B American Society for Mass Spectrometry, 2014

J. Am. Soc. Mass Spectrom. (2014) DOI: 10.1007/s13361-014-0935-7

RESEARCH ARTICLE

Intramolecular Electrophilic Aromatic Substitution in Gasphase Fragmentation of Protonated N-Benzylbenzaldimines Shanshan Shen, Yunfeng Chai, Guofeng Weng, Yuanjiang Pan Department of Chemistry, Zhejiang University, Hangzhou, 310027, China

Abstract. In this study, the gas-phase fragmentations of protonated Nbenzylbenzaldimines were investigated by electrospray ionization tandem mass spectrometry (ESI-MSn). Upon collisional activation, several characteristic fragment ions are produced and their fragmentation mechanisms are rationalized by electrophilic aromatic substitution accompanied by benzyl cation transfer. (1) For N-(p-methoxybenzylidene)-1-phenylmethanimine, concomitant with a loss of HCN, a product ion at m/z 121 was observed. It is proposed to be generated from electrophilic substitution at the ipso-position by transferring benzyl cation rather than cleavage of the C-N double bond. (2) For N-(m-methoxybenzylidene)1-phenylmethanimine, a product ion at m/z 209 was obtained, corresponding to the elimination of NH3 carrying two hydrogens from the two aromatic rings respectively. This process can be rationalized by two sequential electrophilic substitutions and cyclodeamination reaction based on the benzyl cation transfer. Deuterium-labeled experiments, density functional theory (DFT) calculation and substituent effect results also corroborate the proposed mechanism. Keywords: Gas-phase reaction, Electrophilic aromatic substitution, Benzyl cation transfer, Substituent effect, Electrospray ionization tandem mass spectrometry Received: 18 March 2014/Revised: /Accepted: 21 May 2014

Introduction

E

lectrospray ionization mass spectrometry (ESI-MS) not only is a versatile technique for analyzing numerous compounds [1–4] but has proven to be a powerful tool for studying molecular structures, mechanisms, and kinetics [5– 8]. These gas-phase studies make it possible to uncover the intrinsic mechanisms of gaseous reactions, which always reveal subtle relationships with those in condensed phase. A prevalent class of fragmentation processes occurring in organic ions in the gas phase involves many novel rearrangements and subsequent intramolecular formation of new bonds [9–13]. Among these rearrangements, benzyl cation transfer is a well-documented mechanism since the early days of organic mass spectrometry [14–18]. Benzyl cation is thermodynamically stable in the gas phase because of its resonance stabilization [19–22]. Previous theoretical calculations have indicated that the

Electronic supplementary material The online version of this article (doi:10.1007/s13361-014-0935-7) contains supplementary material, which is available to authorized users. Correspondence to: Yuanjiang Pan; e-mail: [email protected]

energy barrier of the isomerization from benzylium ion isomer of benzyl cation to tropylium ion is rather substantial, though tropylium ion possesses lower energy [23, 24]. Therefore, in most MS studies, benzylium ion is more favorable than tropylium [23, 25]. There are many novel reactions involving benzylium ion in the gas phase, including electrophilic aromatic substitution [18, 26, 27], nucleophilic aromatic substitution [25, 28], electron transfer [27, 29], hydride transfer [11, 27], and so on. Electrophilic aromatic substitution (SE) is a classic reaction in organic chemistry and has been the topic of numerous studies in the gas phase. Gas-phase SE accompanied by benzyl cation transfer has been reported in a variety of protonated benzylated molecules, such as benzyl esters [16, 26], benzyl ethers [15], benzylamines [18, 30], et al. But deeper insight into the phenyl substituent effect is still needed. In our quest for expanding the scope of benzylated substrates employing SE, we investigated the collision-induced dissociation (CID) of substituted N-benzylbenzaldimines using ESI-MS. We found intriguing losses of NH3 or HCN, initiated by benzyl cation transfer, corresponding to isomeric substituted N-benzylbenzaldimines, which are consistent with the substituent effect in SE in condensed phase.

S. Shen et al.: Intramolecular Electrophilic Substitution

Experimental Materials The N-benzylbenzaldimine derivatives (Compounds 1–11, Scheme 1) were synthesized and purified according to the classical method [31] with corresponding aromatic aldehydes and benzyl amines. The structures of representative model compounds were confirmed by 1H and 13C NMR. N(p-methoxybenzylidene)-1-phenylmethanimine, 1H NMR (600 MHz, CDCl3): δ(ppm) 8.25 (s, 1H), 7.65 (d, 2H), 7.26–7.25 (m, 4H), 7.19–7.17 (m, 1H), 6.85 (d, 2H), 4.71 (s, 2H), 3.76 (s, 3H); 13C NMR (150 MHz, CDCl3): δ(ppm) 161.8, 161.4, 139.6, 129.9, 129.2, 128.6, 128.1, 127.0, 114.1, 65.1, 55.5. N-(m-methoxybenzylidene)-1phenylmethanimine, 1H NMR (600 MHz, CDCl3): (ppm) 8.28 (s, 1H), 7.31 (s, 1H), 7.26–7.18 (m, 7H), 6.90 (d, 1H), 4.74(s, 2H), 3.75 (s, 3H); 13C NMR (150 MHz, CDCl3): δ(ppm) 162.1, 160.0, 139.3, 137.6, 129.7, 128.6, 128.1, 127.1, 121.8, 117.7, 111.6, 65.1, 55.5.

1.2 with the XIC Manager. Solutions were infused from the ESI source at 10 μL/min−1 with the following parameters applied: ion spray voltage floating (ISVF), 5500 V; temperature, 550°C; curtain gas, 25 psi, and ion source gas (GS1 and GS2) at 40 psi. The collision energy (CE) was 40 eV, and the collision energy spread (CES) was 15 eV in the MS/MS experiments.

Theoretical Calculations Theoretical calculations were carried out using the Gaussian 03 package of programs [32]. All structures were optimized at the B3LYP/6–31++G (d, p) level of density functional theory (DFT), and were identified as the true minima by the absence of imaginary frequencies. Transition states were identified by the presence of only one imaginary frequency. The minima connected by a given transition structure were confirmed by intrinsic reaction coordinate (IRC) calculations. The energies discussed here are the sum of electronic and thermal energies.

Mass Spectrometry The mass spectrometry experiments were performed in the positive ion mode using a Bruker Esquire 3000plus mass spectrometer equipped with an ESI source and an ion trap analyzer. Nitrogen was used as the drying gas at a flow rate of 5 L·min–1 and the nebulizing gas at a pressure of 10 psi. The drying gas temperature was set at 250°C and the capillary voltage was set at –4000 V. The CID mass spectra were obtained with helium as the collision gas at appropriate collision energies (fragmentation amplitude, 0.55–0.8 V) after isolation of the desired precursor ion. The compounds were dissolved in and diluted with methanol. Methanol-d4 was used as solvent for deuterium labeling experiments. The solution was infused into the mass spectrometer at a final concentration of approximate 1 μg·mL–1, with a syringe pump at a flow rate of 180 μL·h–1. Accurate spectrometric experiments were conducted by a TripleTOF4600 system with a DuoSpray ion source operating in the positive ESI mode (AB SCIEX, Foster City, CA, USA). The APCI probe of the source was used for fully automatic mass calibration using the Calibrant Delivery System (DJS). CDS injects a calibration solution matching the polarity of ionization and calibrates the mass axis of the TripleTOF system in all scan functions used (MS or MS/ MS). Data acquisition and processing were carried out using Analyst TF 1.6 and PeakView (AB SCIEX) software version

Scheme 1. Structures of N-benzylbenzaldimine derivatives

Figure 1. CID mass spectra of [M + H]+ Ion of (a) N-(pmethoxybenzylidene)-1-phenylmethanimine (1), (b) N-(pmethoxybenzylidene-1-d)-1-phenylmethanimine, (c) N-(pmethoxybenzylidene)-1-phenylmethanimine-1,1-d2. (Insets show expansion of m/z 197–203 region)

S. Shen et al.: Intramolecular Electrophilic Substitution

Scheme 2. Proposed mechanism of formation of ionB from protonated N-(p-methoxybenzylidene)-1-phenylmethanimine (1) by C-N double bond cleavage

Results and Discussion Dissociation of the Protonated N(p-Methoxybenzylidene)-1-Phenylmethanimine T he E SI- M S/M S s pe ct r u m o f p r oto nat ed N- (pmethoxybenzylidene)-1-phenylmethanimine (1) is shown in Figure 1a. Upon collisional activation, the protonated molecular ion at m/z 226 yielded three identifiable product ions at m/z 91, 121 (ionB) and 199 (ionA), respectively. In general, the dominant product ion at m/z 91 is the benzyl cation that is directly produced by the cleavage of the N8–C9 bond, while ionA corresponds to a loss of HCN. The probable structure for ionB is assigned to methoxybenzylium (CH3O-C6H4-CH2+), and is further confirmed by high-resolution mass measurements (Supplementary Table S1). At first glance, the generation of ionB presumably results from the cleavage of the C7-N8 double bound. Considering the fact that the proton transfer (PT) mechanism is quite prevalent in gas-phase fragmentation reactions, we initially propose that the PT from C9 to C7 via direct 1, 3-PT or stepwise PT is required prior to generating ionB (Scheme 2). However, when the hydrogen on C7 was replaced by a deuteron and the CID spectrum of N-(p-methoxybenzylidene1-d)-1-phenylmethanimine was recorded (Figure 1b), to our surprise, the formation of an ion at m/z 121 rather than m/z 122 was discovered, which implies that C7 is not retained in the formation of the product ion at m/z 121. The existence of

product ion at m/z 121 in the D-labeling experiment undoubtedly indicates the C-N double bond cleavage model is not applicable in this case. Moreover, in the CID spectrum of N-(p-methoxybenzylidene)-1phenylmethanimine-1,1-d2 (Figure 1c), a product ion at m/z 123 (CH3O-C6H4-CD2+) is evident. It follows that specific reconnection of C9 to ring A is concomitant with C1–C7 bond cleavage. Thus, a complicated skeletal rearrangement must be involved in the generation of the product ion at m/z 121. Therefore, two possible mechanism pathways of forming ionB involving benzyl cation transfer (BT) were proposed. As presented in Scheme 3, the fragmentation is initiated by the external proton transfer from imino N8 to the ipsoposition to break C1–C7 bond in Path a, generating an ionneutral complex (INC), a-2. The cation moiety undergoes a heterolytic cleavage of the C–N bond to expel a neutral molecule of HCN, followed by benzyl cation migration to the para-position of methoxybenzene (see more discussion below) to form an arenium ion [33]. The departing HCN carries the proton from ring A to ring B to engender the subsequent benzene loss, yielding ionB (m/z 121). Considering the sequential exchangeability of PT and BT, Path b initiated by BT is also proposed (Scheme 4). An incipient elongation of the N8–C9 bond at the charge center leads to the consequent cleavage to generate an INC (b-1) that consists of benzyl cation and (p-methoxyphenyl)methanimine.

Scheme 3. Proposed fragmentation mechanism of forming ionB for protonated N-(p-methoxybenzylidene)-1phenylmethanimine (1) initiated by PT

S. Shen et al.: Intramolecular Electrophilic Substitution

Scheme 4. Proposed fragmentation mechanism of forming ionB for protonated N-(p-methoxybenzylidene)-1phenylmethanimine (1) initiated by BT

Figure 2. DFT potential energy diagram for fragmentation of protonated N-(p-methoxybenzylidene)-1-phenylmethanimine

Figure 3. Curves generated by the Napierian logarithm of the abundance ratio of selected fragment ions versus excitation amplitude of (a) three-positional methoxybenzylium isomers, and (b) ionB

S. Shen et al.: Intramolecular Electrophilic Substitution

The benzyl cation transfers to the ipso-position of ring A to expel the HC≡NH+ moiety, which gives rise to a proton-bound complex (b-3). After the external proton transfers to the ipso-position of ring B, benzene loss occurs to generate ionB (m/z 121). The two possible pathways cannot be distinguished solely by the D-labeling experiments since both are applicable for the deuterated cases. Thus, in order to determine which one is more reasonable, DFT calculations were carried out to quantitatively describe energy requirements for the two pathways, and potential energy surfaces were generated as shown in Figure 2. Since the product ions arising from PT-initiating Path a and BT-initiating Path b possess the same structures at 221.5 kJ·mol–1, and both of them share the last two steps (a-5/b-3 → ionA → ionB), the incipient intermediates of the two possible pathways control the reactions. For the initiating step, Path a involves PT from the imino nitrogen to C1 where a-TS-1 requires a relatively high energy barrier (258.2 kJ·mol–1) to surmount. Nevertheless, as long as the incipient transition-state energy has been overcome, the subsequent intra-complex reactions (a-2→a-3→a-4→a-5→ionA) seems to be rather competitive since Path a forms a proton-bound INC in a deep energy well located at 165.9 kJ · mol–1 (a-3). On Path a, the departing HCN acts as a proton-transport catalyst [34–37], which contributes to reducing the energy barrier. On Path b, the initiating isomerization of p-M to b-2, through migration of the benzyl cation via an INC (b-1), surmounts a small energy barrier of 197.1 kJ · mol–1. The resulting b-2 lies 179.7 kJ · mol–1 above p-M in energy, indicating a lower benzylation nucleophilicity of C1 than that of imino nitrogen. Thus, based on energy consideration, the preference of the two possible pathways remains to be verified since they both have pros and cons. It is noteworthy that when zero-point vibrational energies and thermal corrections are taken into consideration, the relative energy of aTS-2 is lower than that of a-4. Such cases are not unusual [10, 38]. Notably, the structure of ionB was confirmed by multistage mass spectra. Commonly, evaluation of a characteristic fragment ion that demonstrates the stereochemistry is widely used to identify isomers and tautomers [39, 40]. As shown in the proposed mechanism, next to the initial formation of INC there are three alternative positions to which the benzyl cation can transfer, ipso (C1), ortho (C2 or C6), or meta (C3 or C5) positions of the p-methoxyphenylmethanimine, ultimately yielding para-, meta-, or ortho-methoxybenzylium, respectively, at m/z 121. To experimentally confirm the structure of ionB, plots of excitation amplitude versus the Napierian logarithm of the abundance ratio of two selected fragment ions in multistage mass spectra are further studied. The three standard-reference ions, ortho-, meta-, and para-methoxybenzylium isomers, were formed by elimination of a neutral NH3 in CID MS2 spectra from corresponding methoxybenzylamines. Further CID MS3 spectra of the three methoxybenzylium isomers and

Figure 4. CID mass spectra of (a) [M+H]+ ion of N-(mmethoxybenzylidene)-1-phenylmethanimine (2), (b) [2 + D]+ ion, (c) [M + H]+ ion of N-(m-methoxybenzylidene-1-d)1-phenylmethanimine, (d) [M + H] + ion of N-(mmethoxybenzylidene)-1-phenylmethanimine-1,1-d 2 , (e) [M + H]+ ion of N-(m-methoxybenzylidene)-1-(phenyld 5)methanimine

ionB were recorded under a series of collision energies, and characteristic fragment ions at m/z 91 and 93 were selected to generate the curves. As presented in Figure 3, the

S. Shen et al.: Intramolecular Electrophilic Substitution

Scheme 5. Proposed fragmentation mechanism for protonated N-(m-methoxybenzylidene)-1-phenylmethanimine combined with benzyl cation transfer in the gas phase

curve pattern of ionB (Figure 3b) closely resembles that of p-methoxybenzylium (Figure 3a), which confirms that the structure of ionB is p-methoxybenzylium. Representative CID MS3 spectra of the four fragment ions are given in Supplementary Figure S1. In addition, the conclusion of the foregoing structuredetermining experiments implies that the reaction forming ionB may be more inclined to follow Path a. In Path a (Scheme 3), the intra-complex reaction involves benzyl cation (after losing HCN) and methoxybenzene in a-2. As an electron-donating group, methoxyl directs the attacking benzyl cation to the para- position predominantly and produces the corresponding fragment ions at m/z 199 and 121. In contrast, in Path b (Scheme 4), the intra-complex reaction is between benzyl cation and (pmethoxyphenyl)methanimine. The methanimine group is an electron-withdrawing group, which may lessen the possibility of ipso-attack to repulse HC≡NH+. Instead, the two ortho- locations to the methoxy group are the favorable positions for the attack, which is not so consistent with what Figure 3 reveals.

Dissociation of the Protonated N(m-Methoxybenzylidene)-1-Phenylmethanimine A comparison of CID spectra of protonated N-(mmethoxybenzylidene)-1-phenylmethanimine (2, Figure 4a) revealed another interesting phenomenon. Under identical CID conditions, protonated Compound 2 produces a significant product ion at m/z 209 (ionC) corresponding to elimination of NH3 besides a dominating peak at m/z 91 representing benzyl cation (for accurate mass data, see Supplementary Table S1). Although such a loss seems trivial, the mechanism is not straightforward since the protonated molecule should undergo a sophisticated rearrangement to break the three bonds attached to the imino nitrogen. Extensive deuterium-labeling experiments were carried out as depicted in Figure 4. A deuterated molecular [2+D]+ at m/z 227 was generated by spraying a freshly prepared methanol-d4 solution of 2 in the positive mode, and the product ion for the loss of NDH2 at m/z 209 in the CID spectrum (Figure 4b) ascertained that the exchangeable hydrogen remained bonded to nitrogen during CID fragmentation to eliminate ammonia. Moreover, in the CID spectrum of N-(m-

Figure 5. DFT potential energy diagram for fragmentation of protonated N-(m-methoxybenzylidene)-1-phenylmethanimine

S. Shen et al.: Intramolecular Electrophilic Substitution

Table 1. Selected Ions in the CID Mass Spectra of the [M + H]+ Ions of Compounds 3 to 11 Cmpd.

R

Loss of NH3

Loss of HCN

RC6H4CH2+

3 4 5 6 7 8 9 10 11

p-OH m-OH p-N(CH3)2 m-N(CH3)2 p-CF3 m-CF3 p-NO2 m-NO2 H

– 195 (2) 222 (3) 222 (100) – – – – –

– – 212 (65) 212 (10) – – – – –

107 (1) a – 134 (23) 134 (7) – – – – –

a

m/z (Relative abundance, %)

methoxybenzylidene)-1-(phenyl-d5)methanimine (Figure 4e), a deuterium atom from ring B was exclusively eliminated in the process of forming NH2D (m/z 213), confirming that a hydrogen from the phenyl ring B must transfer specifically to the imino nitrogen during the elimination. However, when the hydrogens on N-adjacent C7 or C9 were deuterated, no deuterium atom was eliminated in the CID spectra (Figure 4c, d). Therefore, it is not difficult to deduce that the hydrogens involved in the loss of NH3 came from the external proton, whereas the other two are from the two phenyl rings, respectively. In order to rationalize the observations, we postulate the mechanism based on BT in gas-phase fragmentation in Scheme 5. The m-M could undergo a charge-driven heterolytic cleavage [41] of the N8–C9 to generate an intermediate (m-1), which could separate directly to form the most intense peak at m/z 91, or 93 and 96 in the deuterated cases. On the other hand, the charged moiety of m-1, benzyl cation, transfers to the ortho- (Path 1) or para- (Path 2) position of mmethoxybenzylidene, followed by donating a ring proton to the imino group to regenerate the aromatic ring. A subsequent ring closure follows to yield dihydroanthracenium derivatives (ionC-1, ionC-2) by eliminating a molecular NH3. DFT calculations for the fragmentation of [2 + H]+ were then performed to evaluate the proposed mechanism. A schematic potential energy diagram is shown in Figure 5, and full details of the structures of the species involved are given in Supporting Information. Obviously, the two parallel fragment reaction pathways of eliminating NH3, Path 1 and Path 2, are almost isoenergetic, with the formation of terminal product ion in Path 2 (ionC-2) demanding only 7.4 kJ·mol–1 higher energy than that for the Path 1 (ionC-1). Following the incipient generation of an intermediate (m-1) located 173.0 kJ·mol–1 above m-M, the two sequential electrophilic attacks are the key steps in which the respective transition-state energies for the two pathways are relatively close. In particular, in the first transition state an energy barrier up to 205.5 kJ·mol–1 exists in Path 1 (1-TS-1), which is slightly higher (by 10.2 kJ·mol–1) than that in Path 2 (2-TS-1), whereas in the second transition state Path 1 possesses a bit lower energy barrier (via 1-TS-2) by 4.6 kJ·mol–1 compared to 2-TS-2 in

Path 2. Aforementioned DFT calculation results reveal that both pathways are feasible in terms of energy. On the other hand, although the DFT calculations predict that benzyl cation is the thermodynamically disfavored product in the CID fragmentation of [2 + H]+, it is still the most abundant product ion (Figure 4a) in the dissociation, which indicates that benzyl cation is preferred because of its straightforward pathway and irreversible activation energy of the N8–C9 bond cleavage. In essence, the fragmentation reactions aforementioned can be classified as gas-phase intramolecular electrophilic aromatic substitution (SE) [42], in which benzyl cation functions as the electrophile whereas methoxyphenylmethanimine functions as the electron-rich substrate. To confirm the proposal, the CID spectra of a series of N-benzylbenzaldimines containing different substituents (Compound 3–11, Scheme 1) were recorded (Supplementary Figure S2), and the target ions were summarized in Table 1. These results support the reactivity and orientation effect of substituents in SE reactions. Specifically, electron-donating groups can expedite the intramolecular SE combined with BT resulting in ipsosubstitution in para-(Compound 3, 5) or cyclodeamination in meta-(Compound 4, 6) substituted compounds, respectively. In contrast, electron-withdrawing groups (Compound 7–10) or H (Compound 11) can inhibit the process since no target ion was obtained.

Conclusion We have observed interesting gaseous electrophilic aromatic substitution (SE) reactions employing benzyl cation transfer by ESI-MSn equipped with an ion trap cell. The proposed mechanism was confirmed by comprehensive experimental and theoretical evidence. A series of analogues bearing different substituents were investigated to further understand the mechanism, which turned out to be well consistent to the proposal. Our research is not only a vital supplement to SE reactions in the gas phase, but also contributes to further understanding cyclodeamination, benzyl cation transfer, and substituent effects.

Acknowledgments The authors gratefully acknowledge financial support from the National Science Foundation of China (nos. 21025207 and 21372199).

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