Article pubs.acs.org/JPCA
New Views on the Reaction of Primary Amine and Aldehyde from DFT Study Yun-qiao Ding,* Yue-zhi Cui, and Tian-duo Li Shandong Provincial Key Laboratory of Fine Chemicals, School of Chemistry and Pharmaceutical Engineering, Qilu University of Technology, 250353, Jinan, Shandong China S Supporting Information *
ABSTRACT: A general theoretical investigation on the reaction of primary amine with aldehyde was carried out by density functional theory. The calculation systems involve three kinds of primary amines (methylamine, vinylamine, and phenylamine) and three kinds of aldehydes (formaldehyde, acetaldehyde, and acrylaldehyde). The steric and electronic inductive effects on the reaction mechanism were studied. Results reveal that the nucleophilic attack of primary amine on aldehyde under neutral conditions leads to carbinolamines, rather than Schiff bases. The nucleophilic attack on the protonated aldehyde produces the protonated Schiff base. The steric hindrance of the aldehyde slows down the nucleophilic attack but allows enough time to abstract a H; consequently, the formation of the protonated Schiff base is preferred. During the carbinolamine protonation, the H+ preferably locates on the amine nitrogen and then is abstracted by the hydroxyl oxygen over an energy barrier, leaving protonated Schiff base after timely water liberation. The formation of a prereaction potential energy well obviously softens the steric and electronic inductive effects on the active barrier for different reactants.
1. INTRODUCTION It is a familiar and important reaction that the nucleophilic attack of primary amines on aldehydes produces a carbinolamine which then dehydrate to form a Schiff base. Both carbinolamines and Schiff bases as reactive intermediates have gotten much attention because of their wide application in catalysts, medicine, crystal engineering, anticorrosion agent, and so on.1−3 Generally, the above reaction is divided into two parts:4 the carbinolamine formation and the imine formation. The zwitterionic feature of the carbinolamine and the high activity of the Schiff base make them hard to trap experimentally. This kind of reaction is much more complicated than it looks. Sayer et al.5 once performed a systematic study on the mechanism of the carbinolamine formation with kinetic and structure− reactivity data, describing in detail the possible pathways for the carbinolamine formation and the structure−activity relationships of various intermediate species that depended greatly upon the environmental conditions. Lavie and coworkers6 put forward a proposal for the mechanism of Schiff base formation in type I dehydroguinate dehydratase, revealing that Schiff base formation is predominantly confined by the substrate. Thus, it can be seen that the practical processes, especially for those in complex systems, are not so simple. To simplify problems so that they may be easily understood, a method of combining both theory and experiment is often adopted. Stone’s group has performed a series of studies on the cross-link formation in NAD. Their study on an interchain carbinolamine cross-link formed in a CpG sequence implies that the equilibrium of various reaction systems in the cross-link process can be modulated by the environmental pH,7 and the © 2015 American Chemical Society
stereospecific formation of interstrand carbinolamine DNA cross-links depends upon the temperature.8 They further discussed the chemistry of interstrand cross-links induced by unsaturated aldehydes derived from lipid peroxidation and environmental sources.9 The study of the native DNA−KWKK linkage10 found that the stabilization of the DNA to thermal denaturation may be improved by carbinolamine-linked DNA− KWKK by intramolecular hydrogen bonding, and theoretical calculation suggests that the carbinolamine-linked DNA− KWKK conjugates exist with the peptide located in the minor groove. For another example, Muñoz’s group performed some related studies on Schiff base formation in the vitamin B6 system with the aid of theoretical methods. In the discussion of the reactivity of pyridoxal phosphate, results emphasized the solvent dependence in the Schiff base formation.11 They studied the protonation of the pyridine and imine on the “electron-sink” effect and proposed its significance in the chemistry of PLP-dependent enzymes as well as in the structure of their active sites.12 They studied the reaction mechanism of pyridoxamine analogues with aldehydes and exposed the significant influence of the hydroxyl group on the reaction.13 They studied the formation of Schiff base between phosphatidylethamolamine and acetaldehyde by the density functional theory (DFT) method and discussed the influence of a cell membrane solvent surface environment on phospholipid glycation. Results showed that the water molecules exchange one of their hydrogen atoms to facilitate the proton transfer, Received: March 6, 2015 Revised: April 10, 2015 Published: April 10, 2015 4252
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orbital (NBO) population23−25 and charge analysis were carried out at the same level of theory, including the natural charge and atom−atom overlap-weighted NAO bond order.26,27 These calculations were performed using the Gaussian 09 package.28 (The selected geometrical and NBO results for the structures are listed in the Table 1* and 2*, respectively, in the Supporting Information.)
which greatly reduced the energy barrier of the carbinolamine formation.14 They studied the Schiff base formation between PLP and two compounds mimicking the polar head of natural aminophospholipids and explored the kinetic process.15 While many reactions involving carbinolamine and Schiff base have great value in scientific research and potential application, the corresponding mechanism are still hot topics of reasearch. Inspired by the preceding works, in the present paper, DFT16 has been performed on the reaction of primary amines with aldehydes, as shown in Scheme 1. Results provide a wide comprehension of the geometry, energy, and stability of various intermediates, transition states, and products under different reaction conditions. The discussion is broken into four subsections: The first and second subsections mainly describe the reactions of primary amines with aldehydes. The third and fourth subsections proposed the reaction mechanism of carbinolamine/Schiff bases under acidic or basic conditions. The study paid significant attention to the structure−activity relationship of reaction components as well as their action mechanism from the theoretical chemistry point of view.
3. RESULTS AND DISCUSSION 3.1. Reactions of Methylamine, Vinylamine, and Phenylamine with Formaldehyde. To compare the steric and electronic inductive effects on reactions, the simple molecules methylamine (CH3NH2), vinylamine (CH2CH− NH2), phenylamine (H5C6−NH2), and formaldehyde (O CH2) were selected as the model reactants for the present DFT calculation. In order to observe the role of water and protonic acid in the reaction of proton transfer, an auxiliary water molecule (paths RA2, RB2, and RC2) and acid proton H+ (paths RA3, RB3, and RC3) were adopted, in comparison to the nowater-aided cases (paths RA1, RB1, and RC1). Accordingly, the nine reactions were elucidated as listed below.
2. COMPUTATIONAL MODELS AND METHODS The geometries of reactants, transition states, intermediates, and products (see Scheme 1 and Figure 1* in Supporting Information) under different reaction conditions were optimized using Becke’s three-parameter hybrid functionals combined with the Lee−Yang−Parr correlation functional method (B3LYP)11,17 of DFT with the 6-311++G** basis set. The frequency calculation to get zero-point energy confirmed the reactants and intermediates (showing all positive force constants), as well as transition states (one imaginary frequency only). The reaction paths were followed from the transition states to both the reactants and the products by using the intrinsic reaction coordinate (IRC) method.18,19 The energies considering the solvent effect simulated by the integral equation formalism model (IEFPCM)20−22 were corrected to constant pressure and 298 K for zero-point energy differences. On the basis of the optimized structures, the natural bond
On the basis of the sum of electronic and thermal enthalpies (ΔH) being negative values, these reactions are exothermic, and those H+-aided reactions give off more heat. The reactions 4253
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Figure 1. Potential energy surfaces for the reactions of primary amines with formaldehyde.
first lead to a prereaction intermediate and then to products by overcoming the energy barrier. Figure 1 described the potential energy surface for the reactions, with perspective views of the structures for intermediates and transition states. The energy with the zero-point energy correction (ΔE) shown in Figure 1 is the relative value benchmarked against the total energy of the separated reactants (ΔE = 0). A three-step mechanism was found for paths RA1, RB1, and RC1: the formation of the prereaction complexes (IMA1, IMB1, and IMC1), the carbon−nitrogen bond formation upon nucleophilic attack, and the abstraction of hydrogen, where the nucleophilic attack is in some sense concerted with the hydrogen abstraction. The three-step mechanism in path RA1 is more distinct than that in paths RB1 and RC1. Natural charge population analysis gives the net natural charges on the nitrogen atom (N1) as −0.89, −0.87, and −0.80 charge units for methylamine, vinylamine, and phenylamine, respectively, so the nucleophilicity of N1 is weakened in order. The distance between the amine nitrogen (N1) and carbonyl carbon (C1) in IMA1 (1.648 Å) is far shorter than that in IMB1 (2.873 Å) and IMC1 (2.864 Å). The CO bond length of the formaldehyde moiety in IMA1 (1.302 Å) is longer than that in IMB1/IMC1 (1.211 Å). The calculated CO bond length is 1.209 Å, 0.001 Å shorter than the average Csp2O length in aldehyde (1.210
Å) by experiment.29 The N1−C1 bond order by NBO calculation for IMA1 (0.552) is obviously larger than that for IMB1 (0.027) and IMC1 (0.031). These data reveal that the interaction between the amine and formaldehyde moieties possesses the chemical bonding characteristic of IMA1 and the van der Waals characteristic of both IMB1 and IMC1. In view of the structures, IMA1 is similar to the zwitterionic form of (methylamino)methanol, H3C−NH2+−CH2−C−O− ⇋ H3C− NH−CH2OH. On the basis of the energy sum of the separated reactants, the reactions have energy barriers of 24.83, 24.40, and 31.79 kcal/mol for paths RA1, RB1, and RC1, respectively. However, if the energy of the prereaction complex is lower than the energy sum of the separated reactants, then reactants fall into a potential-energy well. Consequently, the prereaction complex needs to be released from the well by climbing over the barrier before product formation. In view of the energy evolution shown in Figure 1b, plus the relative energies of IMB1 (ΔE = −6.00 kcal/mol), the actual barrier for path RB1 is 30.40 kcal/mol. The barriers for paths RA1 and RC1 are 24.83 and 31.79 kcal/mol, respectively. The transition state structures of TSA1, TSB1, and TSC1 have little difference. One of the amine hydrogen atoms (H1b) in them fluctuates between N1 and C1 atoms, and the four atoms H1b, N1, C1, and O1 are nearly coplanar. The distance between N1 and C1 is 1.520 Å for 4254
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Figure 2. Potential energy surfaces for the reactions of methylamine with acetaldehyde.
RA2, IMB2-a for path RB2, and IMC2-a for path RC2) and postreaction intermediates (hydrogen-bonded hydrated carbinolamines, IMA2-b, IMB2-b, and IMC2-b), respectively. The water molecule acts as a porter to transit a proton (H+) from N1 to O1. As seen in Figure 1d−f, the energy of hydration of (methylamino)methanol (IMA2-b) is slightly lower than the energy sum of separate (methylamino)methanol and H2O. The results are the inverse for the hydration of (vinylamino)methanol (IMB2-b) and of (methylamino)methanol (IMC2-b). Similar to path RB1, the IMB2-b from vinylamine, H2O, and formaldehyde is in a potential-energy well with an energy of 3.20 kcal/mol. According to this, the reaction barrier is 7.85, 12.84, and 16.43 kcal/mol for paths RA2, RB2, and RC2 respectively, which is obviously smaller than that involving no water. In the transition state structure, six noncoplanar atoms, H1b, N1, C1, O1, H, and O, form one twisted, six-membered ring. In comparison with the corresponding structures of TSA1, TSB1, and TSC1, the H1b−N1 and C1−O1 bonds in TSA2, TSB2, and TSC2 are shortened and the N1−C1 bonds lengthened (see Table 1*a, Supporting Information). Paths RA3, RB3, and RC3 are the acid-catalyzed reactions of primary amine with formaldehyde. The anime protonation gives an amine salt, which makes nucleophilic attack on formaldehyde harder. The present calculation is in fact to study the reaction of primary amine with protonated formaldehyde (H+···OCH2). The protonated formaldehyde is more susceptible to nucleophilic attack than formaldehyde. When primary amine meets with protonated formaldehyde, the nucleophilic attack happens at once, producing a prereaction intermediate similar to the protonated carbinolamine. Their O1−H bond is nearly perpendicular to the plane O1−C1−N1. The N1−C1 bond lengths in IMA3 (1.525 Å), IMB3 (1.545 Å), and IMC3 (1.546 Å) are obviously shorter than those in IMA1 (1.648 Å), IMB1 (2.873 Å), and IMC1 (2.864 Å), and the O1−
TSA1, 1.541 Å for TSB1, and 1.545 Å for TSC1. The angle N1−H1b−C1 is 114.4° for TSA1, 114.3° for TSB1, and 114.6° for TSC1 (see Table 1*a, Supporting Information). The energies of the three carbinolamines are slightly lower than the energy sum of the separated reactants. The N1−C1 bond length in (methylamino)methanol (1.446 Å) is longer than that in (vinylamino)methanol (1.425 Å) and in (phenylamino)methanol (1.422 Å) and shorter than the average Nsp3−Csp3 bond length (1.469 Å) determined by experiment.29 The C1− O1 bond length in (methylamino)methanol (1.428 Å) is shorter than that in (vinylamino)methanol (1.445 Å) and (phenylamino)methanol (1.445 Å) and slightly longer than the average Csp3−O length (1.426 Å) revealed by experiment. Both H1a−N1 and O1−H1b bonds in (vinylamino)methanol and (phenylamino)methanol are shorter than those in (methylamino)methanol (see Table 1*b, Supporting Information). The calculation of the NAO bond order (see Table 2*, Supporting Information) clearly shows that the bond order values of H1a−N1, N1−C1, and O1−H1b bonds in (vinylamino)methanol and (phenylamino)methanol are larger than those in (methylamino)methanol, and the C1−O1 bond order is smaller. This indicates that the electron-withdrawing substitution linked to N1 makes the H1a−N1, N1−C1, and O1−H1b bonds slightly stronger than the electron-releasing substitution does. The situation for the C1−O1 bond is the reverse. The importance of the auxiliary water in the carbinolamine formation has been already reported.5,11 It is different from the direct abstraction of H in paths RA1, RB1, and RC1. Paths RA2, RB2, and RC2 involve an H abstraction process aided by water, in which the nucleophilic attack and H abstraction happen concurrently, and the concertedness is much better than that in paths RA1, RB1, and RC1. The process involving water produces two hydrogen-bonding hydration intermediates before and after the transition state, prereaction intermediates (IMA2-a for path 4255
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Figure 3. Potential energy surfaces for the reactions of carbinolamine with H+ and OH−.
positive charges from the proton in H2CCH−NH+CH2 and H5C6−NH+CH2 being dispersed by the conjugated moieties of the molecules. Figure 1g−i demonstrates that the protonated carbionlamine has a good stability in an acid environment; therefore, the Schiff base formation from those pathways is not a good option, unless the water can be completely and promptly removed from the reaction system. 3.2. Reactions of Methylamine with Formaldehyde, Acetaldehyde, and Acrylaldehyde. The above section discussed the effects of primary amine on the reaction and then the effects of aldehydes. Figure 2 displays the evolvement of the potential energy surfaces for paths RA2, RA3, RA4, RA5, RA6, and RA7. The paths RA2 (Figure 2a), RA4 (Figure 2b), and RA5 (Figure 2c) involve the carbinolamine formation with one auxiliary water molecule, and the paths RA3 (d), RA6 (e), and RA7 (f) involve the formation of the protonated Schiff base with the aid of the proton (H+).
C1 bond lengths in IMA3 (1.383 Å), IMB3 (1.379 Å), and IMC3 (1.378 Å) are obviously longer. On the basis of the energy sum of reactants, the reaction has a very low barrier of 0.75 kcal/mol for RA3, 0.88 kcal/mol for RB3, and 9.20 kcal/mol for RC3, respectively. However, the potential energy well appears due to the formation of protonated carbinolamines, resulting in the energy barrier being higher than the well depth by 35.67 kcal/mol for RA3, 31.93 kcal/mol for RB3, and 33.72 kcal/mol for RC3. For the structure of the transition state, the N1−H1b and O1−C1 bonds in the TSA3 (1.435 and 1.503 Å), TSB3 (1.403 and 1.490 Å), and TSC3 (1.412 and 1.496 Å) are significantly longer than those in the TSA1 (1.244 and 1.391 Å), TSB1 (1.222 and 1.379 Å), and TSC1 (1.225 and 1.380 Å), respectively, and the N1−C1 bond is shortened, from 1.520 Å in TSA1 to 1.458 Å in TSA3, from 1.541 Å in TSB1 to 1.468 Å in TSB3, and from 1.545 Å in TSC1 to 1.466 Å in TSC3. Such structural changes are beneficial to the dehydration of prereaction intermediates to give the protonated Schiff base: protonated N-methylamine methylamine (H3C−NH+CH2) for RA3, protonated N-methylamine vinylamine (H2CCH− NH+CH2) for RB3, and protonated N-methylamine phenylamine (H5C6−NH+CH2) for RC3. The reactions from the prereaction intermediate to the protonated Schiff base are slightly endothermic by an energy of 2.65 kcal/mol for path RA3 and slightly exothermic by an energy of 5.06 and 3.13 kcal/mol for paths RB3 and RC3, respectively. This reveals that path RA3 is more reversible than RB3 or RC3, which is ascribed to the
The distance between N1 and C1 in IMA2-a (1.608 Å) is shorter than that in both IMA4-a (1.668 Å) and IMA5-a (1.702 Å). The calculated barrier height of TSA2 (7.85 kcal/mol) is 4256
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Figure 4. Calculated electron-energy levels and corresponding orbital contour plots for HOMO and LUMO contributing to the reactions of carbinolamines with H+ and OH− using the DFT method at the B3LYP/6-311++g** level.
preferred to the formation of the protonated Schiff base, because the delay of the nucleophilic attack allows enough time for the abstraction of H from −NH to −OH. Protonated (E)N-ethylidenemethanamine (H3C−NH+CH−CH3) has a lower energy by 6.40 kcal/mol than prereaction intermediate IMA6, due to the superconjugation of two methyl groups. The protonated (E)-N-allylidenemethanamine (H3C−NH+CH− CHCH2) has a lower energy by 13.03 kcal/mol than the prereaction intermediate IMA7, due to the π−π conjugation. Both paths RA6 and RA7 are less reversible than pathway RA2. The superconjugation results in a lengthening of CN double bonds and a shortening of the CN bond order (see Tables 1* and 2*, Supporting Information). 3.3. Reactions of Carbinolamines with H+ and OH−. Zwitterionic carbinolamines are stable at neutral condition and can continue to carry out a series of reactions in an acid or basic environment. In the present paper, (methylamino)methanol (path RA1‑1/‑2) and (vinylamine)methanol (path RB1‑1/‑2) are adopted to make a comparative study on their reactions with H+ and OH− (see the equations below).
lower than that of RA4 (13.66 kcal/mol) and RA5 (16.84 kcal/ mol). It is also found that in both paths RA4 and RA5 the total energy of the products is slightly higher than that of the reactants, which indicates that pathways RA4 and RA5 are more reversible than pathway RA2. These facts reveal that the substituent on the carbonyl carbon does not favor the nucleophilic attack of the primary amine. This is not only due to the increase of the steric hindrance but also the structure of the products. The reaction of primary amine with the aldehydes, except formaldehyde, leads to unstable secondary alcohols, (S)-1-(methylamino)ethanol for RA4 and (S)-1(methylamino)prop-2-en-ol for RA5. Paths RA3, RA6, and RA7 are the reactions of methylamine with protonated formaldehyde (Figure 2d), acetaldehyde (Figure 2e), and acryladehyde (Figure 2f), respectively, which finally produce three kinds of protonated Schiff bases after H2O liberation. The energies of the transition states (TSA3, TSA6, and TSA7) are higher than those of the prereaction intermediates, by 35.67 kcal/mol for RA3, 33.59 kcal/mol for RA6, and 33.31 kcal/mol for RA7, respectively. It is not hard to find that the reactions have barriers with little difference. The steric hindrance of the reactants slows down the nucleophilic attack of the amine group on the aldehyde group, which is 4257
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Figure 5. Potential energy surfaces for the protonation reactions of Schiff bases.
first barrier, the second intermediate, protonated (R)-1(methyleneamino)ethanol (IMB1-1-b′), is formed by the −OH transferring from the 1-ol methyl group (−CH2OH) to the methylidyne group (−CH). It must again cross over the much higher barrier to form N-methylenevinylamine, which, moreover, is an endothermic process (5.50 kcal/mol). Path RB1‑1 (thick black dotted line) undergoes a route similar to path RA1‑1, in which IMB1-1-a overcomes a lower barrier (31.92 kcal/mol) than IMB1-1-a′ (45.76 kcal/mol). Small energy differences between TSB1-1 and TSB1-1′ (0.4 kcal/mol) can be neglected. Consequently, path RB1‑1 is more accessible than path RB1‑1′ under the premise of the protecting vinyl group. The encounter of carbinolamines with OH− produces hydroxide carbinolamines first, giving off a small amount of heat, and the hydroxyl group of carbinolamines was found to interact with OH− by forming hydrogen bonds (see Figure 4c,d). The hydrogen-bonding length (O−H···O) is 2.509 Å in hydroxide (methylamino)methanol (IMA1-2-a), 0.03 Å shorter than that in hydroxide (vinylamino)methanol (IMB1-2-a). The O−H···O angle is 176.2° in IMA1-2-a and 178.3° in IMB1-2-a. NBO calculation shows that the charge differences between the alkoxyl oxygen and amine nitrogen in hydroxide (methylamino)methanol is 0.138 but 0.057 in (methylamino)methanol; the charge differences are 0.260 in hydroxide (vinylamino)methanol but 0.114 in (vinylamino)methanol. This reveals that the alkoxyl oxygen in hydroxide carbinolamines has more strength to abstract a hydrogen of amine. The hydroxide (methylamino)methanol needs to cross over a barrier of 34.82 kcal/mol for the N-methylene methylamine− H2O−OH− complex (IMA1-2-b) formation, and hydroxide (vinylamino)methanol needs 29.83 kcal/mol for the Nmethylenevinylamine−H2O−OH− complex (IMB1-2-b). In both IMA1-2-b and IMB1-2-b, the amine nitrogen interacts with hydrated hydroxyl (HOH···OH−) by formation of hydrogen bonds. The distances between amine nitrogen and water oxygen are 3.013 Å in IMA1-2-b and 3.055 Å in IMB1-2b. The N−H−O angles are all 178.4°. The length of the CN double bond is 1.266 Å in IMA1-2-b, and it is lengthened to 1.275 Å in IMB1-2-b. The energy of the Schiff base−H2O− HO− complexes is slightly lower than the energy sum of the Schiff base, H2O, and HO− and higher than that of the corresponding hydroxide carbinolamines, revealing that the conversion of hydroxide carbinolamines to Schiff base is an endothermic process under basic conditions. The hydroxide carbinolamines and Schiff base were anticipated to exist in
As shown in Figure 3a,b, the carbinolamine protonation can easily occur with an acid proton (H+) and finally produce the separated protonated Schiff base and water, before which an intermolecular hydrate complex may be formed by the formation of a hydrogen bond. Such a complex is not stable, most likely because it is very weak. The carbinolamine protonation is highly exothermic, producing the protonated carbinolamine (IMA1-1-a for RA1‑1 and IMB1-1-a/-a′ for RB1‑1). In this present paper, it is interesting to note that the protonation of the carbinolamine happens on the amine nitrogen, rather than on the carbonyl oxygen as reported in a general textbook. The frontier molecular orbital diagram (Figure 4) displays the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) for the reaction of carbinolamine with H+ and OH−. According to the molecule orbital theory, under the premise of the approximate rule of orbital energy, the protonation should happen between the HOMO of the carbinolamine and the LUMO of the H+. For (methylamino)methanol, although both N and O atoms may all accept the H+, the first possible protonation site is the nitrogen atom, with its more plump orbital contour (arrow pointing). Optimization shows that the prereaction intermediates of protonation, IMA11-a and IMB1-1-a, have similar structures as the corresponding IMA3-a and IMB3-a. IMA1-1-a must cross over an energy barrier of 35.82 kcal/mol to form the protonated Nmethylenemethylamine followed by water liberation. The energy difference between the IMA1-1-a and products is very small, and removing water in time from the reaction medium drives the reaction forward. For (vinylamino)methanol, the protonation reactions involve two pathways (RB1‑1 and RB1‑1′) due to the vinyl group. Figure 4b shows clearly that the CH2 CH− group takes priority for accepting a proton over N and O. Prereaction intermediate IMB1-1-a′ [protonated (E)(ethylideneamino)methanol] has lower energy than IMB1-1-a by 14.28 kcal/mol, indicating that the former is more stable than the latter. However, IMB1-1-a′ has to cross over two barriers to get protonated N-methylenevinylamine. Over the 4258
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Figure 6. Calculated electron-energy levels and corresponding orbital contour plots for HOMO and LUMO contributing to the reactions of the protonation reactions of Schiff bases using the DFT method at the B3LYP/6-311++g** level.
agreement with experiment.29 Figure 6 shows that both anomeric carbons in N-methylenevinylamine may be possible to accept the proton, forming two prereaction intermediates, IM1-2-1 (H2CCH−N−CH3+) for the path RB1‑2‑1 and IM12-1′ (+H3C−CHN−CH2) for the path RB1‑2‑1′. The energy of IM1-2-1 is higher than that of IM1-2-1′ by 45.66 kcal/mol. In addition, the activation energy of path RB1‑2‑1 is lower than that of RB1‑2‑1′ by 4.38 kcal/mol, so path RB1‑2‑1 is superior to path IM1-2-1′.
equilibrium with each other, so removal of H2O from the reaction system is required, thereby preventing the reverse reaction. 3.4. Schiff Base Protonation. The nucleophilic attacking of amine on protonated aldehyde produces the protonated Schiff base. The protonated Schiff base as a weak acid can be neutralized with OH− easily, barrierlessly leading to Schiff base, being exothermic by 39.94 kcal/mol for path RA3−1 and by 48.70 kcal/mol for path RB3−1. The CN bond is 1.266 Å in N-methylenemethylamine and 1.275 Å in N-methylenevinylamine, respectively, which is near the typical length for a carbon−nitrogen double bond (1.28 Å) by experiment. Energy calculation indicates that hydrated Schiff bases, composed of Schiff base and water by formation of hydrogen bonding, H2CN(CH3)···H−O−H and H2CN(C2H3)···H−O−H, are more stable than the independent individuals.
4. CONCLUSIONS Real reactions involving primary amines and aldehydes are very complicated. The present paper describes a general theoretical study with the DFT method undertaken in order to get some information on the geometry and energy of various stable/ instable species that occurred during various reactions. Results from theoretical calculations concurred with some conclusions from experiments. In the neutral solution, the reactions of primary amine with aldehyde produce the carbinolamines, rather than the Schiff bases. Primary amine, aldehydes, and water form an intermolecular hydrogen-bonding prereaction intermediate that can effectively assist the intramolecular nucleophilic attack. Water as an active reactant can decrease greatly the barrier, which is in good agreement with the experiment. During the carbinolamine formation, the increasing steric effect of the amine and aldehyde are of no advantage to the reaction. In the acid solution, nucleophilic attack produces protonated Schiff bases after water liberation. Aldehyde protonation can promote the nucleophilic attack, but the formation of the prereaction potential energy well is equivalent to the increase of the active barrier. In this circumstance, the same class of reactions shows little difference in the barrier height; that is, the structures of the reactants exert small influences on the activation energy. The located site of H+ on the amine nitrogen is superior to that on the alkoxyl oxygen during the carbinolamine protonation. In the presence of OH−, Schiff bases and their counterparts can be formed by a neutralization reaction of protonated Schiff bases or carbinolamines.
In the presence of H+, the protonation of Schiff base takes place very easily and has a downhill transition state, which is greatly exothermic by 172.76 kcal/mol for path RA1‑2‑1 (the Nmethylenemethylamine protonation) and 164.00 kcal/mol for path RA3‑1 (the N-methylenevinylamine protonation), respectively, as shown in Figure 5. According to the orbital contour plots in Figure 6, the proton preferentially attacks the anomeric carbon in the double bond. For path RA1‑2‑1, the prereaction intermediate IMA1-2-1 (H3C−N−CH3+) is formed first, being exothermic by 97.97 kcal/mol. The energy of the transition state TSA1-2-1, in which the proton fluctuates between the N and C, is only higher than that of IMA1-2-1 by 1.19 kcal/mol, making the reaction essentially barrierless, after which the proton is abstracted from the anomeric carbon and goes to the nitrogen, continuing to give off plenty of heat. This process is in 4259
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ASSOCIATED CONTENT
S Supporting Information *
The optimized geometries of reactants, intermediates, transition states, and products (Figure 1*a−c); selected geometrical data of structures (Table 1*); NAO bond order (Table 2*); and the energy values of ΔG and ΔE for each reaction (Table 3*). This material is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was financially supported by the Project of Natural Science Foundation of Shandong Province (ZR2014EMM020) and the National Natural Science Foundation of China (Nos. 21276149, 21376125, and 21477065). Part of the work was also supported by the Open Project Program of Shandong Provincial Key Laboratory of Fine Chemicals and Open Project Program for Scientific Research Innovation Team in Colleges and Universities of Shandong Province.
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REFERENCES
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DOI: 10.1021/acs.jpca.5b02186 J. Phys. Chem. A 2015, 119, 4252−4260
