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Regioselectivity of the intramolecular nucleophilic attack in [RCH−NCHC6H4Y]: A mass spectrometric and computational study
Journal of Molecular Structure 1063 (2014) 8–15
Contents lists available at ScienceDirect
Journal of Molecular Structure journal homepage: www.elsevier.com/locate/molstruc
Regioselectivity of the intramolecular nucleophilic attack in [RACH AN@CHAC6H4AY]: A mass spectrometric and computational study Xiang Zhang ⇑ Department of Applied Chemistry, Zhejiang Gongshang University, Hangzhou 310035, China
h i g h l i g h t s
g r a p h i c a l a b s t r a c t
Regioselectivity of intramolecular
nucleophilic attack in [RACH AN@CHAC6H4AY] was studied. ANO2 favors C3-attack to form spiror-adduct and it also contributes to the loss of HCN. Other substituents (AH, AOMe, ANMe2 and ACl) favor C4-attack to yield bicyclo-r-adduct. It is difficult for bicyclo-r-adduct to lose HCN. DFT calculations are well consistent with the tandem mass spectrometry experiments.
a r t i c l e
i n f o
Article history: Received 4 August 2013 Received in revised form 14 January 2014 Accepted 14 January 2014 Available online 30 January 2014 Keywords: Regioselectivity Intramolecular nucleophilic attack Imine Density functional theory Mass spectrometry
a b s t r a c t The investigation into the intramolecular nucleophilic attack in carbanion [RACH AN@CHAC6H4AY] in the gas phase has been carried out by mass spectrometry and density functional theory (DFT). The main results of the present work are as follows: the regioselectivity of the intramolecular attack depends on the substituent on the para-position of the benzene ring. ANO2 favors C3-attack to form spiro-r-adduct and it also contributes to the loss of HCN, while other substituents (AH, AOMe, ANMe2 and ACl) favor C4-attack to yield bicyclo-r-adduct and in this condition, HCN cannot be lost. In the meantime, DFT calculations also demonstrate that the loss of HCN from the spiro-r-adduct is both thermodynamically and kinetically beneficial, while that from the bicyclo-r-adduct is disadvantageous either in kinetics or thermodynamics. Ó 2014 Elsevier B.V. All rights reserved.
1. Introduction Gas phase ion–molecule reactions have attracted the attention of a wide range of chemists as a means to investigate the interplay of structure and reactivity in the absence of a solvent. Among these, gas-phase nucleophilic aromatic substitution (SNAr) has long been the subject of continued investigation [1–7]. They are of ⇑ Tel.: +86 88071024. E-mail address: [email protected] 0022-2860/$ - see front matter Ó 2014 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.molstruc.2014.01.054
considerably practical use for transformations in organic and biological chemistry. For example, as long ago as 1975, Riveros has described a series of gas-phase reactions of halobenzenes with alkoxide anions [8]. Bowie has reported the gas-phase SNAr reaction between o-dinitrobenzene and chloride anion which proceeded in the ICR cell [9]. Recently, Witold described the significant SNAr reaction of halonitrobenzene with carbanion ACH2CN in the gas phase [6]. Besides widespread relevance to organic chemistry, this reaction type is also encountered in biological dechlorination reactions. For instance, both glutathione transferase and
X. Zhang / Journal of Molecular Structure 1063 (2014) 8–15
Scheme 1. Mechanism of the SNAr reaction.
9
4-chlorobenzoyl-coenzyme A dehalogenase operate according to this mode of reactivity [10,11]. The most common mechanism for SNAr reaction involves a multistep addition–elimination pathway through the rate-determining formation of well-characterized r-complex (Meisenheimer complex) intermediate [12], as is shown in Scheme 1. According to the literature, the intermolecular SNAr reactions in the gas phase have been studied in great detail. However, there are few reports relating to the intramolecular ones. This phenomenon might be explained on the basis of the character of the mass spectrometry. Advances in mass spectrometry and ion cyclotron reso-
Scheme 2. Preparation of the special substrate anions and probable intramolecular nucleophilic attack pathways.
Fig. 1. (a) Structures of the substrate anions. (b) Preparation of the carbanion M1. (c) MS/MS spectrum of the anion at m/z 252.
10
X. Zhang / Journal of Molecular Structure 1063 (2014) 8–15
nance (or ion trap) have made it possible for the intermolecular SNAr reactions to be investigated easily in the gas-phase, for the change of m/z can directly indicate the formation of the r-adduct. On the other hand, for the intramolecular SNAr reaction, it is difficult to judge whether it has taken place in the mass analyzer, because the m/z values for the reactant and product ions are the same. Generally, tandem mass spectrometry (Msn) cannot provide enough proof to support the intramolecular bonding process. However, for some special substrate ions, the tandem mass spectrome-
try technique still displays strong advantage in the study of the gas-phase reaction [13]. Loss of the specific neutral fragment can reveal the intramolecular formation of new bonds between originally non-bonded atoms. To further explore the intramolecular nucleophilic attacks in the aromatic systems, some special substrate ions with the imine functional groups (C@N bond) were constructed via the reactions of the a-amino acids with aromatic aldehydes [14] and subsequent decarboxylations [15–17] in this work, as are shown in
Fig. 2. MS3 spectra of the carbanions M1–M6.
Table 1 The detailed activation Gibbs free energies for the C3- or C4-nucleophilic attacks (kcal/mol).
M1 M2 M3 M4 M5 M6
R
Y
DG–i
DG–ii
Spiro-r-adduct : bicyclo-r-adduct
Benzyl Benzyl Benzyl Benzyl Benzyl Methyl
H OMe NMe2 Cl NO2 NO2
39.4 43.2 42.3 42.6 36.8 47.9
30.1 27.5 29.4 33.7 51.6 63.5
0: 100% 0: 100% 0: 100% 0: 100% 100%: 0 100%: 0
X. Zhang / Journal of Molecular Structure 1063 (2014) 8–15
Scheme 2. Once these substrate anions were formed, they were supposed to be converted into the r-adducts under the collision energy. In this process, two probable pathways were proposed: C3-nucleophilic attack (pathway i) versus C4-nucleophilic attack (pathway ii). The former leads to the spiro-r-adduct, while the latter results in the bicyclo-r-adduct. The fragmentation of the ring is likely to release the neutral molecule HCN either in spiroor bicyclo-r-adduct (Scheme 2). Based on this assumption, the loss of HCN can be used as an indicator of the formation of the r-adduct. Besides the substituent effect on the para-benzene ring which has been taken into account, it is expected that this work could start further discussion on the nature of the SNAr reaction.
11
2.2. Mass spectrometry
2. Experimental
The mass spectral data were acquired on a LCQ ion trap mass spectrometer from ThermoFinnigan (San Jose, CA, USA) equipped with an electrospray ionization (ESI) interface operated in the negative ion mode. ESI of a CH3CN/H2O (3:1) solution containing amino acid (about 500 lM) and a like amount of aldehyde was carried out at a flow rate of 15 lL/min into the ESI source. The operation parameters are listed as follows: spray tip potential 3200 V; capillary voltage: 30 V; capillary temperature: 250 °C; Sheath gas flow rate: 9.0 arbitrary units; Tube lens: 52 V. In the MS/MS experiments, the parent ions were isolated monoisotopically in the ion trap and collisionally activated by the same collision energies. Helium (99.99%) was used as the trapping and collision gas.
2.1. Material
2.3. Computational methods
L-alanine, L-phenylalanine, benzaldehyde, p-nitrobenzaldehyde, p-chlorobenzalde -hyde, 4-methoxybenzaldehyde and 4-(dimethylamino)-benzaldehyde were obtained from the Sigma–Aldrich Company.
All structures were computed on the basis of the hybrid density functional theory (B3LYP) and the 6-31+G (d, p) [18–21] basis set which were implemented in Gaussian 09 program package [22]. All the gas phase minima and transition structures (here also re-
Fig. 3. Structures of the transition states for the C3- or C4-nucleophilic attacks (Å).
Scheme 3. Probable mechanism for the loss of HCN from the spiro-r-adduct.
12
X. Zhang / Journal of Molecular Structure 1063 (2014) 8–15
Fig. 4. Free energy profiles for the loss of HCN from spiro-r-adducts S1 and S2. (kcal/mol).
Scheme 4. Probable mechanism for the loss of HCN from the bicyclo-r-adduct.
X. Zhang / Journal of Molecular Structure 1063 (2014) 8–15
13
Fig. 5. Free energy profiles for the loss of HCN from bicycle-r-adducts (kcal/mol).
ferred to as transition states) were characterized by frequency analysis. Frequency calculations identify minimum structures with all real frequencies, while transition states with only one imagi-
nary frequency. To confirm the transition states connecting the designated intermediates, intrinsic reaction coordinate (IRC) calculation was carried out. Zero point energy (ZPE) corrections
14
X. Zhang / Journal of Molecular Structure 1063 (2014) 8–15
were applied at the same level [23]. Computed molecular structures were drawn with the CYLview program [24]. 3. Results and discussion Six carbanions M1–M6 were prepared as the special substrate ions with the similar method, which are shown in Fig. 1a. Especially for M1–M5, different substituents on the para-position of the benzene ring have been considered (M1: AH, M2: AOMe, M3: ANMe2, M4: ACl, M5: ANO2). Next, the preparation method of M1 was described in great detail (Fig. 1b). Reaction of L-phenylalanine and benzaldehyde in solution led to imine A1, which then lost a proton under the ESI (–) condition to yield carboxylate anion A2 at m/z 252. Finally the loss of CO2 from the anion A2 resulted in the target carbanion M1 at m/z 208 by MS/MS technique. The corresponding MS/MS spectrum (Fig. 1c) is very concise and M1 is the main fragment ion. Other substrate ions, including M2–M6, could also be prepared by using the similar methodology. After these carbanions M1–M6 were prepared, we would examine their reactivities at the collision energy to explore whether the intramolecular nucleophilic attack could take place. Thus, MS3 experiments of these carbanions were performed and the corresponding mass spectra are shown in Fig. 2. According to the analyses of Fig. 2a–f, besides some simple cleavage reactions (such as the loss of Me, benzene and toluene), an interesting fragment ion due to the loss of 27 Da appears in Fig. 2e (m/z 226, marked with asterisk) and 2f (m/z 150, marked with asterisk), but it doesn’t appear in Fig. 2a–d. On the basis of the principle of dissociation and ‘‘nitrogen rule’’, it is deduced that the structure of the neutral fragment ( 27 Da) is HCN, which is probably from the imine group. It is obvious that the experiments support our theoretical prediction (see Scheme 2). However, the loss of HCN only occurs in M5 and M6, in which the aromatic ring is activated by ANO2. These experimental phenomena arouse our interest in further exploring the mechanism for the loss of HCN. According to the structures of the substrate anions (M1–M6), it is obvious that before the loss of HCN, the formation of the r-adduct is necessary. Thus, the mechanism for the loss of HCN was assumed as follows: (i) Nucleophilic attack leads to r-adduct, including spiro- and bicyclo-ones (Scheme 2). (ii) The dissociation of the r-adduct results in the loss of HCN. Herein, two cases need considering: (i) whether the type of the r-adduct (spiro- or bicyclo-one) has some impact on the loss of HCN. (ii) Whether the formation of the r-adduct necessarily indicates the loss of HCN. To further comprehend the mechanism of the loss of HCN, theoretical calculations have been performed. The electronic structure method of choice has been density functional theory (DFT), in particular, the B3LYP hybrid functional. The first step focused on the regioselectivity of the C3-nucleophilic attack: C4-nucleophilic attack. The detailed activation Gibbs free energies are listed in Table 1 and the optimized structures of the transition states are shown in Fig. 3. It is found that M1–M4 favor C4-nucleophilic attack, while M5 and M6 favor C3-nucleophilic attack. Specifically, when the substituent on the para-position of the benzene ring is ANO2, spiro-r-adduct is formed exclusively. When other substituents (AOMe, ANMe2 and ACl) are introduced, bicyclo-r-adduct is the sole intermediate. In addition, according to the calculations, the following two points should be paid attention to: (i) Electron-donating groups (AOMe, ANMe2) promote the C4-nucleophilic attack, while electron-withdrawing groups (ACl, ANO2) have the opposite effect. This phenomenon is different from that found in the intermolecular SNAr reaction. The reason might be that in the substrate anions M1–M6, the substituent not only affects the electron cloud density in the benzene ring, but also works upon the negative charge on the C1 atom. (ii) For the C3-nucleophilic attack, there is no rule for the substituent effect to follow.
DFT calculations well predict the regioselectivity of the nucleophilic attack. Comparing the theoretical prediction with the MS3 experiments of the substrate anions (M1–M6, Fig. 2), we were amazed to find when spiro-r-adduct was predicted to be the preponderant intermediate (M5, M6, Table 1), the loss of HCN would occur in the tandem mass spectrometry (Fig. 2e and f) and that when bicyclo-r-adduct was the preponderant one (M1–M4, Table 1), the HCN couldn’t be lost. Therefore, it should be made clear whether the type of the r-adduct determines the loss of HCN. To solve the problem, the dissociation of the r-adduct would be investigated by DFT calculations. Spiro-r-adduct was examined first. Three probable pathways for the loss of HCN have been assumed, as are shown in Scheme 3. Firstly, concerted pathway was proposed, in which dissociations of the C2AC3 and NAC1 bonds take place at the same time. However, despite repeated attempts, the transition state for this concerted pathway could not be found. Secondly, stepwise pathway was put forward, in which two cases should be considered: (1) in stepwise pathway i, the NAC1 bond dissociates first. Unfortunately, the corresponding transition states could not be located either. (2) In stepwise pathway ii, the cleavage of the C2AC3 bond leads to the intermediate, which subsequently loses HCN via the dissociation of the NAC1 bond. Fortunately, all the transition states in stepwise pathway ii have been found successfully and the corresponding potential energy surfaces are depicted in Fig. 4. For spiro-r-adduct S1 (R = Benzyl, Fig. 4a), the activation Gibbs free energies for the dissociations of the C2AC3 and NAC1 bonds are 17.9 and 2.7 kcal/ mol, respectively. Meanwhile, the loss of HCN from S1 is exoergic by 29.1 kcal/mol. Analogously, for spiro-r-adduct S2 (R = Me, Fig. 4b), the activation Gibbs free energies for the cleavages of the C2AC3 and NAC1 bonds are 19.1 and 2.5 kcal/mol, respectively. The process of the loss of HCN from S2 is exoergic by 26.9 kcal/mol. According to the calculations, the loss of HCN from the spiro-r-adduct is both thermodynamically and kinetically beneficial, which is consistent with the tandem mass spectrometry experiments (Fig. 2e and f). The investigation of bicyclo-r-adduct was followed afterwards. Similar to spiro-r-adduct, three probable pathways for the loss of HCN have also been hypothesized, including concerted pathway and stepwise pathways i and ii, as are shown in Scheme 4. For the first two pathways, the corresponding transition states could not be found. However, in the stepwise pathway ii, the initial cleavage of the NAC1 bond successfully results in the loss of HCN. It is found that C5 atom participates in the dissociation of the NAC1 bond. SN2-like transition states were obtained, in which C5 atom attacks C1 atom together with the dissociation of the NAC1 bond. Then, the direct dissociation of the C2AC3 bond leads to the loss of HCN. All the transition states in stepwise pathway ii have been located successfully and the corresponding potential energy surfaces are shown in Fig. 5. According to the calculations, the following two conclusions could be drawn: (1) dissociation of the NAC1 bond is the rate-determining step and the activation Gibbs free energies for this step are as high as 58.0–59.6 kcal/ mol; (2) The losses of HCN from the bicyclo-r-adducts are all endergonic and the corresponding reaction Gibbs free energies vary from 41.1 to 42.3 kcal/mol. It is obvious that the loss of HCN from the bicyclo-r-adduct is disadvantageous either in kinetics or thermodynamics, which is also consistent with the tandem mass spectrometry experiments (Fig. 2a–d). 4. Conclusion On the basis of mass spectrometry technique and DFT calculations, six special substrate anions have been constructed to explore the regioselectivity of the intramolecular nucleophilic attack in the gas phase. Three conclusions are drawn as follows:
X. Zhang / Journal of Molecular Structure 1063 (2014) 8–15
(i) The regioselectivity of the intramolecular nucleophilic attack depends on the substituent on the para-position of the benzene ring. ANO2 favors C3-attack to form spiro-r-adduct, while other substituents (H, OMe, NMe2 and Cl) favor C4-attack to yield bicyclo-r-adduct. (ii) The substrate anion containing ANO2 group (M5, M6) can lose HCN. It is proposed that this phenomenon is owing to the easy cleavage of the spiro-r-adduct, for DFT calculations show that the loss of HCN from the spiro-r-adduct is both thermodynamically and kinetically beneficial. On the other hand, the substrate anion containing other groups (M1–M4) cannot lose HCN, which is due to the hard dissociation of the bicyclo-r-adduct. DFT calculations also demonstrate that the loss of HCN from the bicyclo-r-adduct is disadvantageous either in kinetics or thermodynamics. (iii) According to (i) and (ii), whether or not HCN can be lost could be used to judge the mode of the intramolecular nucleophilic attack. To be more specific, C3-attack favors the loss of HCN, while C4-attack has the opposite effect.
Acknowledgements The author gratefully acknowledges financial support from the start-up costs to introduce research personnel of Zhejiang Gongshang University (1110XJ2010044, 1110XJ2110044). Appendix A. Supplementary material Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.molstruc. 2014.01.054.
15
References [1] W. Danikiewicz, T. Bienkowski, D. Poddebniak, J. Am. Soc. Mass Spectrom. 15 (2004) 927. [2] H. Chen, H. Chen, R.G. Cooks, J. Am. Soc. Mass Spectrom. 15 (2004) 998. [3] S. Haoran, G.D. Stephen, Angew. Chem. Int. Ed. 45 (2006) 2720. [4] J.R. Pliego, D. Pilo-Veloso, Phys. Chem. Chem. Phys. 10 (2008) 1118. [5] G. Bouchoux, R. Flammang, J. De Winter, P. Gerbaux, J. Phys. Chem. A 113 (2009) 11075. [6] D. Witold, B. Tomasz, K. Dorota, Z. Magdalena, J. Am. Soc. Mass Spectrom. 18 (2007) 1351. [7] M. Makosza, Chem. Soc. Rev. 39 (2010) 2855. [8] S.M.J. Briscese, J.M. Riveros, J. Am. Chem. Soc. 97 (1975) 230. [9] J.H. Bowie, B.J. Stapleton, Aust. J. Chem. 30 (1977) 795. [10] Y.J. Zheng, R.L. Ornstein, J. Am. Chem. Soc. 119 (1997) 648. [11] D. Xu, Y. Wei, J. Wu, D. Dunaway-Mariano, H. Guo, Q. Cui, J. Gao, J. Am. Chem. Soc. 126 (2004) 13649. [12] J.F. Bunnett, R.E. Zahler, Chem. Rev. 49 (1951) 273. [13] M. Edelson-Averbukh, A. Mandelbaum, J. Mass Spectrom. 38 (2003) 1169. [14] A. Erkkila, I. Majander, P.M. Pihko, Chem. Rev. 107 (2007) 5416. [15] R.A.J. O’Hair, A.K. Vrkic, P.F. James, J. Am. Chem. Soc. 126 (2004) 12173. [16] M.M. Meyer, G.N. Khairallah, S.R. Kass, R.A.J. O’Hair, Angew. Chem. Int. Ed. 121 (2009) 2978. [17] X. Zhang, J. Mol. Struct. 1049 (2013) 149. [18] A.D. Becke, J. Chem. Phys. 98 (1993) 5648. [19] C. Lee, W. Yang, R.G. Parr, Phys. Rev. B. 37 (1988) 785. [20] S.H. Vosko, L. Wilk, M. Nusair, Can. J. Phys. 58 (1980) 1200. [21] P.J. Stephens, F.J. Devlin, C.F. Chabalowski, M.J. Frisch, J. Phys. Chem. 98 (1994) 11623. [22] M.J. Frisch, et al., Gaussian 09, Revision A.1, Gaussian Inc., Wallingford CT, 2009. [23] A.P. Scott, L. Radom, J. Phys. Chem. 100 (1996) 16502. [24] C.Y. Legault. CYLview, version 1.0b, Universitede Sherbrooke: Sherbrooke, QC, 2009..
Contents lists available at ScienceDirect
Journal of Molecular Structure journal homepage: www.elsevier.com/locate/molstruc
Regioselectivity of the intramolecular nucleophilic attack in [RACH AN@CHAC6H4AY]: A mass spectrometric and computational study Xiang Zhang ⇑ Department of Applied Chemistry, Zhejiang Gongshang University, Hangzhou 310035, China
h i g h l i g h t s
g r a p h i c a l a b s t r a c t
Regioselectivity of intramolecular
nucleophilic attack in [RACH AN@CHAC6H4AY] was studied. ANO2 favors C3-attack to form spiror-adduct and it also contributes to the loss of HCN. Other substituents (AH, AOMe, ANMe2 and ACl) favor C4-attack to yield bicyclo-r-adduct. It is difficult for bicyclo-r-adduct to lose HCN. DFT calculations are well consistent with the tandem mass spectrometry experiments.
a r t i c l e
i n f o
Article history: Received 4 August 2013 Received in revised form 14 January 2014 Accepted 14 January 2014 Available online 30 January 2014 Keywords: Regioselectivity Intramolecular nucleophilic attack Imine Density functional theory Mass spectrometry
a b s t r a c t The investigation into the intramolecular nucleophilic attack in carbanion [RACH AN@CHAC6H4AY] in the gas phase has been carried out by mass spectrometry and density functional theory (DFT). The main results of the present work are as follows: the regioselectivity of the intramolecular attack depends on the substituent on the para-position of the benzene ring. ANO2 favors C3-attack to form spiro-r-adduct and it also contributes to the loss of HCN, while other substituents (AH, AOMe, ANMe2 and ACl) favor C4-attack to yield bicyclo-r-adduct and in this condition, HCN cannot be lost. In the meantime, DFT calculations also demonstrate that the loss of HCN from the spiro-r-adduct is both thermodynamically and kinetically beneficial, while that from the bicyclo-r-adduct is disadvantageous either in kinetics or thermodynamics. Ó 2014 Elsevier B.V. All rights reserved.
1. Introduction Gas phase ion–molecule reactions have attracted the attention of a wide range of chemists as a means to investigate the interplay of structure and reactivity in the absence of a solvent. Among these, gas-phase nucleophilic aromatic substitution (SNAr) has long been the subject of continued investigation [1–7]. They are of ⇑ Tel.: +86 88071024. E-mail address: [email protected] 0022-2860/$ - see front matter Ó 2014 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.molstruc.2014.01.054
considerably practical use for transformations in organic and biological chemistry. For example, as long ago as 1975, Riveros has described a series of gas-phase reactions of halobenzenes with alkoxide anions [8]. Bowie has reported the gas-phase SNAr reaction between o-dinitrobenzene and chloride anion which proceeded in the ICR cell [9]. Recently, Witold described the significant SNAr reaction of halonitrobenzene with carbanion ACH2CN in the gas phase [6]. Besides widespread relevance to organic chemistry, this reaction type is also encountered in biological dechlorination reactions. For instance, both glutathione transferase and
X. Zhang / Journal of Molecular Structure 1063 (2014) 8–15
Scheme 1. Mechanism of the SNAr reaction.
9
4-chlorobenzoyl-coenzyme A dehalogenase operate according to this mode of reactivity [10,11]. The most common mechanism for SNAr reaction involves a multistep addition–elimination pathway through the rate-determining formation of well-characterized r-complex (Meisenheimer complex) intermediate [12], as is shown in Scheme 1. According to the literature, the intermolecular SNAr reactions in the gas phase have been studied in great detail. However, there are few reports relating to the intramolecular ones. This phenomenon might be explained on the basis of the character of the mass spectrometry. Advances in mass spectrometry and ion cyclotron reso-
Scheme 2. Preparation of the special substrate anions and probable intramolecular nucleophilic attack pathways.
Fig. 1. (a) Structures of the substrate anions. (b) Preparation of the carbanion M1. (c) MS/MS spectrum of the anion at m/z 252.
10
X. Zhang / Journal of Molecular Structure 1063 (2014) 8–15
nance (or ion trap) have made it possible for the intermolecular SNAr reactions to be investigated easily in the gas-phase, for the change of m/z can directly indicate the formation of the r-adduct. On the other hand, for the intramolecular SNAr reaction, it is difficult to judge whether it has taken place in the mass analyzer, because the m/z values for the reactant and product ions are the same. Generally, tandem mass spectrometry (Msn) cannot provide enough proof to support the intramolecular bonding process. However, for some special substrate ions, the tandem mass spectrome-
try technique still displays strong advantage in the study of the gas-phase reaction [13]. Loss of the specific neutral fragment can reveal the intramolecular formation of new bonds between originally non-bonded atoms. To further explore the intramolecular nucleophilic attacks in the aromatic systems, some special substrate ions with the imine functional groups (C@N bond) were constructed via the reactions of the a-amino acids with aromatic aldehydes [14] and subsequent decarboxylations [15–17] in this work, as are shown in
Fig. 2. MS3 spectra of the carbanions M1–M6.
Table 1 The detailed activation Gibbs free energies for the C3- or C4-nucleophilic attacks (kcal/mol).
M1 M2 M3 M4 M5 M6
R
Y
DG–i
DG–ii
Spiro-r-adduct : bicyclo-r-adduct
Benzyl Benzyl Benzyl Benzyl Benzyl Methyl
H OMe NMe2 Cl NO2 NO2
39.4 43.2 42.3 42.6 36.8 47.9
30.1 27.5 29.4 33.7 51.6 63.5
0: 100% 0: 100% 0: 100% 0: 100% 100%: 0 100%: 0
X. Zhang / Journal of Molecular Structure 1063 (2014) 8–15
Scheme 2. Once these substrate anions were formed, they were supposed to be converted into the r-adducts under the collision energy. In this process, two probable pathways were proposed: C3-nucleophilic attack (pathway i) versus C4-nucleophilic attack (pathway ii). The former leads to the spiro-r-adduct, while the latter results in the bicyclo-r-adduct. The fragmentation of the ring is likely to release the neutral molecule HCN either in spiroor bicyclo-r-adduct (Scheme 2). Based on this assumption, the loss of HCN can be used as an indicator of the formation of the r-adduct. Besides the substituent effect on the para-benzene ring which has been taken into account, it is expected that this work could start further discussion on the nature of the SNAr reaction.
11
2.2. Mass spectrometry
2. Experimental
The mass spectral data were acquired on a LCQ ion trap mass spectrometer from ThermoFinnigan (San Jose, CA, USA) equipped with an electrospray ionization (ESI) interface operated in the negative ion mode. ESI of a CH3CN/H2O (3:1) solution containing amino acid (about 500 lM) and a like amount of aldehyde was carried out at a flow rate of 15 lL/min into the ESI source. The operation parameters are listed as follows: spray tip potential 3200 V; capillary voltage: 30 V; capillary temperature: 250 °C; Sheath gas flow rate: 9.0 arbitrary units; Tube lens: 52 V. In the MS/MS experiments, the parent ions were isolated monoisotopically in the ion trap and collisionally activated by the same collision energies. Helium (99.99%) was used as the trapping and collision gas.
2.1. Material
2.3. Computational methods
L-alanine, L-phenylalanine, benzaldehyde, p-nitrobenzaldehyde, p-chlorobenzalde -hyde, 4-methoxybenzaldehyde and 4-(dimethylamino)-benzaldehyde were obtained from the Sigma–Aldrich Company.
All structures were computed on the basis of the hybrid density functional theory (B3LYP) and the 6-31+G (d, p) [18–21] basis set which were implemented in Gaussian 09 program package [22]. All the gas phase minima and transition structures (here also re-
Fig. 3. Structures of the transition states for the C3- or C4-nucleophilic attacks (Å).
Scheme 3. Probable mechanism for the loss of HCN from the spiro-r-adduct.
12
X. Zhang / Journal of Molecular Structure 1063 (2014) 8–15
Fig. 4. Free energy profiles for the loss of HCN from spiro-r-adducts S1 and S2. (kcal/mol).
Scheme 4. Probable mechanism for the loss of HCN from the bicyclo-r-adduct.
X. Zhang / Journal of Molecular Structure 1063 (2014) 8–15
13
Fig. 5. Free energy profiles for the loss of HCN from bicycle-r-adducts (kcal/mol).
ferred to as transition states) were characterized by frequency analysis. Frequency calculations identify minimum structures with all real frequencies, while transition states with only one imagi-
nary frequency. To confirm the transition states connecting the designated intermediates, intrinsic reaction coordinate (IRC) calculation was carried out. Zero point energy (ZPE) corrections
14
X. Zhang / Journal of Molecular Structure 1063 (2014) 8–15
were applied at the same level [23]. Computed molecular structures were drawn with the CYLview program [24]. 3. Results and discussion Six carbanions M1–M6 were prepared as the special substrate ions with the similar method, which are shown in Fig. 1a. Especially for M1–M5, different substituents on the para-position of the benzene ring have been considered (M1: AH, M2: AOMe, M3: ANMe2, M4: ACl, M5: ANO2). Next, the preparation method of M1 was described in great detail (Fig. 1b). Reaction of L-phenylalanine and benzaldehyde in solution led to imine A1, which then lost a proton under the ESI (–) condition to yield carboxylate anion A2 at m/z 252. Finally the loss of CO2 from the anion A2 resulted in the target carbanion M1 at m/z 208 by MS/MS technique. The corresponding MS/MS spectrum (Fig. 1c) is very concise and M1 is the main fragment ion. Other substrate ions, including M2–M6, could also be prepared by using the similar methodology. After these carbanions M1–M6 were prepared, we would examine their reactivities at the collision energy to explore whether the intramolecular nucleophilic attack could take place. Thus, MS3 experiments of these carbanions were performed and the corresponding mass spectra are shown in Fig. 2. According to the analyses of Fig. 2a–f, besides some simple cleavage reactions (such as the loss of Me, benzene and toluene), an interesting fragment ion due to the loss of 27 Da appears in Fig. 2e (m/z 226, marked with asterisk) and 2f (m/z 150, marked with asterisk), but it doesn’t appear in Fig. 2a–d. On the basis of the principle of dissociation and ‘‘nitrogen rule’’, it is deduced that the structure of the neutral fragment ( 27 Da) is HCN, which is probably from the imine group. It is obvious that the experiments support our theoretical prediction (see Scheme 2). However, the loss of HCN only occurs in M5 and M6, in which the aromatic ring is activated by ANO2. These experimental phenomena arouse our interest in further exploring the mechanism for the loss of HCN. According to the structures of the substrate anions (M1–M6), it is obvious that before the loss of HCN, the formation of the r-adduct is necessary. Thus, the mechanism for the loss of HCN was assumed as follows: (i) Nucleophilic attack leads to r-adduct, including spiro- and bicyclo-ones (Scheme 2). (ii) The dissociation of the r-adduct results in the loss of HCN. Herein, two cases need considering: (i) whether the type of the r-adduct (spiro- or bicyclo-one) has some impact on the loss of HCN. (ii) Whether the formation of the r-adduct necessarily indicates the loss of HCN. To further comprehend the mechanism of the loss of HCN, theoretical calculations have been performed. The electronic structure method of choice has been density functional theory (DFT), in particular, the B3LYP hybrid functional. The first step focused on the regioselectivity of the C3-nucleophilic attack: C4-nucleophilic attack. The detailed activation Gibbs free energies are listed in Table 1 and the optimized structures of the transition states are shown in Fig. 3. It is found that M1–M4 favor C4-nucleophilic attack, while M5 and M6 favor C3-nucleophilic attack. Specifically, when the substituent on the para-position of the benzene ring is ANO2, spiro-r-adduct is formed exclusively. When other substituents (AOMe, ANMe2 and ACl) are introduced, bicyclo-r-adduct is the sole intermediate. In addition, according to the calculations, the following two points should be paid attention to: (i) Electron-donating groups (AOMe, ANMe2) promote the C4-nucleophilic attack, while electron-withdrawing groups (ACl, ANO2) have the opposite effect. This phenomenon is different from that found in the intermolecular SNAr reaction. The reason might be that in the substrate anions M1–M6, the substituent not only affects the electron cloud density in the benzene ring, but also works upon the negative charge on the C1 atom. (ii) For the C3-nucleophilic attack, there is no rule for the substituent effect to follow.
DFT calculations well predict the regioselectivity of the nucleophilic attack. Comparing the theoretical prediction with the MS3 experiments of the substrate anions (M1–M6, Fig. 2), we were amazed to find when spiro-r-adduct was predicted to be the preponderant intermediate (M5, M6, Table 1), the loss of HCN would occur in the tandem mass spectrometry (Fig. 2e and f) and that when bicyclo-r-adduct was the preponderant one (M1–M4, Table 1), the HCN couldn’t be lost. Therefore, it should be made clear whether the type of the r-adduct determines the loss of HCN. To solve the problem, the dissociation of the r-adduct would be investigated by DFT calculations. Spiro-r-adduct was examined first. Three probable pathways for the loss of HCN have been assumed, as are shown in Scheme 3. Firstly, concerted pathway was proposed, in which dissociations of the C2AC3 and NAC1 bonds take place at the same time. However, despite repeated attempts, the transition state for this concerted pathway could not be found. Secondly, stepwise pathway was put forward, in which two cases should be considered: (1) in stepwise pathway i, the NAC1 bond dissociates first. Unfortunately, the corresponding transition states could not be located either. (2) In stepwise pathway ii, the cleavage of the C2AC3 bond leads to the intermediate, which subsequently loses HCN via the dissociation of the NAC1 bond. Fortunately, all the transition states in stepwise pathway ii have been found successfully and the corresponding potential energy surfaces are depicted in Fig. 4. For spiro-r-adduct S1 (R = Benzyl, Fig. 4a), the activation Gibbs free energies for the dissociations of the C2AC3 and NAC1 bonds are 17.9 and 2.7 kcal/ mol, respectively. Meanwhile, the loss of HCN from S1 is exoergic by 29.1 kcal/mol. Analogously, for spiro-r-adduct S2 (R = Me, Fig. 4b), the activation Gibbs free energies for the cleavages of the C2AC3 and NAC1 bonds are 19.1 and 2.5 kcal/mol, respectively. The process of the loss of HCN from S2 is exoergic by 26.9 kcal/mol. According to the calculations, the loss of HCN from the spiro-r-adduct is both thermodynamically and kinetically beneficial, which is consistent with the tandem mass spectrometry experiments (Fig. 2e and f). The investigation of bicyclo-r-adduct was followed afterwards. Similar to spiro-r-adduct, three probable pathways for the loss of HCN have also been hypothesized, including concerted pathway and stepwise pathways i and ii, as are shown in Scheme 4. For the first two pathways, the corresponding transition states could not be found. However, in the stepwise pathway ii, the initial cleavage of the NAC1 bond successfully results in the loss of HCN. It is found that C5 atom participates in the dissociation of the NAC1 bond. SN2-like transition states were obtained, in which C5 atom attacks C1 atom together with the dissociation of the NAC1 bond. Then, the direct dissociation of the C2AC3 bond leads to the loss of HCN. All the transition states in stepwise pathway ii have been located successfully and the corresponding potential energy surfaces are shown in Fig. 5. According to the calculations, the following two conclusions could be drawn: (1) dissociation of the NAC1 bond is the rate-determining step and the activation Gibbs free energies for this step are as high as 58.0–59.6 kcal/ mol; (2) The losses of HCN from the bicyclo-r-adducts are all endergonic and the corresponding reaction Gibbs free energies vary from 41.1 to 42.3 kcal/mol. It is obvious that the loss of HCN from the bicyclo-r-adduct is disadvantageous either in kinetics or thermodynamics, which is also consistent with the tandem mass spectrometry experiments (Fig. 2a–d). 4. Conclusion On the basis of mass spectrometry technique and DFT calculations, six special substrate anions have been constructed to explore the regioselectivity of the intramolecular nucleophilic attack in the gas phase. Three conclusions are drawn as follows:
X. Zhang / Journal of Molecular Structure 1063 (2014) 8–15
(i) The regioselectivity of the intramolecular nucleophilic attack depends on the substituent on the para-position of the benzene ring. ANO2 favors C3-attack to form spiro-r-adduct, while other substituents (H, OMe, NMe2 and Cl) favor C4-attack to yield bicyclo-r-adduct. (ii) The substrate anion containing ANO2 group (M5, M6) can lose HCN. It is proposed that this phenomenon is owing to the easy cleavage of the spiro-r-adduct, for DFT calculations show that the loss of HCN from the spiro-r-adduct is both thermodynamically and kinetically beneficial. On the other hand, the substrate anion containing other groups (M1–M4) cannot lose HCN, which is due to the hard dissociation of the bicyclo-r-adduct. DFT calculations also demonstrate that the loss of HCN from the bicyclo-r-adduct is disadvantageous either in kinetics or thermodynamics. (iii) According to (i) and (ii), whether or not HCN can be lost could be used to judge the mode of the intramolecular nucleophilic attack. To be more specific, C3-attack favors the loss of HCN, while C4-attack has the opposite effect.
Acknowledgements The author gratefully acknowledges financial support from the start-up costs to introduce research personnel of Zhejiang Gongshang University (1110XJ2010044, 1110XJ2110044). Appendix A. Supplementary material Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.molstruc. 2014.01.054.
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