyde in binary mixtures of nitric and acetic acids. In this investigation they observed that 2-Methyl indole-3-aldehyde gave 6-nitro derivative, together with some 2-methyl-3-nitro- and 2-methyl-3, 6-dinitroindole.

On the other hand, several research groups successfully used trichloroisocyanuric acid (TCCA) as effective green oxidizing and chlorinating agent because it is non-toxic, inexpensive and easily available. Earlier reviews and publications on the chemistry of TCCA [31, 32, 33] suggested that TCCA instantaneously hydrolyses to give hypochlorous acid (HOCl). In an earlier publication Lahoutifard research group [54] efficiently oxidizes nitrite ion in aqueous solutions. In a recent publication we have reported that nitration of aromatic compounds can be easily achieved using TCCA/NaNO2. On the basis of earlier reports [31, 32, 33, 54] and the results of our earlier work [36] we have explained mechanism of the reaction that the HOCl released due to the hydrolysis of TCCA reacts immediately with NaNO2 (which is large excess compared to TCCA) and liberates active nitronium ion electrophile (NO2+). This contention can be supported on the findings of Margerum et al. [55] and Wahman et al. [56]. In these publications they have suggested that the formation of reactive nitryl chloride (NO2Cl) intermediate occurs due to the reaction between nitrite and HOCl. Nitryl chloride (NO2Cl) thus formed may generate Nitronium ion (NO2+) in situ, which may convert indole into nitro indole. Observed spectroscopic and physical data revealed that nitration of parent indole underwent mono nitration at C-3 to afford 3-nitroindole as explained earlier. However, when C-3 is blocked nitration occurred at C-5 while C-5 is protected nitration occurred at C-3, which could be seen from the spectroscopic and physical data given in Table 2. At the same time, 2-Methyl indole underwent mononitration at C-5 and afforded 2-methyl-5-nitroindole, by preventing nitration at C-3. This observation could be probably attributed to the steric hindrance arising from bulky methyl group present at C-2 position which prevented nitration at neighbouring C-3 position. On the basis of foregoing discussions, a most plausible mechanism could be proposed as shown in Scheme 2.
Scheme 2

TCCA/NaNO2 triggered nitration of indoles

3.2 Kinetics and mechanism of the (TCCA–DMF)/NaNO2 and (TCCA–DMA)/NaNO2 triggered nitration

It this part of the present study the isolated [TCCA–DMF], and [TCCA–DMA] adducts were used in presence of large excess of NaNO2 to achieve nitration of indoles. The observed kinetic features (compiled in Table 1 of the present study) are almost similar to those given in our earlier work [57]. The isolated [TCCA–DMF], and [TCCA–DMA] adducts) together with the IR and NMR spectroscopic observations pertaining to TCCA, N,N′-dialkyl amides (DAA: DMF and DMA) recorded in our earlier publications [34, 35, 36] further lend support that a similar mechanism could be operative in the nitration of indoles also. Basically, interaction of N,N′-dialkyl amides (DAA: DMF and DMA) with TCCA suggests the formation of Vilsmeier–Haack type intermediate species (chloromethyleniminum cation: [(CH3)2N = C(R)Cl] +). But in the presence of excess NaNO2, chloromethyleniminum cation species reacts with NaNO2 to generate nitro methyleniminum cation: [(CH3)2N = C(R)(NO2)] +) species, which is similar to Vilsmeier–Haack type species with nitro (NO2) group. Nitro methyleniminum cation species ([(CH3)2N = C(R)(NO2)] +) produced in this step then reacts with indole in the slow step to afford corresponding nitro indole as detailed in Scheme 3.
Scheme 3

Nitration of Indoles triggered by NaNO2/Vilsmeier–Haack type adducts ([TCCA–DMF] or [TCCA–DMA])

3.3 Temperature effect and computation of activation parameters

From the mechanistic schemes 2 and 3, nitration reactions under different conditions are in accordance with second order rate law under conditions ([NaNO2]0 ≫ [Nitronium ion source]0 (where [Nitronium ion source]0 = (i) [TCCA]0 (ii) [TCCA–DMF]0 (iii) [TCCA–DMA]0).
$$\frac{d\left[ P \right]}{dt} = k \left[ {{\text{Nitronium}}\;{\text{ion}}\;{\text{source}}} \right]\left[ {\text{Indole}} \right]$$
(4)
Here, [Nitronium ion source]0 = (i) [TCCA]0 (ii) [TCCA–DMF]0, or (iii) [TCCA–DMA]0) depending on the reaction system. Therefore, above equation can be written as,
$$\frac{d\left[ P \right]}{dt} = k \left[ {{\text{TCCA}}\;{\text{Reagent}}} \right]\left[ {\text{Indole}} \right]$$
(5)
where [TCCA Reagent]0 = (i) [TCCA]0 (ii) [TCCA–DMF]0, or (iii) [TCCA–DMA]0) because nitronium ion (NO2+) electrophile herein is generated in situ under the conditions ([NaNO2]0 ≫ [TCCA Reagent]0. Second order rate constants (k) were determined at different temperatures, which increased with temperature as suggested by Arrhenius theory of temperature effect [on reaction rates (Tables 3, 4). Eyring’s theory of reaction rates [59, 60] is used for the computation of free energy of activation (∆G#) at any specific temperature (T),
$$k = \left( {{\text{k}}_{\text{t}} } \right)\left( {{\text{RT}}/{\text{Nh}}} \right){\text{exp }}\left( { - \Delta {\text{G}}^{\# } /{\text{RT}}} \right)$$
(6)
where the transmission coefficient (kt) is generally equal to unity. Taking natural logarithms of Eq. (6), (∆G#) equation could be rearranged as,
Table 3

Second order rate constant (k) and free energy of activation (∆G#) values

Substrate

Temp (K)

(k) dm3/mol.min

(∆G#) kJ/mol

TCCA

(TCCA + DMF)

(TCCA + DMA)

TCCA

(TCCA + DMF)

(TCCA + DMA)

2-Methyl indole

303

1.36

1.12

3.92

73.5

73.9

70.8

 

308

2.56

1.68

5.16

73.1

74.2

71.3

 

313

4.72

2.52

6.76

72.7

74.4

71.8

 

318

8.40

3.72

8.84

72.4

74.6

72.3

 

323

14.84

5.44

11.36

72.1

74.8

72.8

5-Bromo indole

303

0.74

0.46

0.70

75.0

76.2

75.1

 

308

0.96

0.60

0.92

75.6

76.8

75.7

 

313

1.22

0.80

1.20

76.3

77.4

76.3

 

318

1.54

1.04

1.54

76.9

77.9

76.9

 

323

1.92

1.32

2.02

77.6

78.6

77.4

Indole

303

2.80

1.20

0.90

71.6

73.8

74.5

 

308

3.04

1.44

1.18

72.7

74.6

75.1

 

313

3.44

1.80

1.58

73.6

75.2

75.6

 

318

3.92

2.12

2.10

74.4

76.1

76.1

 

323

4.22

2.50

2.74

75.5

76.8

76.6

Indole-3-acetic acid

303

0.48

0.50

0.52

76.1

75.9

75.9

 

308

0.60

0.62

0.66

76.8

76.7

76.6

 

313

0.74

0.78

0.80

77.6

77.4

77.4

 

318

0.90

0.94

0.96

78.3

78.2

78.1

 

323

1.10

1.20

1.16

79.1

78.8

78.9

Indole-3-carboxaldehyde

303

1.12

1.36

1.80

73.9

73.5

72.8

 

308

1.48

1.64

2.24

74.5

74.2

73.4

 

313

1.84

2.04

2.84

75.2

74.9

74.1

 

318

2.36

2.56

3.64

75.8

75.6

74.6

 

323

2.96

2.92

4.64

76.4

76.4

75.2

Indole-3-ethylamine

303

1.36

1.20

1.48

73.5

73.8

73.2

 

308

1.80

1.44

1.92

74.0

74.6

73.8

 

313

2.40

1.76

2.36

74.5

75.3

74.5

 

318

3.08

2.12

3.00

75.1

76.1

75.1

 

323

3.92

2.56

3.76

75.6

76.8

75.7

Table 4

Activation parameters (∆H# and ∆S#) using TCCA and TCCA Adducts

Activation parameter

Substrate

TCCA

(TCCA + DMF) adduct

(TCCA + DMA) adduct

∆H# (kJ/mol)

2-Methyl indole

94.5

61.8

40.8

 

5-Bromo indole

36.1

40.7

40.3

 

Indole

14.9

27.6

43.0

 

Ind-3-acetic acid

31.0

32.7

29.6

 

Ind-3-carboxaldehyde

36.6

29.5

36.155

 

Ind-3-ethylamine

40.6

28.4

35.0

− ∆S# (J/K/mol)

2-Methyl indole

− 69.6

40.2

99.0

 

5-Bromo indole

128

117

115

 

Indole

187

152

104

 

Ind-3-acetic acid

148

143

155

 

Ind-3-carboxaldehyde

123

145

121

 

Ind-3-ethylamine

108

150

126

$$\Delta {\text{G}}^{\# } = {\text{RTln}} \left( {RT/{\text{Nh}}k} \right)$$
(7)
Substitution of proper values of R, N, and h values (SI units) into Eq. (7), ∆G# could be again simplified to Eq. (8),
$$\Delta {\text{G}}^{\# } = 8.314 \times {\text{T}}\left[ {23.7641 + \ln \left( {{\text{T}}/{\text{k}}} \right)} \right]$$
(8)
Second order rate constants (k) and computed (∆G#) values at various temperatures are compiled in Table 3. At this stage enthalpy and entropies of activation (∆H# and ∆S#) values could be obtained from the Gibbs–Helmholtz plot of (∆G#) versus temperature (T) according to Eq. (9).
$$\Delta {\text{G}}^{\# } = \Delta {\text{H}}^{\# } - {\text{T}}\Delta {\text{S}}^{\# }$$
(9)
Accordingly, the plot of (∆G#) versus (T) should give a straight line with negative slope (∆S#) and intercept (∆H#) on ordinate. But in practice, either positive or negative slope may be obtained depending on the nature of the transition state (Figs. 13, 14, 15). If the slope is negative, magnitude of entropy of activation (∆S#) is positive and vice versa. Positive (∆S#) shows a dissociative mechanism, and a non-rigid or loosely bound transition state in which reactant molecules move randomly by making it unstable. On the contrary, negative magnitude of (∆S#) generally suggests greater solvation of the transition state, followed by an associative mechanism in which two reaction partners form a single activated complex [61]. Obtained enthalpy of activation (∆H#), and entropy of activation (∆S#) values are compiled in Table 4.
Fig. 13

Gibbs-Helmholtz plot (∆G# vs. T) for TCCA/NaNO2 triggered nitration of indoles

Fig. 14

Gibbs-Helmholtz plot (∆G# vs. T) for (TCCA–DMF)/NaNO2 triggered nitration of indoles

Fig. 15

Gibbs-Helmholtz plot (∆G# vs. T) for (TCCA–DMA)/NaNO2 triggered nitration of indoles

3.3.1 Enthalpy (ΔH#) and entropy of activation (ΔS#) relationship and compensation effect

A closer insight into the data presented in Table 4 revealed that the enthalpy (ΔH#) and entropy of activation (ΔS#) the reactions are neither isentropic (iso entropic) nor isenthalpic (iso enthalpic) but represent compensation effect of both (ΔH#) and (ΔS#), as suggested by Shorter and Hinshelwood [62, 63, 64, 65, 66]. According to their classification, isenthalpic (iso-enthalpic) reactions do not show any variation in (ΔH#) values with the structural variation of substituent and the reactions are completely controlled by entropy of action (ΔS#) values. Contrary to this in isentropic (iso entropic) reactions structural variation of substituent do not show any variation in the entropy of action (ΔS#) values and the reactions are controlled by enthalpy of activation (ΔH). In the last category, structural variation of substituent has significant effect on both (ΔH#) and (ΔS#) factors. The (ΔH#) values are paralleled by and (ΔS#) factors, in such way that the reactions could be either enthalpy (ΔH#) controlled or entropy (ΔS#) controlled. To understand further and interpret these reactions, Leffler [67, 68] introduced the concept of isokinetic temperature (β) in chemical kinetics (and isoequilibrium temperature (β) in chemical equilibria), and suggested an equation to calculate (β):
$$\Delta {\text{H}}^{\# } =\upbeta\Delta {\text{S}}^{\# } + \Delta {\text{H}}_{0}^{\# }$$
where ΔH 0 # is constant irrespective of the nature of substituents. Further, it was also stated that at isokinetic temperature (β), all the compounds in the reaction series occur with the same reaction rate. The variation of substituent does not alter the rate constant and corresponding free energy of activation (ΔG#). chemical reaction. However, in isentropic (or iso entropic) reactions, isokinetic temperature (β) value is very high (as high as if it would be infinity) and the reactions are controlled by enthalpy of activation, while the isokinetic temperature (β) is zero for an isenthalpic (iso-enthalpic) series, and the reactivity is determined by the entropy of activation. In the present work the Leffler plots of (ΔH#) versus (ΔS#) were found to be linear with very high (R2) values as shown in Figs. 16, 17 and 18.
Fig. 16

Leffler’s Plot of ∆H# versus ∆S# for TCCA–Indoles reactions

Fig. 17

Leffler’s Plot of ∆H# versus ∆S# for (TCCA–DMF)-Indoles reactions

Fig. 18

Leffler’s Plot of ∆H# versus ∆S# for (TCCA–DMA)-Indoles reactions

The isokinetic temperature (β) values for the studied nitration protocols are shown below:

Reagent

β (K)

TCCA/NaNO2

303

(TCCA + DMF) adduct/NaNO2

303

(TCCA + DMA) adduct/NaNO2

244

The isokinetic temperature (β) values presented for (TCC/NaNO2) and [(TCCA + DMF) Adduct/NaNO2] mediated nitration reactions (303 K for both the systems) are very close to the experimental temperature range (303 K to 323 K), while the (β) value for [(TCCA + DMA) Adduct/NaNO2] mediated nitration reactions (244 K) is far below the experimental temperature. The observed isokinetic temperature (β) values most probably suggest that the reactions are controlled by entropy factors as suggested by earlier literature reports. At this point it is worth mentioning that Leffler’s approach for the determination of isokinetic temperature (β) is criticized by some research groups [69, 70], yet the theory is used by several other research groups [71, 72, 73, 74].

3.4 Conclusions

In the present work we have developed trichloroisocyanuric acid (TCCA)/NaNO2, (TCCA–DMF)/NaNO2 and (TCCA–DMA)/NaNO2 mediated nitration of indoles by keeping [NaNO2] large excess over other [reactants] under acid free conditions. The reaction followed second order kinetics with first order dependence on [Nitrating agent] and [Indole]. A closer look into the obtained kinetic data revealed that the reaction is sensitive to the structural variation of indole. Nitration of parent indole took place at C-3 position of parent indole and gave 3-nitroindole. But, when C-3 is protected nitration underwent at C-5, when C-5 is protected nitration took place at C-3. At the same time, 2-Methyl indole underwent mononitration at C-5 and afforded 2-methyl-5-nitroindole, by preventing nitration at C-3. This observation could be probably attributed to the steric hindrance arising from bulky methyl group present at C-2 position which prevented nitration at neighbouring C-3 position.

Notes

Acknowledgements

Authors sincerely thank Head, Department of Chemistry and other senior Professors for facilities and constant encouragement.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of ChemistryOsmania UniversityHyderabadIndia

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