A Chemical Ionization Study of Deuteron Transfer Initiated Propene Loss from Propoxypyridines

Eric S. E. van Beelen, Tineke A. Molenaar-Langeveld, and Steen Ingemann Faculty of Science, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands

ϩ The mechanism of propene loss from the metastable [M ϩ D] ions of isomeric 2-, 3-, and 4-n-propoxypyridines and the related isopropoxypyridines has been examined by chemical ionization (CI) and tandem mass spectrometry in combination with deuterium labeling. The ϩ ϩ [M D] ions were generated with CD3OD, CD3CN, (CD3)2CO, or pyrrole-D5 (listed in order of increasing proton affinity) as the CI reagent. The results reveal that the deuteron added in the CI process is not interchanged with the hydrogen atoms of the propyl group prior to ϩ propene loss from the metastable [M ϩ D] ions of the propoxypyridines. The site selective ϩ labeling of the ␣-, ␤-, or ␥-position of the propyl group indicates that the [M ϩ D] ions of 2-n-propoxypyridine expel propene with formation of an ion-neutral complex composed of a ϩ propyl carbenium ion and 2-pyridone. By contrast, the [M ϩ D] ions of 3-n-propoxypyridine expel propene by: (1) Formation of ion-neutral complexes, and (2) a conventional 1,5-hydride shift from the ␤-position of the n-propyl group to the ring and/or a 1,2-elimination type process. For the 4-isomer, the results suggest the occurrence of propene loss by a 1,2- elimination in addition to the intermediate formation of ion-neutral complexes. Loss of ϩ propene with one deuterium atom is the only reaction of the [M ϩ D] ions of the isopropoxypyridines labeled at the ␣-position of the isopropyl group. The results for the isopropoxypyridines labeled with three deuterium atoms at the ␤-position are consistent with: (1) The loss of propene by ion-neutral complex formation and the occurrence of a substantial isotope effect in the subsequent proton/deuteron transfer within the complex, and/or (2) the loss of propene by a 1,2-elimination type reaction. (J Am Soc Mass Spectrom 2003, 14, 1166–1176) © 2003 American Society for Mass Spectrometry

ite-specific proton affinities (PA) and the occur- initial step in protonation of an organic compound is rence of proton transfer reactions in the absence of related directly to the dissociation reactions of the [M ϩ ϩ Ssolvent molecules are of fundamental importance H] ions. Furthermore, polyfunctional organic species in mass spectrometry [1–6]. can show a complex behavior as protonation can occur The site of protonation depends not only on the at distinct sites and nonetheless lead to dissociation by ϩ proton affinity of the distinct sites in a molecule, but a single process. For example, the metastable [M ϩ H] also on the existence of possible energy barriers for the ions of phenyl n-propyl ether are known to dissociate proton transfer reaction [7–10]. In particular, proton exclusively by propene loss irrespective of the fact that transfer to the aromatic ring can be hindered by a protonation can occur at the phenyl ring as well as at kinetic barrier even though this entity of a substituted the oxygen atom of the substituent [16, 17, 19–23]. As benzene is often associated with a higher proton affinity emphasized in several CI studies of aryl n-propyl ethers than a substituent such as an OH or OR group [11–18]. with deuterium labeled reagents, the metastable [M ϩ Insight into the molecular properties that determine ϩ D] ions expel propene molecules that contain the the regioselectivity of proton transfer reactions is also of deuteron transferred from the conjugate acid of the CI importance for studies concerned with structure eluci- dation with the use of Chemical Ionization [1]. This is reagent to the ether in the ion source [16, 17, 19–22]. In particularly pertinent as it is often observed that the previous reports, the incorporation of the deuterium atom from the CI reagent was suggested to involve

Published online August 11, 2003 initial deuteron transfer to the oxygen atom of phenyl Address reprint requests to Dr. S. Ingemann, Faculty of Science, Swammer- n-propyl ether and fluorine or methyl substituted ana- dam Institute for Life Sciences, University of Amsterdam, Nieuwe Achter- logues [16, 17]. By contrast, deuteron transfer to the gracht 166, Amsterdam 1018 WV, The Netherlands. E-mail: [email protected] aromatic ring was proposed to result in the loss of a

© 2003 American Society for Mass Spectrometry. Published by Elsevier Inc. Received January 16, 2003 1044-0305/03/$30.00 Revised May 30, 2003 doi:10.1016/S1044-0305(03)00449-5 Accepted May 30, 2003 J Am Soc Mass Spectrom 2003, 14, 1166–1176 PROPENE LOSS FROM PROPOXYPYRIDINES 1167

Ϫ propene molecule that contained only the hydrogen performed at a different total pressure (between 10 6 Ϫ atoms of the original propyl group. mbar and 10 4 mbar) of the CI reagent and the In order to obtain more insight into the influence of propoxypyridine in the combined EI/CI source. The ion the initial protonation site on the mechanism of alkene source parameters were: Electron energy 70 eV, temper- elimination from protonated aromatic ethers, we de- ature 175–200 °C, ion repeller potential 0–2 V, and cided to examine propene loss from a series of isomeric acceleration voltage 8 kV. Collision-induced Dissocia- propoxypyridines. The propoxypyridines were chosen tion (CID) experiments were performed with helium as as model compounds because it can be anticipated that the collision gas and with the reduction of the main protonation at the nitrogen atom of the ring is preferred beam intensity to 50%. considerably over protonation at the oxygen atom of the substituent. This expectation is corroborated by the Materials and Synthesis calculated proton affinity of the nitrogen atom in 2-hy- Ϫ droxypyridine (PA ϭ 931 kJ mol 1), which is 183 kJ The unlabeled 2-, 3-, and 4-hydroxypyridines, Ϫ1 mol higher than the calculated value of the oxygen CH3CH2CD2OH, CD3CD2CD2OD, CH3CD(OH)CH3 Ϫ1 atom (748 kJ mol ) [24]. In other words, the propoxy- and CD3CD(OD)CD3 were commercially available and pyridines offer the possibility to study the loss of used without further purification. The labeled pro- propene from aromatic ethers that may be protonated panols were reacted with 48% HBr in water in order to only at the heteroatom of the ring. In addition, the obtain the related bromopropanes. The unlabeled 2- 3-, selection of 2-, 3- and 4-propoxypyridines allows an and 4-propoxypyridines and their deuterated ana- examination of influence of the distance between the logues were prepared by reacting the 2-, 3-, and 4-hy- protonation site and the substituent on the mechanism droxypyridines with sodium ethanolate followed by of propene loss. reaction with an appropriately labeled 1- or 2-bro- In the studies concerned with propene loss from [M mopropane [30, 31]. ϩ ϩ D] ions of phenyl n-propyl ethers and their deriva- tives, a number of CI reagent gasses were used in order CH CD CH OH to generate the ionic species [16, 17]. In these studies it 3 2 2 was shown that the incorporation of the deuterium 1-propanol labeled at the 2-position was prepared by atom from the CI reagent in the propene molecule is repeated hydrogen-deuterium exchange of methyl ma- enhanced if the CI reagent gas has a relatively high lonic acid with D2O to afford DOOCCD(CH3)COOD. ϩ proton affinity. For example, the metastable [M ϩ D] Decarboxylation of one of the carboxylic groups leading to ions of phenyl n-propyl ether expel C3H5D and C3H6 in CH3CD2COOH was followed by reduction of the other ϭ Ϫ1 ratio of 18:82 if CD3OD (PA 754 kJ mol ) [25] is the carboxylic group by LiAlH4 to give CH3CD2CH2OH [32]. CI reagent, whereas the ratio between C3H5D and C3H6 ϭ Ϫ1 loss is 27:73 with CD3CN (PA 779 kJ mol ) [25] as CD CH CH OH the CI gas [16]. With the purpose of examining the 3 2 2 possible influence of the dynamics of the initial deu- 1-propanol labeled at the 3-position was prepared by teron transfer to the propoxypyridines on the ensuing treating HOOCCH2COOH with NaH followed by reac- loss of propene, we decided to form the metastable [M tion with CD3I. Decarboxylation and reduction as de- ϩ ϩ D] ions of the propoxypyridines with CD3OD, scribed above gave CD3CH2CH2OH. CD3CN, (CD3)2CO or pyrrole-D5 (listed in order of increasing proton affinity) as the reagent gas. CD3-CH(OH)-CH3

Experimental Grignard reaction of CD3MgI with freshly distilled acetaldehyde gave the appropriately labeled 2-propa- The Chemical Ionization (CI) spectra and the mass- nol. analyzed ion kinetic energy (MIKE) [26, 27] spectra of All ethers were purified by preparative gas chroma- the (un)labeled propoxypyridines were recorded with tography (column: Reoplex 400, temperature 125 °C). the use of a Micromass (Manchester, UK) VG ZAB- The identity of the ethers as well as the labeling content HFqQ reverse geometry double focusing hybrid mass (Ͼ99%) was determined by 1H NMR and EI mass spectrometer [28, 29]. The CI reagent (CD3OD, CD3CN, spectrometry. (CD3)2CO, or pyrrole-D5) were mixed with a propoxy- pyridine in a volume ratio of 9:1. The binary chemical Results sample was introduced into a combined electron ion- ization/chemical ionization (EI/CI) source through a Chemical Ionization of the propoxypyridines with one ϳ heated septum inlet system (temperature 175 °C) until of the selected reagents (CD3OD, CD3CN, (CD3)2CO Ϫ5 Ϫ4 the pressure was in the range of 10 –10 mbar as and Pyrrole-D5) leads in the ion source to relatively ϩ ϩ measured by an ionization gauge placed in a side arm abundant [M ϩ D] ions. The [M ϩ D] ions of the to the entrance of the diffusion pump situated beneath unlabeled propoxypyridines react on the ␮s time-scale ϩ the ion source housing. A few experiments were also only by the loss of C3H6 with the formation of C5H5DNO 1168 VAN BEELEN ET AL. J Am Soc Mass Spectrom 2003, 14, 1166–1176

The same ratio between the losses of C3H5D and ϩ ϩ C3H4D2 is observed for the [M D] ions of the ␤ ␤ ␣ ␣ [ , -D2]-2-n-propoxypyridines as for the [ , -D2]-la- ␥ ␥ ␥ beled species (see Table 1). For the [ , , -D3]-labeled species, the loss of a propene molecule with one D atom less than in the propyl group in the parent species is

relatively pronounced; that is, C3H4D2 and C3H3D3 are expelled in a ratio of 33:67 from the metastable [M ϩ ϩ D] ions. The introduction of two deuterium atoms at the ␣-position of the 3-n-propoxypyridines results in the

losses of C3H5D and C3H4D2 in an average ratio of 21:79 ␤ ␤ (Table 2). For the related [ , -D2]-labeled ions (eq 3), loss of C3H5D is more pronounced than observed for ␣ ␣ the [ , -D2]-labeled species. ϩ Figure 1. Reactions of the metastable [M ϩ D] ions of 2-n- ϩ propoxypyridine labeled with two deuterium atoms at the ␤-po- [D ] sition of the propyl group. O¡ 3-(C5H4N)O(CH2CD2CH3) (3) ions (eq 1) irrespective of the CI gas. The exclusive loss of 46% ϩ ϩ O¡ ϩ ϩ C3H6 from the metastable [M D] ions of the unlabeled C5H4D2NO C3H5D (3a) ethers reveals that the deuterium atom from the reagent is ϩ [MϩD] —— not involved directly in the dissociation reaction. This is 54% ϩ further corroborated by the sole occurrence of the loss of O¡ C H DNO ϩ C H D (3b) ϩ ϩ 5 5 3 4 2 C3D6 from the metastable [M D] ions of propoxypyri- dines with a perdeuterated propyl group (vide infra). The results for the loss of propene from the metastable ϩ [M ϩ D] ions of 4-n-propoxypyridine are dependent ϩ ͓D ] on the position of the labeling (Table 3). For example, O¡ ϩ ϩ (C5H4N)OCH2CH2CH3 [M D] deuterium incorporation at the ␣Ϫposition results in a

ratio of 22:78 between the losses of C3H3D and C3H4D2 O¡ ϩ ϩ from the metastable ions, whereas the ratio between C5H5DNO C3H6 (1) these losses is 38:62 if two D atoms are present at the ␤-position (eq 4).

ϩ n-Propoxypyridines [D ] O¡ Site-specific deuterium labeled n-propoxypyridines 4-(C5H4N)O(CH2CD2CH3) (4) were examined subsequently in order to obtain more insight into the origin of the H atom transferred from 38% O¡ ϩ ϩ the propyl group to the remaining part of the ionized C5H4D2NO C3H5D (4a) species prior to the expulsion of propene. The presence ϩ ϩ of two D atoms at the ␣-position of the 2-n-propoxy- [M D] —— 62% ϩ pyridines is observed to lead to the losses of C3H5D and O¡ ϩ ϩ ϩ C5H5DNO C3H4D2 (4b) C3H4D2 from the metastable [M D] ions (eq 2). The average ratio between the losses of C3H5D and C3H4D2 is determined to be 24:76 by measuring the area of the Gaussian shaped metastable peaks (see Figure 1). Isopropoxypyridines ϩ [D ] O¡ In order to investigate the influence of the structure of 2-(C5H4N)O(CD2CH2CH3) (2) the propyl group on the process of propene loss, a ␤ ␤ ␤ series of [ , , -D3]-labeled isopropoxypyridines 24% were studied. In contrast to the results for the n- O¡ ϩ ϩ C5H4D2NO C3H5D (2a) propoxypyridines, the ratio between the losses of ϩ ϩ ϩ [MϩD] —— C3H4D2 and C3H3D3 from the metastable [M D] 76% ions of the isopropoxypyridines appeared to be inde- O¡ ϩ ϩ C5H5DNO C3H4D2 (2b) pendent of the position of the substituent with re- J Am Soc Mass Spectrom 2003, 14, 1166–1176 PROPENE LOSS FROM PROPOXYPYRIDINES 1169

ϩ ϩ Table 1. Relative extent (in %) of the losses of C3H6,C3H5D, C3H4D2,C3H3D3 and C3D6 from the metastable [M D] ions of 2-n-propoxypyridine and deuterium labeled analogues Relative extent of the loss ofa

Compound M Reactant ion CI reagent C3H6 C3H5D C3H4D2 C3H3D3 C3D6 b ϩ ϩ 2-(C5H4N)-OCH2CH2CH3 [M D] CD3OD 100

CD3CN 100 ¢ (CD3)2C O 100 Pyrrole-D5 100 c ϩ ϩ 2-(C5H4N)-OCD2CH2CH3 [M D] CD3OD 24 76 CD3CN 23 77 ¢ (CD3)2C O 25 75 Pyrrole-D5 26 74 c ϩ ϩ 2-(C5H4N)-OCH2CD2CH3 [M D] CD3OD 24 76 CD3CN 25 75 ¢ (CD3)2C O 24 76 Pyrrole-D5 23 77 c ϩ ϩ 2-(C5H4N)-OCH2CH2CD3 [M D] CD3OD 32 68

CD3CN 33 67 ¢ (CD3)2C O 33 67 Pyrrole-D5 33 67 d ϩ ϩ 2-(C5H4N)-OCD2CD2CD3 [M D] CD3OD 100

CD3CN 100 ¢ (CD3)2C O 100 Pyrrole-D5 100 aThe ratios are considered to be accurate to within a few percent. b ϩ ϩ ϩ Propene loss from the [M D] ions yields only C5H5DNO (m/z 97) ions. c ϩ ϩ ϩ ϩ Propene loss from the [M D] ions yields C5H5DNO (m/z 97) and C5H5D2NO (m/z 98) ions. d ϩ ϩ ϩ Propene loss from the [M D] ions yields only C5H4D2NO (m/z 98) ions.

ϩ spect to the nitrogen atom (see Table 4 and eq 5). In [D ] ␣ O¡ addition, deuterium incorporation at the -position 4-(C5H4N)OCH(CH3)CD3 (5) of the isopropoxy group revealed that the ␣-hydro- gen atom is not involved in the loss of propene.

ϩ ϩ Table 2. Relative extent (in %) of the losses of C3H6,C3H5D, C3H4D2,C3H3D3 and C3D6 from the metastable [M D] ions of 3-n-propoxypyridine and deuterium labeled analogues Relative extent of the loss ofa

Compound M Reactant ion CI reagent C3H6 C3H5D C3H4D2 C3H3D3 C3D6 b ϩ ϩ 3-(C5H4N)-OCH2CH2CH3 [M D] CD3OD 100 0 CD3CN 100 0 ¢ (CD3)2C O 100 0

Pyrrole-D5 100 0 c ϩ ϩ 3-(C5H4N)-OCD2CH2CH3 [M D] CD3OD 21 79 CD3CN 20 80 ¢ (CD3)2C O 21 79 Pyrrole-D5 21 79 c ϩ ϩ 3-(C5H4N)-OCH2CD2CH3 [M D] CD3OD 46 54 CD3CN 46 54 ¢ (CD3)2C O 48 52 Pyrrole-D5 46 54 c,d ϩ ϩ 3-(C5H4N)-OCH2CH2CD3 [M D] CD3OD 22 78 CD3CN 18 82 ¢ (CD3)2C O 14 86 Pyrrole-D5 22 78 e ϩ ϩ 3-(C5H4N)-OCD2CD2CD3 [M D] CD3OD 100 ¢ (CD3)2C O 100

Pyrrole-D5 100 aThe ratios are considered to be accurate to within a few percent. b ϩ ϩ ϩ Propene loss from the [M D] ions yields only C5H5DNO (m/z 97) ions. c ϩ ϩ ϩ ϩ Propene loss from the [M D] ions yields C5H5DNO (m/z 97) and C5H4D2NO (m/z 98) ions. d ␥ ␥ ␥ The results for the [ , , -D3] labeled ions as based upon peak areas are considered to be less accurate than the other values in the table due to enhanced overlap of the metastable peaks. e ϩ ϩ ϩ Propene loss from the [M D] ions yields only C5H4D2NO (m/z 98) ions. 1170 VAN BEELEN ET AL. J Am Soc Mass Spectrom 2003, 14, 1166–1176

ϩ ϩ Table 3. Relative extent (in %) of the losses of C3H6,C3H5D, C3H4D2,C3H3D3 and C3D6 from the metastable [M D] ions of 4-n-propoxypyridine and deuterium labeled analogues Relative extent of the loss ofa

Compound M Reactant ion CI reagent C3H6 C3H5D C3H4D2 C3H3D3 C3D6 b ϩ ϩ 4-(C5H4N)-OCH2CH2CH3 [M D] CD3OD 100 0

CD3CN 100 0 ¢ (CD3)2C O 100 0 Pyrrole-D5 100 0 c ϩ ϩ 4-(C5H4N)-OCD2CH2CH3 [M D] CD3OD 21 79 CD3CN 21 79 ¢ (CD3)2C O 23 77 Pyrrole-D5 22 78 c ϩ ϩ 4-(C5H4N)-OCH2CD2CH3 [M D] CD3OD 38 62 CD3CN 39 61 ¢ (CD3)2C O 37 63 Pyrrole-D5 34 66 c ϩ ϩ 4-(C5H4N)-OCH2CH2CD3 [M D] CD3OD 26 74

CD3CN 27 73 ¢ (CD3)2C O 29 71 Pyrrole-D5 28 72 d ϩ ϩ 4-(C5H4N)-OCD2CD2CD3 [M D] CD3OD 100

CD3CN 100 ¢ (CD3)2C O 100 Pyrrole-D5 100 aThe ratios are considered accurate to within a few percent. b ϩ ϩ ϩ Propene loss from the [M D] ions yields only C5H5DNO (m/z 97) ions. c ϩ ϩ ϩ ϩ Propene loss from the [M D] ions yields C5H5DNO (m/z 97) and C5H4D2NO (m/z 98) ions. d ϩ ϩ ϩ Propene loss from the [M D] ions yields only C5H4D2NO (m/z 98) ions.

34% of a deuteron from the Brønsted acid of the CI gas has O¡ ϩ ϩ C5H4D2NO C3H4D2 (5a) no influence on the origin of the H or D atoms incor- ϩ porated in the ionic product of propene loss from the [MϩD] —— ϩ 66% [M ϩ D] ions. Similar results were obtained for the O¡ ϩ ϩ C5H5DNO C3H3D3 (5b) n-propoxypyridines (see Tables 1–3). In addition, the

same ratio between the losses of C3H5D and C3H4D2 ϩ ϩ ␤ ␤ from the metastable [M D] ions of [ , -D2]-3-n- For the isopropoxypyridines, the results for propene propoxypyridines is obtained for a total pressure of 5 ϫ Ϫ Ϫ loss from the metastable ions are independent of the 10 6 mbar and at a pressure of 1 ϫ 10 4 mbar in the ion nature of the CI gas. In other words the initial transfer source (see also Experimental).

ϩ ϩ Table 4. Relative extent (in %) of the losses of C3H6,C3H5D, C3H4D2,C3H3D3 and C3D6 from the metastable [M D] ions of isopropoxypyridine and deuterium labeled analogues Relative extent of the loss ofa Reactant

Compound M ion C3H6 C3H5D C3H4D2 C3H3D3 C3D6 b ϩ ϩ 2-(C5H4N)-OCH(CH3)2 [M D] 100 c ϩ ϩ 2-(C5H4N)-OCD(CD3)2 [M D] 100 b ϩ ϩ 2-(C5H4N)-OCD(CH3)2 [M D] 100 d ϩ ϩ 2-(C5H4N)-OCH(CD3)(CH3) [M D] 31 69 b ϩ ϩ 3-(C5H4N)-OCH(CH3)2 [M D] 100 b ϩ ϩ 3-(C5H4N)-OCD(CD3)2 [M D] 100 b ϩ ϩ 3-(C5H4N)-OCD(CH3)2 [M D] 100 d ϩ ϩ 3-(C5H4N)-OCH(CD3)(CH3) [M D] 34 66 b ϩ ϩ 4-(C5H4N)-OCH(CH3)2 [M D] 100 b ϩ ϩ 4-(C5H4N)-OCD(CD3)2 [M D] 100 b ϩ ϩ 4-(C5H4N)-OCD(CH3)2 [M D] 100 d ϩ ϩ 4-(C5H4N)-OCH(CD3)(CH3) [M D] 34 66 aThe relative abundances are independent of the CI gas used (see Results section) and accurate to within a few percent. b ϩ ϩ ϩ Propene loss from the [M D] ions yields only C5H5DNO (m/z 97) ions. c ϩ ϩ ϩ Propene loss from the [M D] ions yields only C5H4D2NO (m/z 98) ions. d ϩ ϩ ϩ ϩ Propene loss from the [M D] ions yields C5H5DNO (m/z 97) and C5H4D2NO (m/z 98) ions. J Am Soc Mass Spectrom 2003, 14, 1166–1176 PROPENE LOSS FROM PROPOXYPYRIDINES 1171

Collision-Induced Dissociation A series of CID experiments [33] were performed with ϩ the [M ϩ D] ions of the propoxypyridines (see Exper- imental). The collisionally induced loss of propene from ϩ the [M ϩ D] ions of the unlabeled 2-, 3-, and 4-n- propoxypyridines involves only the expulsion of C3H6. ϩ ϩ ␣ ␣ ␤ ␤ For the [M D] ions of the [ , -D2]- or [ , -D2]- labeled 2-, 3-, and 4-n-propoxypyridines, the ratio be- tween the losses of C3H5D and C3H4D2 is essentially the same in the CID experiments as observed for the metastable ions. Notably, the ratio between the losses of

C3H5D and C3H4D2 in the CID experiments is 75:25 for ϩ ϩ ␤ ␤ the [M D] ions of the [ , -D2]-2-n-propoxypyridine ␤ ␤ and about 40:60 for the [ , -D2]-3-n-propoxypyridine (see also Tables 1 and 2). Similar results are obtained for the competing losses of C3H4D2 and C3H3D3 from the ϩ ϩ ␥ ␥ ␥ [M D] ions of the [ , , -D3]-labeled n-propoxypyri- dines. It should be mentioned, however, that propene ϩ loss from the metastable [M ϩ D] ions contribute to the intensities of the peaks in the CID spectra and—a priori—it is not possible to separate the collisionally induced processes from the spontaneous reactions of the ions. The relative peak intensities in the CID spectra, therefore, may not necessarily provide a unambiguous measure of the relative extent of the collisionally in- ϩ ϩ duced losses of C3H5D and C3H4D2 from the [M D] ␤ ␤ ions of, for example, the [ , -D2]-3-n-propoxypyridine. The structures of the product ions of propene loss were also examined by high kinetic energy CID exper- iments. These experiments were performed with the product ions of propene loss as formed to a minor ϩ extent in the ion-source reactions of the [M ϩ D] ions of the unlabeled propoxypyridines. The spectrum ob- ϩ tained for the C5H5DNO ions generated by C3H6 loss ϩ ϩ Figure 2.(a) The Collision-induced Dissociation mass spectrum from the [M D] ion of 3-n-propoxypyridine is shown ϩ of the C5H5DNO ion formed by C3H6 loss from the metastable in Figure 2a and appears to very similar to the CID ϩ ϩ ϩ [M D] ions of 3-n-propoxypyridine. (b) The CID spectrum of ϩ ϩ spectrum of the [M D] ion of 3-hydroxypyridine the [M ϩ D] ion of 3-hydroxypyridine as generated with

(see Figure 2b). Comparable results were obtained for CD3COCD3 as the CI reagent gas. the other product ions of propene loss from the ionized propoxypyridines and the related protonated hydroxy- complex of a benzene molecule and a secondary propyl pyridines. carbenium ion reacts reversibly by proton transfer thus leading to partial incorporation of the hydrogen atom Discussion from the CI reagent into the propene molecule expelled from the metastable ions. Comparable studies have The dissociation reactions of ions in the gas phase often been reported for the loss of propene from the metasta- involve the intermediate formation of ion-neutral com- ble protonated aryl n-propyl ethers [16, 17, 20]. For plexes held together by electrostatic interactions and/or these compounds, protonation under CI conditions may hydrogen bonds [21, 34–40]. The involvement of ion- occur either on the aromatic ring or on the oxygen atom neutral complexes is generally manifested in the ener- of the ether function, thus leading to isomeric ions that getics of the processes and the loss of the positional can expel propene by different pathways. In previous identity of, for example, hydrogen atoms prior to dis- studies it was concluded that only the transfer of a sociation. For example, the metastable ions formed by deuteron to the oxygen atom results in interchange proton transfer to n-propyl benzene under CI condi- between the propyl hydrogen atoms and the deuterium tions are reported to isomerize irreversibly to proton- atom of the labeled CI reagent [16, 17]. The extent of ated isopropylbenzene prior to propene loss [36, 41, 42]. incorporation of the deuterium atom from the CI re- The suggested pathway involves cleavage of the bond agent into the propene molecule was observed to de- to the n-propyl group concomitant with a 1,2-hydride pend on the presence and position of a methyl group or shift in the incipient carbenium ion. The ion-neutral a fluorine atom on the ring. In particular, the ratio 1172 VAN BEELEN ET AL. J Am Soc Mass Spectrom 2003, 14, 1166–1176

ϩ Scheme 1. Proposed mechanism of propene loss from the metastable [M ϩ D] ions of 2-n- propoxypyridine with intermediate formation of ion-neutral complexes and complete loss of the positional identity of the hydrogen/deuterium atoms of the propyl carbenium ion.

between the losses of C3H5D and C3H6 from the meta- the combined results indicate that loss of propene ϩ ϩ stable [M ϩ D] ions of n-propyl-3-methylphenyl ether involves predominantly [M ϩ D] ions formed by was reported to be 13:87, whereas this ratio becomes deuteronation at the nitrogen atom. 27:73 if the methyl group is situated at the 4-position of In spite of the conclusion that the results are in line the ring [16]. In terms of the initial protonation site, the with formation of nitrogen deuteronated species, the presence of a methyl at the 4-position may disfavor results suggest the occurrence of propene loss by a proton transfer to the ring [43] and—as a result— number of pathways; that is, propene loss from the ϩ protonation at the oxygen atom becomes relatively metastable [M ϩ D] ions of the propoxypyridines can important under CI conditions. involve: (1) Ion-neutral complex formation and loss of For the present series of aromatic ethers, the results the positional identity of all hydrogen atoms of the ϩ reveal that the loss of propene from [M ϩ D] ions propyl carbenium ion part of the complex, (2) ion- occurs without interchange between the deuterium neutral complex formation by cleavage of the ether atom from the CI reagents and the hydrogen atoms of bond associated with an irreversible 1,2-hydride shift in the propyl group. Even though the site-specific proton the carbenium ion if a n-propyl group is present in the affinities of the pyridine ring of the ethers are unknown, parent compound or with no loss of positional identity deuteron transfer to the nitrogen atom is expected to be of the hydrogen atoms of the carbenium ion if the ether associated with strong thermodynamic driving force. contains an isopropyl group, (3) a 1,5-hydride shift from The existence of a strong thermodynamic preference for the ␤-position of the propyl group to the pyridine ring transfer to the nitrogen atom is substantiated by the concomitant with dissociation, and (4) a 1,2-elimination Ϫ calculated proton affinity of 946 kJ mol 1 for this site in type process. 3-hydroxypyridine, whereas the value for the oxygen The formation of ion-neutral complexes is suggested Ϫ atom is suggested to be much lower (726 kJ mol 1) [44, to be the predominant or even the exclusive pathway ϩ 45]. For the propoxypyridines, it may be anticipated involved in the loss of propene from the [M ϩ D] ions that the proton affinity of the oxygen atom may be of the 2-n-propoxypyridine. For this particular species, somewhat higher as compared to the same position in the experimental ratio between the losses of C3H5D and the hydroxypyridines due to the stabilization of the C3H4D2 (24:76) from the [D2]-labeled propoxypyridines positive charge by the alkyl group in the oxygen pro- is slightly different from the ratio (29:71) calculated on tonated species. This could imply that that some endo- the basis of formation of an ion-neutral complex with a thermic deuteron transfer to the oxygen atom of the propyl carbenium that may react by reversible 1,2- propoxypyridines may occur in the experiments with hydride and deuteride shifts prior to proton or deu- ϭ Ϫ1 ϭ CD3OD (PA 754 kJ mol ) and CD3CN (PA 779 kJ teron transfer (Scheme 1). This is further confirmed by Ϫ1 ␥ ␥ ␥ mol ), whereas the reagents, (CD3)2CO and pyrrole- the ratios of the loss of propene from the [ , , -D3]-2- ϭ D5, may be too strong bases (PA 812 and 875 kJ n-propoxypyridines, which expel C3H4D2 and C3H3D3 Ϫ mol 1, respectively) [25] to allow the occurrence of in a ratio (33:67) that is also different from the statistical deuteron transfer to this site in the ethers under the value (43:57). This statistical analysis is based, however, present CI conditions. Notwithstanding that it cannot upon a neglect of isotope effects on the ensuing acid- be excluded that some deuteron transfer occurs to other base reaction between the partners of the complex. sites than the nitrogen atom in the present experiments, Possibly, the initial cleavage of the bond between the J Am Soc Mass Spectrom 2003, 14, 1166–1176 PROPENE LOSS FROM PROPOXYPYRIDINES 1173

ϩ Scheme 2. Proposed mechanisms of propene loss from the metastable [M ϩ D] ions of 3-n- propoxypyridine. The first pathway (I) involves intermediate formation of ion-neutral complexes, the second pathway (II) is a 1,2-elimination type process and the third reaction (III) involves a 1,5-H shift. oxygen atom and the ␣-carbon atom of the propyl less pronounced than expected for the ion-neutral com- group is followed by a proton/deuteron transfer step plex pathway shown in Scheme 1, for the 2-isomer (on with a small but discernible isotope effect (vide infra). average 54% instead of the predicted 71%). Evidently,

Even though the precise structure of the C5H4NDO part of the observed 46% C3H5D loss (Table 2) arises by molecule in the complexes shown in Scheme 1 is a pathway that involves the specific transfer of a uncertain, it may be anticipated that cleavage of the deuterium atom from the ␤-position of the propyl ether bond leads to 2-pyridone. Upon the assumption group. A possible reaction would be a 1,5-hydride shift that 2-pyridone is generated, proton transfer from the to the 2-position of the ring concomitant with propene propyl carbenium ion to the oxygen atom is estimated loss and formation of the keto-species shown in Scheme Ϫ to be exothermic with ϳ180 kJ mol 1 as based on the 2. It should be emphasized, that the CID spectrum of experimental proton affinity of propene (PA ϭ 751 kJ the product ions of propene loss is similar to the Ϫ mol 1) [25] and the calculated value of the oxygen atom spectrum obtained of the deuteronated 3-hydroxypyri- Ϫ in 2-pyridone (933 kJ mol 1) [24]. A large difference in dine (see also Results and Figure 2). A competing proton affinity between propene and the 2-pyridone reaction such as the 1,2-elimination with direct forma- molecule within the ion-neutral complex shown in tion of the 3-hydroxypyridine (deuteronated at the Scheme 1 will cause proton transfer to be essentially nitrogen atom), therefore, cannot be excluded. irreversible in line with the absence of incorporation of The occurrence of propene loss by another pathway the deuterium atom from the CI reagent into the pro- than ion-neutral complex formation can reflect that the pene molecules. initial cleavage of the ether bond will lead to the ϩ The loss of propene from the metastable [M ϩ D] zwitterion form of 3-hydroxypyridine (see Scheme 2). ions of the 3-n-propoxypyridine is likely to involve one The relative stability of this form of 3-hydroxypyridine of the other pathways in addition to the formation of is uncertain but it is expected to be significantly less ion-neutral complexes as indicated by the different stable than the hydroxy form [46, 47]. As a result, the experimental ratios between the losses of C3H5D and pathway involving ion-neutral complexes may be asso- ␣ ␣ ␤ ␤ C3H4D2 from the [ , -D2]- and the [ , -D2]-labeled ciated with a relatively high critical energy and allow ␣ ␣ species (Table 2). For the [ , -D2]-labeled ions, the other processes to be able to compete with this reaction average ratio of 21:79 suggests that transfer of a deute- pathway. Estimation of the relative extent of ion-neutral rium atom from this position is less important than complex formation and, for example, the 1,5-hydride predicted for formation of an ion-neutral complex and shift initiated propene loss is hampered, however, by complete loss of the positional identity of the hydrogen the likely occurrence of kinetic isotope effects. For and deuterium atoms of the propyl group (29% C3H5D example, a statistical analysis (see Appendix) of pro- ϩ ϩ loss and 71% C3H4D2 loss). In addition, the loss of pene loss from the metastable [M D] ions of the ␤ ␤ ␤ ␤ C3H4D2 from the [ , -D2]-labeled ions is significantly [ , -D2]-labeled 3-n-propoxypyridine suggest that 1174 VAN BEELEN ET AL. J Am Soc Mass Spectrom 2003, 14, 1166–1176

ϩ Scheme 3. Proposed mechanism of propene loss from the metastable [M ϩ D] ions of the 2-, 3-, and 4-n-isopropoxypyridines with intermediate formation of ion-neutral complexes and no loss of the positional identity of the hydrogen/deuterium atoms of the isopropyl carbenium ion. about 24% of the ions dissociate by the pathway involv- Even though the precise nature of the competing pro- ing a 1,5-hydride shift (see also reference [48] for a cess is unknown, it is clear that it should involve a review on composite atom interchange in gaseous ions). specific transfer of a hydrogen or deuterium atom from ␣ ␣ A similar analysis for the [ , -D2]-labeled ions, indi- the ␤-position prior to propene loss. cates that slightly more ions (about 30%) dissociate by For the isopropoxypyridines, the absence of the loss ϩ ϩ such a mechanism, whereas a significantly larger part of of C3H5D from the [M D] ions of 2-, 3- and the [␥ ␥ ␥ , , -D3]-labeled ions (45–50%) appears to react by 4-(C5H4N)-OCD(CH3)2 indicates that the positional the 1,5-hydride initiated propene loss as based upon the identity of the hydrogen atom at the ␣-position of the ␣ ␣ simplified statistical analysis. For the [ , -D2]- and isopropyl group is retained during propene loss ␤ ␤ [ , -D2]-labeled ions, the occurrence of an isotope effect (Scheme 3). In the context of ion-neutral complex for- in the 1,5-hydride shift could be held responsible for the mation this observation suggests that the initial cleav- suggestion that a lower fraction of the ions reacts by this age of the bond to the isopropyl group leads to an ␤ pathway if the label is at the -position. On the other isopropyl carbenium ion with insufficient internal en- hand, the apparent pronounced loss of propene by the ␥ ␥ ␥ ergy to undergo reversible 1,2-hydride shifts (see also 1,5-hydride shift from the [ , , -D3]-labeled species reference [49]). would tend to suggest the occurrence of a significant ϩ For the metastable [M ϩ D] ions of the [␤,␤,␤-D ]- isotope effect in the ion-neutral complex pathway thus 3 isopropoxypyridines the competing losses of C H D favouring the other reaction channel(s). Despite the 3 4 2 and C H D should occur to an equal extent in the limitations of the statistical analysis (as based on the 3 3 3 absence of an isotope effect. By contrast, the observed absence of isotope effects), these considerations lead to average ratio is 33:67 from all the isomeric ions (Table the conclusion that more than one pathway is involved 4). The experimental results indicate clearly the occur- in propene loss from the 3-n-propoxypyridine. ϩ ϳ The results for the metastable [M ϩ D] ions of the rence of a significant kinetic isotope effect of 2in 4-n-propoxypyridine appear to some extent to be inter- propene loss from the ionized and labeled isopropoxy- mediate to the findings for the 2-n- and 3-n-propoxy- pyridines. A similar kinetic isotope effect has been pyridine isomers. In mechanistic terms, the results reported for the loss of propene from the metastable [M ϩ ϩ reveal a slight preference for the involvement of the H] ions of C6H5CH(CH3)CD3 and ascribed to the ␤ existence of a significant energy barrier between the -position of the propyl group as exemplified by the ϩ ϩ observation that the average ratio between the losses of [C6H6 iso-C3H7 ] and [C6H7 C3H6] complexes involved in the process [42]. For the present systems, it should be C3H5D and C3H4D2 (38:72) differs from the ratio (29:71) predicted for the sole occurrence of ion-neutral complex mentioned that the results can be interpreted also in formation and randomization of the hydrogen and terms of the occurrence of propene loss by a 1,2- ϩ deuterium atoms within the propyl carbenium ion. For elimination as shown in Scheme 2 for the [M ϩ D] ions the 4-isomer, it is proposed that the competing process of 3-n-propoxypyridine. Such a process may well be may be a 1,2-elimination in line with the expectation associated with a significant isotope effect. In other ϩ that the charge distribution within the [M ϩ D] ions words, a distinction between the different possible ϩ will disfavour a 1,5-hydride shift to the aromatic ring. pathways in propene loss from the [M ϩ D] ions of the J Am Soc Mass Spectrom 2003, 14, 1166–1176 PROPENE LOSS FROM PROPOXYPYRIDINES 1175

isopropoxypyridines cannot be reached on the basis of in the form of C3H5D is by this pathway. The remaining the present results. 24% of the total loss of propene (as C3H5D) originates from a specific transfer of a D from the ␤-position. ϩ ϩ Similarly, the loss of C3H4D2 from the [M D] ions of Conclusions ␥ ␥ ␥ the [ , , -D3]-n-propoxypyridens is assumed to origi- Chemical Ionization of isomeric propoxypyridines with nate only from ion-neutral complexes mediated pro- deuterium labeled reagents (CD3OD, CD3CN, cesses as based on the experimental ratio 22:78 between ϩ ϩ (CD3)2CO and pyrrole-D5) yields abundant [M D] the losses of C3H4D2 and C3H3D3. As a result, it is ions that expel only propene on the ␮s time-scale. The estimated that 49% of the total propene loss (in the form main mechanism of propene loss is proposed to be the of C3H3D3) is expelled by the pathway involving a formation of ion-neutral complexes composed of a specific H-transfer from the ␤-position. propyl carbenium ion and a hydroxypyridine in the keto form if the propoxy group is situated at the 2- or 4-position, whereas a zwitterion is formed if the References propoxy group is at the 3-position in the parent com- 1. Harrison, A. G. Chemical Ionization Mass Spectrometry, 2nd ed.; pound. The subsequent proton/deuteron transfer is CRC Press: Boca Raton, FL, 1992, pp 1–208. associated with an isotope effect that is particularly ϩ 2. Kebarle, P. Gas-phase Ion Thermochemistry Based on Ion- pronounced for the loss of propene from the [M ϩ D] equilibria from the Ionosphere to the Reactive Centers of of the isopropoxypyridines. In addition to the pathway Enzymes. Int. J. 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