Experimental deprotonation (acidity) thermochemistry of paracetamol
To determine the gas-phase acidity of paracetamol applying the EKM method (equation 3a), we have chosen four reference acids Aref(i)H with GAs ranging from 1388.4 to 1419.4 kJ·mol-1 (see supplementary material): 2,3,5,6-tetramethylbenzoic acid, 2,2,2-trifluoroacetamide, trimethylacetic acid, isobutyric acid. The CID branching ratio of the product ions were recorded at eight collision energies (Ecm), from 1.75 to 3.75 eV. The natural logarithms of the branching ratios, ln([A.]/[]), were plotted against the values of () (first thermokinetic plot depicted in Fig.1a) where = 1437.1 ± 8.8 kJ·mol-1 is the average of deprotonation enthalpies of reference acids (see supplementary material). The data are fitted by a set of eight regression lines, each one corresponding to experiments done with collision energies Ecm. The second thermokinetic plot (Figure 1a) is generated by plotting the negative Y-intercept values (related with the expression between brackets in the equation 3a) vs slopes 1/RTeff obtained from the results of the first graph. The deprotonation thermochemical values of paracetamol (Table 1) were derived from slope and negative Y-intercept values of the linear fit of the second plot (see supplementary material): .acidH0 = 1430.3 ± 8.8 kJ·mol-1, .acidS0 = 86.2 ± 8.4 J·mol-1·K-1 and GA = 1404.7 ± 8.8 kJ·mol-1. avgrefacidH.
Experimental protonation (basicity) thermochemistry of aracetamol
Four compounds with GBs ranging from 856.7 to 880.1 kJ·mol-1 (see supplementary material) were chosen as references: 1,2,3-triazole, pyrazole, 3-methylpyrazole, benzylamine. The CID branching ratio of the product ions were recorded at eight collision energies (Ecm), from 0.75 to 3.0 eV. The corresponding first set thermokinetic plots (eq. 3b) ln([BH+ ]/[]) vs is presented in Figure 1b. The proton affinity PA of paracetamol was obtained from the second set of thermokinetic plot. It was generated from Y-intercepts values obtained from the first set of the plots against the corresponding slopes 1/RTeff. The protonation thermochemical values of paracetamol (Table 1) were derived from slope and Y-intercept values of the linear fit of the second plot (see supplementary material): PA = 909.4 ± 8.4 kJ·mol-1, .pS0 = 132.8 ± 8.4 J·mol-1·K-1 and GB = 869.9 ± 8.4 kJ·mol-1. )(avgrefref(i)PAPA.
Structural and energetic features of neutral, protonated and deprotonated paracetamol
Paracetamol has two stable conformers (Ipar and IIpar depicted in Figure 2) with approximately CS symmetry and similar stability. In enthalpic terms Ipar and IIpar differ only by about 1.5 kJ·mol-1, the latter being less stable. Except for the hydrogens of the methyl group, the remaining fragments of each conformer are coplanar. Rotation of the hydroxyl group in Ipar around the CPh–O(H) bond leads to structure IIpar. The equilibrium constant pertaining to the reaction Ipar IIpar, is 0.67. It follows that, at ca. 298.15 K, a sample of gaseous paracetamol is an equilibrating mixture of approximately 60 and 40% of Ipar and IIpar, respectively. The values correspond to calculations at B3LYP/6-311++G(3df,2p) level of theory.
