# Kinetic and Mechanistic Investigation of Pyrano[2,3-d]pyrimidine Formation in the Presence of Catalyst under Novel One-Pot Three-Component Reaction

Authors: Sayyed Mostafa Habibi-Khorassani; Malek Taher Maghsoodlou; Mehdi Shahraki; Sadegh Talaiefar; Jasem Aboonajmi
Journal: Organic Chemistry International
 (2014)

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## Abstract

Sodium acetate was applied as an efficient catalyst for the one-pot, three-component condensation reactions consisting of 4-nitrobenzaldehyde2, malononitrile 3, and thiobarbituric acid 1. Use of nontoxic reaction components, short reaction times, environmental, easy work-up, and high yields are some remarkable advantages of this method. Kinetics and mechanism of the reaction were spectrally studied and the second order rate constant (kovr = k1) was automatically calculated by the standard equations contained within the program. The second order rate constant [Ln(kovr = k1), Ln(kovr = k1)/T] that depended on reciprocal temperature was in good agreement with the Arrhenius and Eyring equations, respectively. This data provided the suitable plots for calculating the activation energy and parameters (Ea, ΔG‡, ΔS‡, and ΔH‡) of the reaction. Furthermore, from studying the effects of solvent, concentration, and catalyst on the reaction rate, useful information was obtained regarding the mechanism. The results showed that the first step of the reaction mechanism is a rate determining step (RDS). The proposed mechanism was confirmed in accordance with the experimental data and also the steady state approximation.


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## Body

## 1. Introduction

Multicomponent reactions (MCRs) involving pot, atom, and step-economy have received substantial consideration from the organic community due to their advantages over conventional multistep synthesis [1–6]. This kind of reactions have some advantages over conventional linear syntheses, including shorter reaction times, lower costs, high atom-economy, energy saving, the possibility for combinatorial surveying of structural variations, and environmental friendliness.The benzopyrans and their derivatives, in particular, have shown several biological and pharmacological properties, such as spasmolytic, diuretic, antianaphylactin, antisterility, and anticancer agents [7–10]. The polyfunctionalized benzopyrans were used as cosmetics, pigments, and biodegradable agrochemicals [11, 12]. Due to their applications, the syntheses of heterocyclic derivatives of these ring systems have great importance in medicinal chemistry and organic synthesis. Strategies for the synthesis of these compounds have varied from one-pot to multistep approaches [13]. In recent years, the syntheses of pyrano[2,3-d]pyrimidine were reported using a plethora of reagents in the presence of catalyst, such asL-proline [14], microwave irradiation [15], H6P2W18O62·18H2O [16], 4-(dimethylamino) pyridine (DMAP) [17], and diammonium hydrogen phosphate [18]. However, some of these methods have drawbacks, such as long reaction times, unsatisfactory yields. Furthermore, some of the used catalysts are either expensive or difficult to prepare. Owing to the importance of pyrano[2,3-d]pyrimidine from a pharmaceutical and biological point of view, there is still a need to develop an efficient, mild reaction benign protocol for the synthesis of pyrano[2,3-d]pyrimidine. As a part of our current studies on development of efficient multicomponent reactions for the preparation of interesting bioactive molecules [19–22], especially the synthesis of pyrano[2,3-d]pyrimidine [23], we report here, a simple and efficient procedure for the synthesis of pyrano[2,3-d]pyrimidine via a one-pot, three-component condensation reaction between 4-nitrobenzaldehyde2, malononitrile3, and thiobarbituric acid1 in the presence of catalytic amounts of NaOAc 5 mol% in a mixture of aqueous ethanol at 50°C (Scheme 1).Scheme 1The kinetics and mechanism of the mentioned reaction were monitored using the UV-vis spectrophotometery apparatus. Kinetics and mechanism of numerous reactions have been previously studied using the UV-vis technique [24–28]. In recent years, we have endeavored to expand the synthesis of phosphorous ylides along with developing experimental and theoretical studies on the kinetics and mechanisms of these reactions [29–36]. In these studies, reactions occurred by at least three steps. The first step of the proposed mechanism was recognized as a rate-determining step and this was confirmed based upon the steady-state approximation. Moreover, the overall reaction order followed second-order kinetics. The rate of all reactions was increased in solvents with upper dielectric constant value that could be related to the differences in stabilization of the reactants and the zwitterionic intermediate by the solvents [29–36]. In present work, we describe kinetic results together with detailed mechanistic studies for the one-pot, three-component condensation reactions consisting of 4-nitrobenzaldehyde2, malononitrile3, and thiobarbituric acid1in the presence of sodium acetate as a catalystin methanol and environmental friendless solvents (mixture of ethanol and H2O 50/50) based on a global kinetic analysis methodology using the UV-vis spectrophotometry apparatus.


## 2. Experimental

In order to optimize the reaction conditions, the synthesis of reaction between 4-nitrobenzaldehyde2 (1 m mol), malononitrile3 (1 m mol), and thiobarbituric acid1 (1 m mol) was carried out using different quantities of sodium acetate under different conditions. It was found that the best results were obtained under condition with 5 mol% sodium acetate under H2O : EtOH (4 : 1, 5 mL) at 50°C (Table 1).Table 1
Entry
Substrate
1,3-Dicabonyl
Product
Time (min)
Yield (%)a
M.P observed (°C)
M.P reported (°C)
1
4-NO2C6H4
3
4
14
98
234–236
235-236 [5]
aYields refer to the pure isolated products.


### 2.1. Chemicals and Apparatus

The 4-nitrobenzaldehyde2, malononitrile3, thiobarbituric acid1, and sodium acetate were obtained from Merck (Darmstadt, Germany), Acros (Geel, Belgium), and Fluka (Buchs, Switzerland) and used without further purification. All extra pure solvents including the methanol and ethanol were also obtained from Merck (Darmstadt, Germany). A Cary UV/Vis spectrophotometer model Bio-300 with a 10 mm light-path quartz spectrophotometer cell was employed throughout the current work.


### 2.2. General Procedure for the Synthesis of a Pyrano[2,3-d]pyrimidine

A mixture of 4-nitrobenzaldehyde2 (1 m mol), malononitrile3 (1 m mol), thiobarbituric acid1 (1 m mol), and sodium acetate (5 mol%) in water and ethanol (4 : 1, 5 mL) was heated for an appropriate length of time. During the procedure, the reaction was monitored by TLC, after completion of the reaction, the mixture was filtered and the precipitated solid re-crystallized from ethanol 98% to give compound4 in high yield. Spectroscopic data of product4 is given below: 7-Amino-6-cyano-5-(4-nitrophenyl)-4-oxo-2-thioxo-5Hpyrano [2, 3-d]pyrimidinone. Yellow solid, Yield: 98%=0.337g; IR (KBr) υ: 3369 (NH2), 3191 (N–H), 2201 (C≡N), 1684 (C=O), 1572 (C=S), 1278 (C–O) cm−1; 1H NMR (400 MHz, DMSO-d6) δ: 4.48 (1H, s, CH), 7.30 (2H, s, NH2), 7.55–8.15 (4H, m, H–Ar), 12.46 (1H, brs, NH), 13.50 (1H, brs, NH) ppm.


## 2.1. Chemicals and Apparatus

The 4-nitrobenzaldehyde2, malononitrile3, thiobarbituric acid1, and sodium acetate were obtained from Merck (Darmstadt, Germany), Acros (Geel, Belgium), and Fluka (Buchs, Switzerland) and used without further purification. All extra pure solvents including the methanol and ethanol were also obtained from Merck (Darmstadt, Germany). A Cary UV/Vis spectrophotometer model Bio-300 with a 10 mm light-path quartz spectrophotometer cell was employed throughout the current work.


## 2.2. General Procedure for the Synthesis of a Pyrano[2,3-d]pyrimidine

A mixture of 4-nitrobenzaldehyde2 (1 m mol), malononitrile3 (1 m mol), thiobarbituric acid1 (1 m mol), and sodium acetate (5 mol%) in water and ethanol (4 : 1, 5 mL) was heated for an appropriate length of time. During the procedure, the reaction was monitored by TLC, after completion of the reaction, the mixture was filtered and the precipitated solid re-crystallized from ethanol 98% to give compound4 in high yield. Spectroscopic data of product4 is given below: 7-Amino-6-cyano-5-(4-nitrophenyl)-4-oxo-2-thioxo-5Hpyrano [2, 3-d]pyrimidinone. Yellow solid, Yield: 98%=0.337g; IR (KBr) υ: 3369 (NH2), 3191 (N–H), 2201 (C≡N), 1684 (C=O), 1572 (C=S), 1278 (C–O) cm−1; 1H NMR (400 MHz, DMSO-d6) δ: 4.48 (1H, s, CH), 7.30 (2H, s, NH2), 7.55–8.15 (4H, m, H–Ar), 12.46 (1H, brs, NH), 13.50 (1H, brs, NH) ppm.


## 3. Kinetics Studies

### 3.1. Method

Kinetics measurements of the reaction between 4-nitrobenzaldehyde2, malononitrile3, and thiobarbituric acid1 in the presence of sodium acetate as a catalyst were performed using the UV-vis spectrophotometry technique. Firstly, it was necessary to find the suitable wavelength for the kinetic study of the reaction. For this reason in thefirst experiment, 10−2 M solution of each compound1,2,3 and 10−2 M solution of sodium acetate were prepared in methanol as solvent. The relevant spectrum of each compound was recorded over the wavelength range 200–600 nm. In thesecond experiment, the reaction mixture was started into a 10 mm black quartz spectrophotometer cell along with a 10−2 M solution of each compound (1,2 and3) and 10−2 M sodium acetate according to stoichiometry of each compound in the overall reaction. The reaction was monitored by conducting scans of the entire spectrum with 10-second intervals during the whole reaction time at ambient temperature. The typical UV spectra are shown in Figure 1. Herein, the upward direction of the arrow indicates the progress of product versus time. From this, the appropriate wavelength was discovered to be 390, 415, 420, 430, and 435 nm. Since at these wavelengths, compounds1,2,3, and sodium acetate have relatively no absorbance value, it gave us the chance to find the practical conditions that allow kinetics and a mechanistic investigation of the reaction. Herein, in all the experiments, the UV-vis spectrum of the compound product was measured over the concentration range (10−3 M ≤ M product ≤ 10−2 M) to confirm a linear relationship between the absorbance and concentrations values.(a) The UV-vis spectra of the reaction between 4-nitrobenzaldehyde2 (10−2 M), malononitrile3 (10−2 M), and thiobarbituric acid1 (10−2 M) in the presence of sodium acetate as a catalyst in methanol as reaction proceeds into a 10 mm light-path cell. Herein, the upward direction of the arrow indicates the progress of product versus times. (b) The UV spectrum of the final product.
(a)
(b)In thethird experiment under the same concentration of each compound (10−2 M), experimental absorbance curve was recorded versus time at 25°C temperature and wavelength 430 nm. Figure 2 shows that the experimental curve (dotted line) is fitted to second order curve (solid line). It is obvious that the reaction is second order. Then, the rate constant (12.64 min−1·M−1) of the reaction was automatically calculated by the software associated [38] within the UV-vis spectrophotometer.(a) The experimental absorbance values for reaction compounds1,2,3, and catalyst in a mixture of ethanol and water. (b) The experimental absorbance change (dotted line) along with the second order fit curve (solid line) against time for the reaction between 4-thiobarbituric acid1 (10−2 M), malononitrile3 (10−2 M), 4-nitrobenzaldehyde2 (10−2 M), and (10−2 M) catalyst, at 430 nm, 25.0°C, and in methanol.
(a)
(b)In this case, overall order of rate low can be written asα+β+γ=2. Consider the following:
(1)Rate=kovr[3]α[2]β[1]γ[Cat].


## 3.1. Method

Kinetics measurements of the reaction between 4-nitrobenzaldehyde2, malononitrile3, and thiobarbituric acid1 in the presence of sodium acetate as a catalyst were performed using the UV-vis spectrophotometry technique. Firstly, it was necessary to find the suitable wavelength for the kinetic study of the reaction. For this reason in thefirst experiment, 10−2 M solution of each compound1,2,3 and 10−2 M solution of sodium acetate were prepared in methanol as solvent. The relevant spectrum of each compound was recorded over the wavelength range 200–600 nm. In thesecond experiment, the reaction mixture was started into a 10 mm black quartz spectrophotometer cell along with a 10−2 M solution of each compound (1,2 and3) and 10−2 M sodium acetate according to stoichiometry of each compound in the overall reaction. The reaction was monitored by conducting scans of the entire spectrum with 10-second intervals during the whole reaction time at ambient temperature. The typical UV spectra are shown in Figure 1. Herein, the upward direction of the arrow indicates the progress of product versus time. From this, the appropriate wavelength was discovered to be 390, 415, 420, 430, and 435 nm. Since at these wavelengths, compounds1,2,3, and sodium acetate have relatively no absorbance value, it gave us the chance to find the practical conditions that allow kinetics and a mechanistic investigation of the reaction. Herein, in all the experiments, the UV-vis spectrum of the compound product was measured over the concentration range (10−3 M ≤ M product ≤ 10−2 M) to confirm a linear relationship between the absorbance and concentrations values.(a) The UV-vis spectra of the reaction between 4-nitrobenzaldehyde2 (10−2 M), malononitrile3 (10−2 M), and thiobarbituric acid1 (10−2 M) in the presence of sodium acetate as a catalyst in methanol as reaction proceeds into a 10 mm light-path cell. Herein, the upward direction of the arrow indicates the progress of product versus times. (b) The UV spectrum of the final product.
(a)
(b)In thethird experiment under the same concentration of each compound (10−2 M), experimental absorbance curve was recorded versus time at 25°C temperature and wavelength 430 nm. Figure 2 shows that the experimental curve (dotted line) is fitted to second order curve (solid line). It is obvious that the reaction is second order. Then, the rate constant (12.64 min−1·M−1) of the reaction was automatically calculated by the software associated [38] within the UV-vis spectrophotometer.(a) The experimental absorbance values for reaction compounds1,2,3, and catalyst in a mixture of ethanol and water. (b) The experimental absorbance change (dotted line) along with the second order fit curve (solid line) against time for the reaction between 4-thiobarbituric acid1 (10−2 M), malononitrile3 (10−2 M), 4-nitrobenzaldehyde2 (10−2 M), and (10−2 M) catalyst, at 430 nm, 25.0°C, and in methanol.
(a)
(b)In this case, overall order of rate low can be written asα+β+γ=2. Consider the following:
(1)Rate=kovr[3]α[2]β[1]γ[Cat].


## 4. Result and Discussion

### 4.1. Effects of Concentration

Partial order of the reactants is obtained under pseudoorder. In thefourth experiment, we followed the reaction kinetics by plotting the UV-vis absorbance versus time at wavelength 420 nm for the 10−2 M, 10−2 M, and 10−3 M solution of each compound (1,2, and3), respectively, at 25.0°C along with 10−2 M solution of sodium acetate. For this case, the rate law can be expressed as follows:
(2)Rate=kovr[3]α[2]β[1]γ[Cat]Rate=kobs[3]αkobs=kove[2]β[1]γ[Cat].
The infinity absorbance (A∞) is the absorbance at reaction completion and is obtainable from Figure 3 at t=85 min. With respect to this value, the zero, first, or second curve fittings can be drawn automatically for the reaction using the software [38] associated with the UV/Vis instrument. The original experimental absorbance against time data made a pseudo-first-order available fit curve at 420 nm, which exactly fits the experimental curve (dotted line) and is displayed in Figure 3. Herein, observation rate constant (kobs) was automatically calculated for (2) by the software associated within the UV/Vis instrument. It is obvious that the reaction is of the first order type with respect to malononitrile3, α=1.Figure 3
First pseudoorder fit curve (solid line) along with the original experimental curve (dotted line) in relation to malononitrile3, for the reaction between1 (10−2 M),2 (10−2 M), and3(10−3 M) which was processed in methanol at 25°C and 420 nm.Also to gain a partial order of the reaction with respect to 4-nitrobenzaldehyde2, (10−3 M), under pseudoorder condition, compounds3 and1 were used in excess (10−2 M).Fifth experiment was employed as the previous experiment (fourth). The rate low can be written as follows:
(3)Rate=kovr[3]α[2]β[1]γ[Cat]Rate=kobs[2]βkobs=kovr[3]α[1]γ[Cat].
The original experimental absorbance against time data (Figure 4) creates a first order fit curve (full line) at 415 nm, which fits the experimental curve precisely. Therefore, the reaction is of the first order type with respect to (3) in relation to the 4-nitrobenzaldehyde2, β=1.Figure 4
First pseudoorder fit curve (solid line) accompanied by the original experimental curve (dotted line) with respect to 4-nitrobenzaldehyde2, for the reaction between1 (10-2 M),3(10-2 M), and2(10-3 M) which proceeded in methanol at 25°C and 415 nm.In thesixth experiment, the reaction was followed in the presence of an excess of compounds3 and2 (10−2 M of each) along with 10−3 M of compound1, so the rate low can be expressed as follows:
(4)Rate=kovr[3]α[2]β[1]γ[Cat]Rate=kobs[1]γkobs=kovr[3]α[2]β[Cat].
The experimental absorbance curve versus time along with a second-order fit was recorded at 25°C and wavelength 435 nm (Figure 5). Then, the rate constant (kobs = 12.40 min−1·M−1) of the reaction was automatically obtained by the software programme. In fact, the obtained rate constant (12.40) for (4) from the sixth experiment is equal to second order rate constant (12.64) of third experiment ((1) for 10−2 M of each compound). Although in both (sixth and third) experiments, whole conditions are the same, with the exception of concentration of compound1, that is, 10−3 M and 10−2 M, respectively; nevertheless, in the two cases, the reaction is second order and independent of concentration1; this is possible when γ is zero in both (1) and (4). It means that the reaction is zero and of the second order type in relation to compound1 and sum of2 and3 (α+β=2), respectively. As a result, the overall order of reaction is two which is the same as the previous experiment (third experiment).Figure 5
Second order fit curve (solid line) along with the original experimental curve (dotted) for the reaction between 4-hydroxycoumarin1 (10−3 M), malononitrile3 (10−2 M), and 4-nitrobenzaldehyde2 (10−2 M) which was proceed in methanol at 25.0°C and 435 nm.Utilizing the above results, the simplified scheme of the proposed reaction mechanism (Scheme2, [29–31]) as a possible explanation is shown in Figure 6 [14, 18, 37].Scheme 2Figure 6
The simplified Scheme for the proposed reaction mechanism [14, 18, 37].To investigate which steps of the proposed mechanism is the rate-determining step, the rate law was written using the final step of reaction as follows:(5)Rate=k5[I4].
The steady state approximation can be applied for obtaining the concentration of [I4], which is generated from the following equations:
(6)d[I4]dt=k4[I3][Cat]-k5[I4]=0(7)k4[I3][Cat]=k5[I4].
The value of (7) can be replaced in (5) so the rate equation becomes
(8)Rate=k4[I3][Cat].
For obtaining the concentration of intermediate [I3], the following equation is yielded by applying the steady state assumption:
(9)d[I3]dt=k3[I2][Cat-]-k4[I3][Cat]=0,k3[I2][Cat-]=k4[Cat][I3],
and with the replacement of (9) in (8), the following equation is obtained:
(10)Rate=k3[I2][Cat-].
And we can obtain the value of [I2] as follows which can be replaced in (10) for generation of (13):
(11)d[I2]dt=k2[I1][Cat-][1]-k3[I2][Cat-]=0(12)k2[I1][Cat][1]=k3[I2][Cat-](13)Rate=k2[I1][1][Cat].
The concentration of intermediate [I1] is obtained using steady state approximation, and by substituting (15) into (13), (16) is yielded as follows:
(14)d[I1]dt=k1[2][3][Cat]-k-1[I1][Cat][H2O]-k2[I1][1][Cat](15)[I1]=k1[2][3]k-1[H2O]+k2[1](16)Rate=k1k2[1][2][3][Cat]k-1[H2O]+k2[1].
Equation (16) is not compatible with the experimental data
(17)Rate=kovr[2][3][Cat].
Therefore, the rate constants k-1 and k2 have no chance to be a rate determining step; nevertheless, if k2≫k-1[H2O], the following equations can be obtained:
(18)Rate=(k1=kovr)[2][3][Cat].
The final equation (18) (remerge from steady state assumption) indicates that the overall order of the reaction is two; additionally, in accordance with this equation, the order of reaction with respect to each compound (3,2 and1) is 1, 1, and zero, respectively, which was previously confirmed by the experimental data (17). It is obvious that overall constant (kove) in (17) is equal to rate constant (k1) in (18). Because of the presence of k1 in the rate low (18), it is obvious that first step (k1) is a rate determining step and k2 should be a fast step. In this case, the transition state (see Scheme 2, step 1) in reaction carries a dispersed charge effect of solvent (next section, mixture of water and ethanol, 50/50) which has higher dielectric constant (ε=52.12) more than methanol (with lower dielectric constant ε=32.6) on this dispersed charge which would be much stronger compared to that on reactants (2 and3) that do not have any charge. The solvent thus stabilizes the species at the transition state more than it does the reactants, and therefore Ea would be lower and speeding up the reaction rate (see Table 2, effect of both solvents). As is evident, the concentration of sodium acetate as a catalyst appears in the rate law (18), since, at the end of mechanism, (Scheme 2) sodium acetate is generated once again, and keep a constant value in its concentration. With respect to (18), k1 is a rate determining step; therefore, the activation parameters which involve ΔG‡, ΔS‡, and ΔH‡ can be now calculated for the first step (rate determining step, k1), as an elementary reaction, on the basis of Eyring equation (a) of Figure 7(a), Ln(k1=kove)/T versus 1/T and also a different linearized form of Eyring equation (b) of Figure 7(b), T×Ln(k1=kove)/T against (T) [39]. The results are accumulated in Figures 7(a) and 7(b). Statistical analysis of the Eyring equation clearly confirms that the standard errors of ΔS‡ and ΔH‡ correlate (Tav is the center of the temperature range used) as follows:
(19)σ(ΔS‡)=1Tavσ(ΔH‡).
It follows that in most solution phase studies σ(ΔS‡)≈σ(ΔH‡)×0.003K-1. This correlation has been mentioned elsewhere [39, 40]. The standard errors for activation parameters have been calculated according to the above instructions [39–41] and they have been reported along with these parameters in Figures 7(a) and 7(b). With respect to the values of ΔS‡ and ΔH‡ (see Figures 7(a) and 7(b)), (ΔG‡=54.32kJmol-1) is reported for the reactions between1,2, and3 in a mixture of ethanol and water at 430 nm and 298.2 K.Table 2
Rate constantskobs (min−1 M−1), k1=kove (min−1 M−2) for the reaction between 2 (10−2 M), 3 (10−2 M), and 1 (10−2 M) in the presence of sodium acetate (as a catalyst) and both solvents methanol (32.6)a and a mixture of ethanol and water (ethanol : water, 1 : 1), (52.12)d.
Solvent: methanol (32.6)a
T (°C)
T
= 20°C
T
= 25°C
T
= 30°C
T
= 35°C
T
= 40°C
T
= 45°C
T
= 50°C
k
obs
3.5092
6.2492
9.0095
11.7607
14.50
18.15
22.10
(0.0011)b
(0.0094)
(0.0102)
(0.0065)
(0.0189)
(0.0099)
(0.0199)
k
ove
c
350.92
624.92
900.95
1176.07
1450
1815
2210
Solvent: mix ethanol/water (52.12)d
T (°C)
T
= 20°C
T
= 25°C
T
= 30°C
T
= 35°C
T
= 40°C
T
= 45°C
T
= 50°C
k
obs
9.4693
12.6398
14.9811
17.7596
20.507
24.609
29.705
(0.007)b
(0.0093)
(0.0116)
(0.0139)
(0.0164)
(0.0186)
(0.0193)
k
ove
946.93
1263.98
1498.11
1775.96
2050.7
2460.9
2970.5
a,dDielectric constant.
bSD (standard deviation).
cIs overall rate constant.(a, b) Eyring plots according to (1) and (2), for the reaction between1,2,3, and sodium acetate catalyst in methanol.
(a)
(b)


### 4.2. Effect of Solvents and Temperature

In order to determine the effect of change in temperature and solvent environment on the reaction rate, various experiments were arranged with different temperatures and solvent polarity under the same conditions with the previous experiment. For this purpose, dry methanol and a mixture of ethanol and water (ethanol : water, 1 : 1) have been used in the experiment. The results showed that the rate of reaction speeds up in solvent with high dielectric constant (ethanol and water) compared to lower dielectric constant (methanol) at all investigated temperatures (see Table2).Also, as can be seen in Table2, rate of the reaction increases by raising the temperature. In the studied temperature range, the second-order rate constant (Lnk1) of the reaction was inversely proportional to the temperature, which is in agreement with the Arrhenius equation. This behavior is shown in Figure 7. The activation energy, for the reaction between1,2, and3 was obtained in lone a mixture of ethanol and water (1 : 1) (45.98±0.25kJ·mol-1) form the slope of Figure 8.Figure 8
The dependence12 of the second order rate constant (Lnk1) on reciprocal temperature for the reaction between compounds1,2, and3measured in methanol at wavelength of 430 nm according to the Arrhenius equation.


### 4.3. Effect of Catalyst

The rate of reaction was reduced in the presence of Zn (CH3CO2)2 as a second catalyst in a mixture of ethanol and water (1 : 1) in comparison with the first catalyst (NaCH3CO2). It seems that Zn+2 ions have more interactions with polar solvent in relation to Na+ ions. This reduces the rate of reaction in the second catalyst media (see Table 3).Table 3
Effect of various catalysts on a reaction between1, 2, and 3 compounds in the presence of methanol solvent.
Catalyst
k
1
×
10
2 (min−1·M−2)
SD
T
= 25°C
NaCH3CO2
6.25
0.0118
Zn(CH3CO2)2
2.08
0.0160


## 4.1. Effects of Concentration

Partial order of the reactants is obtained under pseudoorder. In thefourth experiment, we followed the reaction kinetics by plotting the UV-vis absorbance versus time at wavelength 420 nm for the 10−2 M, 10−2 M, and 10−3 M solution of each compound (1,2, and3), respectively, at 25.0°C along with 10−2 M solution of sodium acetate. For this case, the rate law can be expressed as follows:
(2)Rate=kovr[3]α[2]β[1]γ[Cat]Rate=kobs[3]αkobs=kove[2]β[1]γ[Cat].
The infinity absorbance (A∞) is the absorbance at reaction completion and is obtainable from Figure 3 at t=85 min. With respect to this value, the zero, first, or second curve fittings can be drawn automatically for the reaction using the software [38] associated with the UV/Vis instrument. The original experimental absorbance against time data made a pseudo-first-order available fit curve at 420 nm, which exactly fits the experimental curve (dotted line) and is displayed in Figure 3. Herein, observation rate constant (kobs) was automatically calculated for (2) by the software associated within the UV/Vis instrument. It is obvious that the reaction is of the first order type with respect to malononitrile3, α=1.Figure 3
First pseudoorder fit curve (solid line) along with the original experimental curve (dotted line) in relation to malononitrile3, for the reaction between1 (10−2 M),2 (10−2 M), and3(10−3 M) which was processed in methanol at 25°C and 420 nm.Also to gain a partial order of the reaction with respect to 4-nitrobenzaldehyde2, (10−3 M), under pseudoorder condition, compounds3 and1 were used in excess (10−2 M).Fifth experiment was employed as the previous experiment (fourth). The rate low can be written as follows:
(3)Rate=kovr[3]α[2]β[1]γ[Cat]Rate=kobs[2]βkobs=kovr[3]α[1]γ[Cat].
The original experimental absorbance against time data (Figure 4) creates a first order fit curve (full line) at 415 nm, which fits the experimental curve precisely. Therefore, the reaction is of the first order type with respect to (3) in relation to the 4-nitrobenzaldehyde2, β=1.Figure 4
First pseudoorder fit curve (solid line) accompanied by the original experimental curve (dotted line) with respect to 4-nitrobenzaldehyde2, for the reaction between1 (10-2 M),3(10-2 M), and2(10-3 M) which proceeded in methanol at 25°C and 415 nm.In thesixth experiment, the reaction was followed in the presence of an excess of compounds3 and2 (10−2 M of each) along with 10−3 M of compound1, so the rate low can be expressed as follows:
(4)Rate=kovr[3]α[2]β[1]γ[Cat]Rate=kobs[1]γkobs=kovr[3]α[2]β[Cat].
The experimental absorbance curve versus time along with a second-order fit was recorded at 25°C and wavelength 435 nm (Figure 5). Then, the rate constant (kobs = 12.40 min−1·M−1) of the reaction was automatically obtained by the software programme. In fact, the obtained rate constant (12.40) for (4) from the sixth experiment is equal to second order rate constant (12.64) of third experiment ((1) for 10−2 M of each compound). Although in both (sixth and third) experiments, whole conditions are the same, with the exception of concentration of compound1, that is, 10−3 M and 10−2 M, respectively; nevertheless, in the two cases, the reaction is second order and independent of concentration1; this is possible when γ is zero in both (1) and (4). It means that the reaction is zero and of the second order type in relation to compound1 and sum of2 and3 (α+β=2), respectively. As a result, the overall order of reaction is two which is the same as the previous experiment (third experiment).Figure 5
Second order fit curve (solid line) along with the original experimental curve (dotted) for the reaction between 4-hydroxycoumarin1 (10−3 M), malononitrile3 (10−2 M), and 4-nitrobenzaldehyde2 (10−2 M) which was proceed in methanol at 25.0°C and 435 nm.Utilizing the above results, the simplified scheme of the proposed reaction mechanism (Scheme2, [29–31]) as a possible explanation is shown in Figure 6 [14, 18, 37].Scheme 2Figure 6
The simplified Scheme for the proposed reaction mechanism [14, 18, 37].To investigate which steps of the proposed mechanism is the rate-determining step, the rate law was written using the final step of reaction as follows:(5)Rate=k5[I4].
The steady state approximation can be applied for obtaining the concentration of [I4], which is generated from the following equations:
(6)d[I4]dt=k4[I3][Cat]-k5[I4]=0(7)k4[I3][Cat]=k5[I4].
The value of (7) can be replaced in (5) so the rate equation becomes
(8)Rate=k4[I3][Cat].
For obtaining the concentration of intermediate [I3], the following equation is yielded by applying the steady state assumption:
(9)d[I3]dt=k3[I2][Cat-]-k4[I3][Cat]=0,k3[I2][Cat-]=k4[Cat][I3],
and with the replacement of (9) in (8), the following equation is obtained:
(10)Rate=k3[I2][Cat-].
And we can obtain the value of [I2] as follows which can be replaced in (10) for generation of (13):
(11)d[I2]dt=k2[I1][Cat-][1]-k3[I2][Cat-]=0(12)k2[I1][Cat][1]=k3[I2][Cat-](13)Rate=k2[I1][1][Cat].
The concentration of intermediate [I1] is obtained using steady state approximation, and by substituting (15) into (13), (16) is yielded as follows:
(14)d[I1]dt=k1[2][3][Cat]-k-1[I1][Cat][H2O]-k2[I1][1][Cat](15)[I1]=k1[2][3]k-1[H2O]+k2[1](16)Rate=k1k2[1][2][3][Cat]k-1[H2O]+k2[1].
Equation (16) is not compatible with the experimental data
(17)Rate=kovr[2][3][Cat].
Therefore, the rate constants k-1 and k2 have no chance to be a rate determining step; nevertheless, if k2≫k-1[H2O], the following equations can be obtained:
(18)Rate=(k1=kovr)[2][3][Cat].
The final equation (18) (remerge from steady state assumption) indicates that the overall order of the reaction is two; additionally, in accordance with this equation, the order of reaction with respect to each compound (3,2 and1) is 1, 1, and zero, respectively, which was previously confirmed by the experimental data (17). It is obvious that overall constant (kove) in (17) is equal to rate constant (k1) in (18). Because of the presence of k1 in the rate low (18), it is obvious that first step (k1) is a rate determining step and k2 should be a fast step. In this case, the transition state (see Scheme 2, step 1) in reaction carries a dispersed charge effect of solvent (next section, mixture of water and ethanol, 50/50) which has higher dielectric constant (ε=52.12) more than methanol (with lower dielectric constant ε=32.6) on this dispersed charge which would be much stronger compared to that on reactants (2 and3) that do not have any charge. The solvent thus stabilizes the species at the transition state more than it does the reactants, and therefore Ea would be lower and speeding up the reaction rate (see Table 2, effect of both solvents). As is evident, the concentration of sodium acetate as a catalyst appears in the rate law (18), since, at the end of mechanism, (Scheme 2) sodium acetate is generated once again, and keep a constant value in its concentration. With respect to (18), k1 is a rate determining step; therefore, the activation parameters which involve ΔG‡, ΔS‡, and ΔH‡ can be now calculated for the first step (rate determining step, k1), as an elementary reaction, on the basis of Eyring equation (a) of Figure 7(a), Ln(k1=kove)/T versus 1/T and also a different linearized form of Eyring equation (b) of Figure 7(b), T×Ln(k1=kove)/T against (T) [39]. The results are accumulated in Figures 7(a) and 7(b). Statistical analysis of the Eyring equation clearly confirms that the standard errors of ΔS‡ and ΔH‡ correlate (Tav is the center of the temperature range used) as follows:
(19)σ(ΔS‡)=1Tavσ(ΔH‡).
It follows that in most solution phase studies σ(ΔS‡)≈σ(ΔH‡)×0.003K-1. This correlation has been mentioned elsewhere [39, 40]. The standard errors for activation parameters have been calculated according to the above instructions [39–41] and they have been reported along with these parameters in Figures 7(a) and 7(b). With respect to the values of ΔS‡ and ΔH‡ (see Figures 7(a) and 7(b)), (ΔG‡=54.32kJmol-1) is reported for the reactions between1,2, and3 in a mixture of ethanol and water at 430 nm and 298.2 K.Table 2
Rate constantskobs (min−1 M−1), k1=kove (min−1 M−2) for the reaction between 2 (10−2 M), 3 (10−2 M), and 1 (10−2 M) in the presence of sodium acetate (as a catalyst) and both solvents methanol (32.6)a and a mixture of ethanol and water (ethanol : water, 1 : 1), (52.12)d.
Solvent: methanol (32.6)a
T (°C)
T
= 20°C
T
= 25°C
T
= 30°C
T
= 35°C
T
= 40°C
T
= 45°C
T
= 50°C
k
obs
3.5092
6.2492
9.0095
11.7607
14.50
18.15
22.10
(0.0011)b
(0.0094)
(0.0102)
(0.0065)
(0.0189)
(0.0099)
(0.0199)
k
ove
c
350.92
624.92
900.95
1176.07
1450
1815
2210
Solvent: mix ethanol/water (52.12)d
T (°C)
T
= 20°C
T
= 25°C
T
= 30°C
T
= 35°C
T
= 40°C
T
= 45°C
T
= 50°C
k
obs
9.4693
12.6398
14.9811
17.7596
20.507
24.609
29.705
(0.007)b
(0.0093)
(0.0116)
(0.0139)
(0.0164)
(0.0186)
(0.0193)
k
ove
946.93
1263.98
1498.11
1775.96
2050.7
2460.9
2970.5
a,dDielectric constant.
bSD (standard deviation).
cIs overall rate constant.(a, b) Eyring plots according to (1) and (2), for the reaction between1,2,3, and sodium acetate catalyst in methanol.
(a)
(b)


## 4.2. Effect of Solvents and Temperature

In order to determine the effect of change in temperature and solvent environment on the reaction rate, various experiments were arranged with different temperatures and solvent polarity under the same conditions with the previous experiment. For this purpose, dry methanol and a mixture of ethanol and water (ethanol : water, 1 : 1) have been used in the experiment. The results showed that the rate of reaction speeds up in solvent with high dielectric constant (ethanol and water) compared to lower dielectric constant (methanol) at all investigated temperatures (see Table2).Also, as can be seen in Table2, rate of the reaction increases by raising the temperature. In the studied temperature range, the second-order rate constant (Lnk1) of the reaction was inversely proportional to the temperature, which is in agreement with the Arrhenius equation. This behavior is shown in Figure 7. The activation energy, for the reaction between1,2, and3 was obtained in lone a mixture of ethanol and water (1 : 1) (45.98±0.25kJ·mol-1) form the slope of Figure 8.Figure 8
The dependence12 of the second order rate constant (Lnk1) on reciprocal temperature for the reaction between compounds1,2, and3measured in methanol at wavelength of 430 nm according to the Arrhenius equation.


## 4.3. Effect of Catalyst

The rate of reaction was reduced in the presence of Zn (CH3CO2)2 as a second catalyst in a mixture of ethanol and water (1 : 1) in comparison with the first catalyst (NaCH3CO2). It seems that Zn+2 ions have more interactions with polar solvent in relation to Na+ ions. This reduces the rate of reaction in the second catalyst media (see Table 3).Table 3
Effect of various catalysts on a reaction between1, 2, and 3 compounds in the presence of methanol solvent.
Catalyst
k
1
×
10
2 (min−1·M−2)
SD
T
= 25°C
NaCH3CO2
6.25
0.0118
Zn(CH3CO2)2
2.08
0.0160


## 5. Conclusion

In this work, we report a novel three-component one-pot synthesis of functionalized pyrano[2,3-d]pyrimidine in the presence of NaOAc and Zn(OAc)2 as the highly effective base catalyst under thermal conditions. The catalyst shows an environmentally friendly character, which is inexpensive, clean, safe, nontoxic, and easily obtained. Moreover, the procedure offers several advantages including high yields, operational simplicity, clean reaction conditions, and minimum pollution of the environment, which makes it a useful and attractive process for the synthesis of these compounds.Also, the following results are obtained from kinetics and mechanism studies.(1)
The overall order of the reaction followed second-order kinetics and the reaction order of each reactant 4-nitrobenzaldehyde2, malononitrile3, and thiobarbituric acid1 is one, one, and zero, respectively.(2)
The overall rate constants of all reactions were calculated successfully at all investigated solvents and temperatures.(3)
In solvents with higher dielectric constants, the rate of all reactions increased and this can be related to the stabilization differences of the reactants and the activated complex by the solvent in the transition state.(4)
Based on the experimental data, the first step of suggested mechanism was identified as a rate-determining step (k1) and this was confirmed by the steady-state assumption.(5)
The activation energy (45.9764±0.246kJ·mol-1) and parameters of the reaction involving ΔG‡, ΔS‡, and ΔH‡ have been calculated, on the basis of both Eyring equation and a different linearized form.(6)
The rate of reaction speeds up in the presence of catalyst with more charge potential (counter ion Zn+2 versus Na+).



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*Source: 210327-2014-05-11.xml*