Protonation of Curcumin Triggers Sequential Double Cyclization in the Gas-Phase: An Electrospray Mass Spectrometry and DFT Study.

ESI-protonated natural curcumin (1) undergoes gas-phase cyclization and dissociates via competitive expulsions of 2-methoxy phenol and C4H4O2 (diketene or an isomer). Evidence from mechanistic mass spectrometry and from Density Functional Theory (DFT) reveals that a two-step sequential cyclization occurs for the protonated molecule prior to the unusual loss of the elements of 2-methoxy phenol. Furthermore, the presence of the methoxy group at postion-3 is essential for the second cyclization. The transformation of curcumin upon protonation in the gas phase may be predictive of its solution chemistry and explain how curcumin plays a protective role in biology.

Protonated N-Alkyl-2-nitroanilines Undergo Intramolecular Oxidation of the Alkyl Chain upon Collisional Activation.

The collisional activation of protonated N-propyl-2-nitroaniline obtained by electrospray ionization shows two major competitive dissociation pathways: the elimination of the elements of propionic acid, [M + H - C3H6O2]+ to give an m/z 107 ion, and of the elements of ethanol, [M + H - C2H6O]+ to give an m/z 135 ion. The mechanistic study reported here addresses these unusual fragmentations to reveal that both occur via a common intermediate formed by the transfer of an oxygen atom from the nitro group to the first carbon atom of the propyl group, allowing elimination of propionic acid and (H2O + ethene), respectively. The corresponding loss of CH4O does not occur when the propyl group is replaced by an ethyl group, but elimination of the elements of propanol does occur when propyl is replaced by a butyl group. Further, the product ions of m/z 107 and 135 are also formed when the propyl chain is replaced with a hexyl group.

McLafferty-type rearrangement of protonated N-[nicotinoyl]phenylethyl amines and consequent elimination of styrene.

RATIONALE: McLafferty rearrangements occur in radical cations of molecules containing a carbonyl group and a γ hydrogen atom but are not common in the [M+H](+) ions of carbonyl compounds. We propose to investigate the collision-induced dissociation (CID) of the [M+H](+) ions of nicotinoyl and picolinoyl amides of 1- and 2-phenylethylamines to explore the possibility of McLafferty-type rearrangement. METHODS: The compounds for study were synthesized by the reaction of methyl nicotinate or methyl picolinate with 1- and 2-phenylethylamines. The CID mass spectra of electrospray ionization (ESI)-generated protonated molecules were obtained using a QSTAR XL quadrupole time-of-flight (QTOF) mass spectrometer, and density functional theory (DFT) calculations using the B3LYP method were employed to elucidate the fragmentation mechanisms. The total electronic and thermal energies of intermediate transition states (TSs) and product ions are reported relative to those of the [M+H](+) ions. RESULTS: CID of the [M+H](+) ions of N-[nicotinoyl]-2-phenylethylamine (1) yielded product ions of m/z 105 (1-phenylethyl cation) and 123 ([M+H-styrene](+) cation). The competitive formation of the ions of m/z 123 and 105 is proposed to involve a McLafferty-type rearrangement. Similarly, the [M+H](+) ions of the isomeric compound 2 and the N-[picolinoyl] phenylethyl amines (3 and 4) dissociate to yield ions of m/z 123 and 105. CONCLUSIONS: A molecule of styrene was eliminated from the ESI-generated [M+H](+) ions of N-[nicotinoyl]phenylethylamines and the isomeric N-[picolinoyl]phenylethylamines, through a mechanism involving a McLafferty-type 1,5-H shift. The transition state energy for the 1,5-H shift is less for the amides of 1-phenylethylamine than for the amides of 2-phenylethylamine. The process occurs as a charge remote process and the presence of the pyridine ring is essential for the process.

Protonated N-benzyl- and N-(1-phenylethyl)tyrosine amides dissociate via ion/neutral complexes.

RATIONALE: The collisional-induced dissociations (CID) of the [M+H]+ ions of molecules having benzyl groups attached to N-atoms have been proposed to involve migration of the benzyl group through the intermediacy of ion/neutral complexes (INCs). We report the investigation of the mechanism of dissociation of protonated N-benzyl- and N-(1-phenylethyl)tyrosine amides by electrospray ionization (ESI) tandem mass spectrometry (MS/MS) and density functional theory (DFT) calculations. METHODS: The amides were synthesized from the corresponding amino acids and amines. The ESI-MS/MS spectra were recorded using an Agilent QTOF 6540 mass spectrometer. The DFT calculations were performed by using Gaussian 09 software. The structures of the [M+H]+ ions, intermediates, products and transition states (TS) were optimized at the B3LYP/6-31G(d,p) level of theory. RESULTS: CID of the [M+H]+ ions of N-benzyltyrosine amide yields two product ions due to rearrangements: (i) the [M+H-74]+ ion (m/z 197) due to benzyl migration to the hydroxyphenyl ring and (ii) the [M+H-45]+ ion (m/z 226) due to benzyl migration to the NH2 group. DFT calculations suggest that the rearrangements occur through an INC in which the benzyl cation is the cation partner. The [M+H]+ ion of N-(1-phenylethyl)tyrosine amide rearranges to an INC of the 1-phenylethyl cation. Subsequent elimination of styrene occurs by transfer of a proton from the 1-phenylethyl cation to the neutral partner. CONCLUSIONS: The [M+H]+ ions of both N-benzyl (1) and N-(1-phenylethyl) (2) tyrosine amide rearrange into INCs. The dissociation of [M+H]+ ion of 1 yields the benzyl cation and [M+H-74]+ and [M+H-45]+ due to benzyl migration to the hydroxyphenyl ring and NH2 group, respectively. However, the formation of the [M+H-74]+ ion is not observed when the aromatic ring is deactivated. The [M+H]+ ion of 2 either dissociates to form the 1-phenylethyl cation or [M+H-styrene]+ . Copyright © 2015 John Wiley & Sons, Ltd.

The role of methoxy group in the Nazarov cyclization of 1,5-bis-(2-methoxyphenyl)-1,4-pentadien-3-one in the gas phase and condensed phase.

ESI-protonated 1,5-bis-(2-methoxyphenyl)-1,4-pentadien-3-one (1) undergoes a gas-phase Nazarov cyclization and dissociates via expulsions of ketene and anisole. The dissociations of the [M + D](+) ions are accompanied by limited HD scrambling that supports the proposed cyclization. Solution cyclization of 1 was effected to yield the cyclic ketone, 2,3-bis-(2-methoxyphenyl)-cyclopent-2-ene-1-one, (2) on a time scale that is significantly shorter than the time for cyclization of dibenzalacetone. The dissociation characteristics of the ESI-generated [M + H](+) ion of the synthetic cyclic ketone closely resemble those of 1, suggesting that gas-phase and solution cyclization products are the same. Additional mechanistic studies by density functional theory (DFT) methods of the gas-phase reaction reveals that the initial cyclization is followed by two sequential 1,2-aryl migrations that account for the observed structure of the cyclic product in the gas phase and solution. Furthermore, the DFT calculations show that the methoxy group serves as a catalyst for the proton migrations necessary for both cyclization and fragmentation after aryl migration. An isomer formed by moving the 2-methoxy to the 4-position requires relatively higher collision energy for the elimination of anisole, as is consistent with DFT calculations. Replacement of the 2-methoxy group with an OH shows that the cyclization followed by aryl migration and elimination of phenol occurs from the [M + H](+) ion at low energy similar to that for 1.