Research Article

Received: 14 July 2010 Revised: 19 October 2010 Accepted: 20 October 2010 Published online in Wiley Online Library: 2011

Rapid Commun. Mass Spectrom. 2011, 25, 395409 (wileyonlinelibrary.com) DOI: 10.1002/rcm.4839

Electron ionization mass spectral studies of bridgeheadsubstituted norbornan-2-ones: camphor derivativesy

a Fraile1, Santiago de la Moya Cerero2**, Enrique Teso Vilar1*, Amelia Garc nez2 nez-Ruiz2 and Florencio Moreno Jime Paloma Mart
1 2

n a Distancia (UNED), Senda del Rey 9, E-28040 Madrid, Spain Facultad de Ciencias, Universidad Nacional de Educacio nica I, Facultad de Ciencias Qu mica Orga micas, Universidad Complutense de Madrid (UCM), Departamento de Qu Ciudad Universitaria s/n, E-28040 Madrid, Spain

The electron ionization (EI) mass spectra of a series of bridgehead-substituted 3,3-dimethylnorbornan-2-ones, derived from natural (1R)-(R)-camphor, have been studied and their cleavage mechanisms rationalized on the basis of the substituent shifts as well as on the identication of relevant peaks through accurate mass measurements and collision-induced dissociation (CID) tandem mass spectrometric experiments. The fragmentation patterns are very dependent on both the structural nature and the electronic properties of the bridgehead substituent. The driving force for the main fragmentation pathways are competitive cleavages of the C(1)C(2) and C(2)C(3) bonds directed by the bridgehead substituent and either the gem-dimethyl or carbonyl groups. These cleavages lead to distonic ions in which the charge is preferentially located either at the C(1), C(2) or C(3) positions depending on the electronic character and structural nature of the bridgehead substituent. This charge distribution determines the subsequent rearrangements and fragmentations. Copyright 2011 John Wiley & Sons, Ltd.

Chiral bicyclo[2.2.1]heptan-2-ones (2-norbornanones) such as natural camphor and fenchone, as well as a huge number of their derivatives, play a relevant role as chirality transfer agents in stereoselective synthesis.[1] In the course of our studies on the synthesis, applications and chemistry of enantiopure bridgehead norbornane derivatives,[24] we have carried out facile and convenient procedures for the enantiospecic synthesis of bridgeheadsubstituted 3,3-dimethylnorbornan-2-ones starting from natural (1R)-()-camphor.[2] These compounds, due to the ability of the norbornane framework to undergo stereocontrolled CC bond rearrangements and fragmentations, constitute interesting synthons for the preparation of other chiral norbornane derivatives such as norbornane amino alcohols,[3] with applications in catalytic asymmetric synthesis, as well as chiral non-racemic molecules with industrial, theoretical or pharmacological interest.[2,4] Following our studies on the electron ionization (EI) behavior of bridgehead norbornane derivatives[5] we report here on the fragmentation patterns of a selected library of

camphor-derived 3,3-dimethylnorbornan-2-ones substituted at the C(1) position of the norbornane framework (bridgehead-substituted camphenilones) with a variety of functional groups with different electronic properties (Fig. 1). The conclusions derived from this study, in combination with earlier studies reported on the EI behavior of other norbornane derivatives,[616] constitute an interesting contribution to facilitating the mass spectral characterization of this valuable class of chiral molecules for which no systematic mass spectral studies have been carried out due to the lack of general synthetic procedures for their preparation.

EXPERIMENTAL
Norbornanones 1ap (Fig. 1) were prepared according to the our previously reported procedures[17] starting from commercially available (1R)-()-camphor (Sigma-Aldrich, St. Louis, USA). The corresponding IR, 1H- and 13C-NMR spectra agree with the expected structures. The low-resolution 70 eV EI mass spectra were recorded using a QP 5000 quadrupole mass spectrometer (resolution at unit mass) coupled to a GC-17 capillary gas chromatograph (Shimadzu Scientic Instruments Inc., Columbia, MD, USA). The mass spectrometer was operated at a scan rate of 2 scans s1 and a scan speed of 1000 m/z units s1 in full scan mode. The scan range was m/z 40350, and the detector voltage was set at 1.2 kV. The mass spectrometer was calibrated before each analysis session with heptacosauorotri-n-butylamine, (C4F9)3N, using the autotuning function provided by the Shimadzu Class 5000 software. A SGL-1 capillary column (Sugelabor SA, Madrid, Spain; length 30 m, 320 mm i.d. and 0.25 mm lm thickness) was

* Correspondence to: E. Teso Vilar, Facultad de Ciencias, Uni n a Distancia (UNED), Senda versidad Nacional de Educacio del Rey 9, E-28040 Madrid, Spain. E-mail: eteso@ccia.uned.es mica ** Correspondence to: S. M. Cerero, Departamento de Qu nica I, Facultad de Ciencias Qu micas, Universidad ComOrga plutense de Madrid (UCM), Ciudad Universitaria s/n, E-28040 Madrid, Spain. E-mail: santmoya@quim.ucm.es y a Mart nez on the Dedicated to Professor D. Antonio Garc occasion of his 70th birthday.

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4 3 7 6 5

X
1a -p Substituent X a : OSO2CF3 b: OCOCH3 c: OCOCH2CH3 d: I e :NH2 f: NHCOCH3 g: NHCOCH2CH3 h: NHSO2CF3 i: CN j: COOH k: COOMe l: SO3H m: SO2OEt n: SO2NEt2 o: SO2NHPri p: SO2NHBn

Figure 1. Studied bridgehead-substituted 3,3-dimethylnorbornan-2-ones 1a p . used. The GC program conditions were: initial temperature 1008C; initial time 5 min; 108C min1 ramp; nal temperature 2608C; injector temperature 2208C; interface temperature 2508C. Helium was used as the carrier gas at an initial ow rate of 0.8 mL min1. A split injection mode was used at a split ratio of 1:100. The compounds were injected as individual samples (1 mg mL1 solution in CH2Cl2 of analytical grade) by means of a 10 mL syringe. The injection volume was 0.20.4 mL. The spectral data were processed by means of the Shimazdu Class 5000 software. The spectra were acquired at the top of the chromatographic peak with background subtraction at the start of the peak. For high-resolution measurements (70 eV; mass resolution 7000 FWHM, carried out for compounds 1a, b, d, fi, k, n, p) a GCT 1084 time-of-ight (TOF) mass spectrometer (Micromass, Manchester, UK) coupled to a 6890N capillary gas chromatograph (Agilent Technologies, Santa Clara, CA, USA), equipped with an RTX-5MS capillary column (Restek, Bellefonte, PA, USA; length 30 m, 250 mm i.d., 0.25 mm lm thickness) was used. The GC program conditions were: initial temperature 508C; initial time 1 min; 208C min1 ramp; nal temperature 2508C; injector temperature 2508C; interface temperature 2608C. A split injection mode was used at a split ratio of 1:100. The individual samples were injected by means of a 10 mL syringe. The injection volume was 1.02.0 mL (0.1 mg mL1 solution in CH2Cl2 analytical grade). Helium was used as the carrier gas at an initial ow rate of 1.0 mL min1. The mass spectrometer was operated at a scan rate of 2 scans s1 and a scan speed of 1000 m/z units s1 in full scan mode. The scan range was m/z 40800, and the detector voltage was 1.2 kV. The elemental composition of the ions was determined by a lock mass technique using heptacosauorotri-n-butylamine for internal recalibration in real time. The EI-CID MS/MS experiments, carried out for compounds 1a, b, d, fi, k, np, were performed on a Varian 1200L triple quadrupole mass spectrometer (resolution at unit mass), equipped with an EI source (70 eV), coupled to a Varian CP-3800 gas chromatograph (Varian, Palo Alto, CA, USA) equipped with a Varian Factor IV capillary column of length 30 m, 0.25 mm i.d. and 0.25 mm lm thickness. The GC program conditions were: initial temperature 508C; initial time 1 min; 208C min1 ramp; nal temperature 2508C; injector temperature 2508C; interface temperature 3008C. A split injection mode was used at a split ratio of 1:100. The samples of individual compounds were injected by means of

a 10 mL syringe. The injection volume was 1.02.0 mL (0.1 mg mL1 solution in CH2Cl2 of analytical grade). Helium was used as the carrier gas at an initial ow rate of 1.0 mL min1. The mass spectrometer was operated at a scan rate of 2 scans s1 in full scan mode. The scan range was m/z 30400, and the detector voltage was 1.4 kV. The mass spectrometer was calibrated before each analysis session with heptacosauorotri-n-butylamine, (C4F9)3N. For CID MS/MS experiments, the argon gas pressure in the collision cell was 1.681.71 mTorr. The laboratory frame collision energy (525 eV) was optimized for each experiment. The samples were rst analyzed in full scan mode and then the corresponding CID MS/MS experiments (product ion scan, precursor ion scan and constant-neutral loss scan) were carried out to verify the results, as indicated later.

RESULTS AND DISCUSSION

The most signicant ions (see Schemes 16) of the EI mass spectra are listed in the rst column of Table 1. Ions whose elemental compositions were established by accurate mass measurements are listed in the rst column of Table 2. A common characteristic in the fragmentation patterns of 1ap is the fragment ion at m/z 69 which arises from fragmentation routes common to all the studied compounds. Other specic fragment ions such as [M71], [M70], and m/z 57, 58, 72 and 106, are also present in these fragmentation patterns depending on the nature and electronic properties of the bridgehead substituent. A distinctive characteristic in the fragmentation patterns of some compounds is the loss of carbon monoxide from the molecular ion, which constitutes a relevant pathway for further rearrangements and fragmentation processes. Thus, compounds 1ad and 1lp, in which the loss of CO is not observed, display a different fragmentation pattern from the other compounds.

Common fragmentation pathways As a common feature of most norbornan-2-ones studied here, the primary EI fragmentation routes can be explained on the basis of initial C(1)C(2) and C(2)C(3) bond cleavages of the molecular ion leading to distonic ions whose subsequent fragmentations lead to the formation of the major ions in the spectra of all the compounds. Depending on the structural nature and electronic properties of the bridgehead substituent, the charge in the molecular ion can be preferentially located at the ketonic carbonyl oxygen, or on the heteroatomic substituent. Accordingly, as shown in Scheme 1, the molecular ion of 1ap can undergo competitive homo- or heterolytic C(1)C(2) and C(2)C(3) bond cleavages as occurs in the case of camphor,[912] although the subsequent fragmentation processes are quite different. The C(2)C(3) bond cleavage can be radical- or charge-driven leading to isomeric radical cations in which the positions of the unpaired electron and the charge are reversed. Heterolytic inductive cleavage of C(2)C(3) bond, whose driving force is the stabilization of the charge at the quaternary center C(3), gives rise to the distonic radical cation 2 in which the charge is located at C(3) and the unpaired electron at the acyl group. Inductive cleavage becomes an important process, even more than a-cleavage, in bicyclic

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EI-MS studies of bridgehead-substituted norbornan-2-ones

path A 6 CO X O 2 O C O X i-cleavage iso-6 CO O X iso-2

4 5 3 7 2

3 m/z 69 X

or

-cleavage C O

Oi
-cleavage (for 1a -h) i-cleavage (for 1i-k) O H H O X O X 7 path C1 X CO

-cleavage (for 1i-m)

path B1 O X 4 path B2 H X 5 (M-70)

X 1a -p

CO

X 6 path C3

X 8 (M-71) C3H7

path D H O H

H path C2 X iso-6 H

+ OH X 10

X 9

Scheme 1. General EI fragmentation pathways proposed for 1ap. ketones such as camphor[912] and strained steroidal ketones[18] as a consequence of stabilization of the charge by formation of a tertiary carbocation. Homolytic C(2)C(3) bond cleavage leads to iso-2 in which the charge is located at the acyl group and the unpaired electron at C(3). Cleavage of the C(1)C(2) bond, directed either by the carbonyl group at C(2) or by the bridgehead substituent at C(1), gives rise to the distonic radical cations 4 and 7, respectively, in which the charge is located at C(2) and the unpaired electron at C(1), and vice versa. The predominance of either 4 or 7 is dependent on the structure and electronic character of the bridgehead substituent. Several competitive fragmentation pathways (paths AD) can now be postulated starting from the radical cations 2, 4 and 7 (see Scheme 1). Path A involves concomitant homolytic C(1)C(7) and C(4)C(5) bond cleavages in 2, with the loss of the radical C4H4OX, leading to the fragment ion 3, at m/z 69, which constitutes the base peak in the spectra of compounds 1d, 1h, 1ik and 1m and the second most abundant ion in the spectra of 1a, 1b and 1l (see Table 1). Fragment ion 3 also constitutes the base peak in the spectra of fenchone and camphenilone.[8] Path A leading to ion 3 from the molecular ion is supported by the corresponding EI CID MS/MS experiments. The precursor ion spectra of 3, carried out with compounds 1a, d, I and k, show its connectivity with the molecular ion (among others indicating other possible competitive paths for its formation). Constant neutral loss scans, carried out with the same compounds, set to monitor loss of the mass corresponding to the radical C4H4OX, also agree with the proposed fragmentation of 2 to 3. However, the formation of 3, as we will see later, can take place through other fragmentation pathways, as revealed by the same EI CID MS/MS experiments. Path B1, starting from the distonic ion 4, formed by homolytic C(1)C(2) bond cleavage directed by the carbonyl group, involves an heterolytic C(3)C(4) bond cleavage, with the loss of dimethylketene, giving rise to the radical cation 5 ([M70]) which constitutes the base peak in the spectra of compounds 1i and 1j and the third most abundant ion in the spectra of 1k and 1l. Losses of ketene and dimethylketene, corresponding to the elimination of the C(2)C(3) fragment from the molecular ion, were also observed in the mass spectra of camphor[912] (M42 ion, 38%) and fenchone[8] (M70 ion, 40%). An alternative route for the formation of 5 is path B2 involving the loss of carbon monoxide from 4, to give 6, followed by a 1,2-hydride rearrangement in the gemdimethyl group and concomitant heterolytic C(3)C(4) bond cleavage with the loss of propene. In addition, the possibility of the formation of 6 (the precursor of 5) from 2, by loss of CO, cannot be ignored. The precursor ion spectra of 5, carried out with compounds 1i and k, show connectivity between this ion, ion 6 and the

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Table 1. Partial EI mass spectra of bridgehead-substituted 3,3-dimethylnorbornan-2-ones 1ap Compound 1a Cation MR. 3 5 6 8 10 11 12, 13, 17 14 15, 16 18 19 24 25 27 28/8e 29 31 32 34 35 36 37 38 [C9H13O]([M-X]) [M-CH3O] [5-C2H4] [C9H12O] [C8H15N] (6e) [6-SO2CF3] [C8H14O] [C6H7O2] [C8H13] [C8H12] [C8H11] [C7H9] [C7H7] [C6H11] [C6H7] [C6H5] [C4H8O] [C5H7] [C5H6] [C5H5] [C3H8N] [C3H6N] [C4H7] [C4H5] [C2H6N] [C3H7] C3H 5 286 (3) 69 (95) 215 (7) 153 (3) 83 (23) 125 (15) 55 (100) 97 (5) 137 (2) 72 (7) 67 (8) 43 (16) 41 (59) 1b 196 (3) 69 (40) 125 (11) 83 (22) 55 (26) 43 (100) 126 (5) 108 (11) 93 (12) 67 (5) 41 (38) 1c 210 (1) 69 (12) 139 (6) 83 (10) 55 (16) 57 (100) 126 (3) 108 (4) 93 (3) 43 (5) 41 (14) 1d m/z (% relative 264 (19) 69 (100) 193 (33) 192 (9) 137 (27) 109 (13) 93 (5) 91 (6) 79 (7) 77 (8) 72 (22) 67 (39) 66 (36) 65 (13) 55 (9) 43 (24) 41 (83) 1e abundance) 69 (13) 125 (12) 82(23) 57 (100) 110 (17) 108 (3) 93 (4) 67 (4) 55 (6) 41(37) 1f 69 (22) 167 (14) 124 (51) 43 (75) 99 (15) 57 (100) 110 (24) 82 (34) 98 (26) 125 (7) 108 (19) 93 (11) 91 (3) 79 (7) 77 (10) 67 (7) 65 (4) 55 (13) 41(56) 1g 69 (15) 181 (11) 138 (20) 113 (7) 57 (100) 110 (20) 82 (26) 112 (18) 125 (7) 108 (14) 93 (5) 67 (5) 55 (11) 43 (7) 41 (37) 1h 69 (100) 257 (2) 214 (57) 124 (10) 108 (8) 93 (8) 91 (14) 83 (13) 79 (4) 72 (3) 67 (7) 55 (25) 43 (13) 41 (61) (Continues)

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EI-MS studies of bridgehead-substituted norbornan-2-ones

Table 1. (Continued) Compound 1i Cation MR. 3 5 6 8 10 11 12, 13, 17 14 15, 16 18 19 24 25 27 28/8e 29 31 32 34 35 36 37 38 [C9H13O]([M-X]) [M-CH3O] [5-C2H4] [C9H12O] [C8H15N] (6e) [6-SO2CF3] [C8H14O] [C6H7O2] [C8H13] [C8H12] [C8H11] [C7H9] [C7H7] [C6H11] [C6H7] [C6H5] [C4H8O] [C5H7] [C5H6] [C5H5] [C3H8N] [C3H6N] [C4H7] [C4H5] [C2H6N] [C3H7] C3H 5 163 (10) 69(100) 93 (100) 135 (10) 92 (12) 120 (19) 134 (9) 107 (12) 91 (8) 79 (5) 77 (9) 67 (13) 66 (28) 65 (19) 55 (6) 53 (23) 43 (65) 41 (100) 1j 182 (13) 69(100) 112 (100) 154 (34) 111 (21) 110 (13) 139 (5) 137 (5) 136 (9) 111 (21) 109 (36) 108 (16) 93 (15) 91 (10) 79 (10) 77 (13) 72 (5) 67 (58) 66 (12) 65 (16) 55 (18) 53 (20) 43 (48) 41 (100) 1k 196 (6) 69 (100) 126 (24) 168 (7) 125 (15) 124 (6) 137 (3) 165 (7) 136 (6) 111 (4) 109 (20) 108 (12) 93 (21) 91 (4) 79 (7) 77 (4) 67 (18) 66 (4) 65 (7) 55 (7) 53 (9) 43 (13) 41 (66) 1l m/z (% relative 69 (27) 148 (5) 108 (3) 41 (100) 1m abundance) 69 (100) 176 (6) 148 (13) 109 (11) 108 (18) 93 (9) 91 (4) 79 (5) 77 (4) 67 (11) 65 (4) 55 (6) 53 (4) 43 (9) 41 (30) 1n 69 (15) 72 (100) 258 (6) 180 (2) 71 (32) 137 (5) 109 (8) 107 (5) 93 (14) 91 (5) 79 (3) 77 (5) 67 (20) 65 (5) 58 (25) 56 (16) 55 (7) 53 (6) 44 (29) 43 (20) 41 (40) 1o 69 (50) 58 (100) 244 (34) 194 (4) 57 (55) 137 (6) 109 (14) 108 (14) 93 (47) 91 (10) 79 (10) 77 (9) 67 (34) 66 (7) 65 (11) 55 (14) 53 (13) 44 (32) 43 (53) 41 (95) 1p 69 (18) 106 (106) 243 (7) 93 (10) 91 (23) 79 (7) 77 (9) 67 (10) 65 (6) 55 (4) 43 (8) 41 (29)

molecular ion, providing evidence for the fragmentation paths described above. Additional evidence for fragmentation path B1 is provided by the constant neutral loss spectra, set to monitor a loss of 70 Da (in compounds 1i and k), that show connectivity between 5 and the molecular ion.

The radical cation [M70] could also be attributed to iso-5, with the charge located at C(1) and the unpaired electron at C(4). However, as can be seen in Table 1, with the exception of 1np (which display a quite different fragmentation pattern from the other compounds), the [M70] peak

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Compound 1b 1d 1f Elemental comp. Calcd. HRMS Calcd. HRMS Calcd. HRMS Error (ppm) Elemental comp. Error (ppm) Elemental comp. Error (ppm) Elemental comp. C10H13O4F3S C5H9 C6H6O3F3S C9H13O2 C5H7O C8H13O C4H7 C3H3O C6H11 C7H13 C9H13O C7H9 C7H7 C4H8O C5H7 C5H5 C3H7 C3H5 93.0704 72.0575 93.0693 72.0565 12.1 14.1 C7H9 C4H8O 109.1017 91.0548 79.0548 77.0391 72.0575 67.0548 66.0470 65.0391 41.0391 109.1029 91.0551 79.0547 77.0392 72.0587 67.0548 66.0471 65.0394 41.0388 10.9 3.6 1.0 1.0 16.6 0.0 2.3 4.2 7.9 C8H13 C7H7 C6H7 C6H5 C4H8O C5H7 C5H6 C5H5 C3H5 93.0704 91.0548 79.0548 77.0391 65.0391 41.0391 93.0708 91.0552 79.0546 77.0397 65.0400 41.0390 196.1099 69.0704 126.1045 125.0603 83.0497 55.0548 43.0184 196.1135 69.0707 126.1049 125.0618 83.0502 55.0555 43.0188 18.1 4.0 3.4 12.4 6.1 13.2 9.5 C11H16O3 C5H9 C8H14O C7H9O2 C5H7O C4H7 C2H3O 264.0011 69.0704 192.9514 191.9436 137.0966 264.0003 69.0706 192.9512 191.9462 137.0974 3.1 2.5 1.2 13.5 5.5 C9H13OI C5H9 C5H6I C5H5I C9H13O 195.1259 69.0704 167.1310 124.0762 99.0684 57.0578 110.0970 82.0657 98.0606 195.1270 69.0707 167.1305 124.0784 99.0690 57.0584 110.0966 82.0662 98.0608 5.5 4.0 3.1 17.4 5.9 9.7 3.4 6.4 2.2 16.3 4.7 2.2 7.5 13.5 3.1 C11H17NO2 C5H9 C10H17NO C7H10NO C5H9NO C3H7N C7H12N C5H8N C5H8NO C7H9 C7H7 C6H7 C6H5 C5H5 C3H5

Table 2. Partial high resolution EI mass spectra of bridgehead-substituted 3,3-dimethylnorbornan-2-ones 1ap

1a

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Cation

Calcd.

HRMS

Error (ppm)

Copyright 2011 John Wiley & Sons, Ltd.

286.0475 69.0704 214.9990 153.0927 83.0497 125.0966 55.0548 55.0184 83.0861 97.1017 137.0966

286.0480 69.0697 214.9988 153.0929 83.0497 125.0973 55.0545 55.0186 83.0860 97.1017 137.0977

1.7 10.5 0.8 1.3 0.0 5.3 5.0 3.8 0.9 0.0 7.7

MR. 3 5 6 8 10 11 12, 13 14 15 16 17 18 19 24 25 27 28/8e 29 31 32 34 35 36 37 38 [C9H13O] ([MX]) [C8H14N] [C8H13] [C7H9] [C7H7] [C6H7] [C6H5] [C4H8O] [C5H7] [C5H6] [C5H5] [C3H7] [C3H5]

Rapid Commun. Mass Spectrom. 2011, 25, 395409

93.0704 91.0548 72.0575 67.0548 65.0391 43.0548 41.0391

93.0712 91.0549 72.0580 67.0550 65.0407 43.0546 41.0390

8.3 1.4 6.7 3.4 24.2 4.1 3.1

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Compound 1h 1i 1k

1g

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Elemental comp. Calcd. 285.0647 69.0704 257.0697 214.0150 285.0636 69.0706 257.0711 214.0136 3.7 2.5 5.3 6.4 C10H14 NO3SF3 C5H9 C9H14NO2SF3 C6H7NO2SF3 163.0997 69.0704 93.0578 135.1048 92.0500 120.0813 134.0970 137.0966 163.1001 69.0704 93.0586 135.1053 92.0514 120.0826 134.0969 137.0974 2.4 0.0 8.1 3.7 14.9 10.6 0.6 5.5 C10H13NO C5H9 C7H9N C9H13N C6H6N C8H10N C9H12N C9H13O 196.1099 69.0704 126.0681 168.1150 125.0603 124.0525 137.0966 196.1098 69.0698 126.0679 168.1150 125.0602 124.0524 137.0968 0.7 9.1 1.4 0.0 0.4 0.0 1.2 HRMS Calcd. HRMS Calcd. HRMS C12H19NO2 C5H9 C11H19NO C8H12NO C6H11NO C3H7N C7H12N C5H8N C6H10NO Error (ppm) Elemental comp. Error (ppm) Elemental comp. Error (ppm) Elemental comp. C12H19NS C5H9 C7H10O2 C10H16O2 C7H9O2 C7H8O2 C9H13O C7H9 C7H7 C6H7 C6H5 C5H5 C3H7 C3H5 93.0704 91.0548 79.0548 77.0391 65.0391 43.0548 41.0391 93.0706 91.0551 79.0552 77.0384 65.0392 43.0553 41.0378 1.9 3.6 5.4 9.4 1.2 12.2 31.6 124.1126 124.1124 2.5 C8H14N C7H9 C7H7 C6H7 C6H5 C5H5 C3H7 C3H5 91.0548 79.0548 77.0391 66.0470 65.0391 43.0548 41.0391 91.0506 79.0543 77.0387 66.0460 65.0389 43.0545 41.0388 46.1 6.0 5.5 14.4 3.5 6.4 7.9 C7H7 C6H7 C6H5 C5H6 C5H5 C3H7 C3H5 109.1017 93.0704 91.0548 79.0548 77.0391 67.0548 66.0470 65.0391 43.0548 41.0391 109.1016 93.0722 91.0548 79.0538 77.0385 67.0543 66.0468 65.0390 43.0546 41.0388 1.2 19.1 0.0 12.3 8.1 7.1 2.3 1.9 4.1 7.9 C8H13 C7H9 C7H7 C6H7 C6H5 C5H7 C5H6 C5H5 C3H7 C3H5

EI-MS studies of bridgehead-substituted norbornan-2-ones

Cation

Calcd.

HRMS

Error (ppm)

209.1416 69.0704 181.1467 138.0919 113.0841 57.0578 110.0970 82.0657 112.0762

209.1434 69.0710 181.1461 138.0925 113.0835 57.0563 110.0964 82.0656 112.0761

8.7 8.3 3.1 4.4 5.0 27.2 5.2 0.9 1.2

Copyright 2011 John Wiley & Sons, Ltd.

MR. 3 5 6 8 10 11 12, 13 14 15 16 17 18 19 24 25 27 28/8e 29 31 32 34 35 36 37 38 [C9H13O] ([MX]) [C8H14N] [C8H13] [C7H9] [C7H7] [C6H7] [C6H5] [C4H8O] [C5H7] [C5H6] [C5H5] [C3H7] [C3H5]

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93.0704 91.0548 79.0548 77.0391 65.0391 43.0548 41.0391

93.0693 91.0547 79.0551 77.0396 65.0396 43.0548 41.0386

12.1 0.8 4.1 6.2 7.3 0.0 12.8

(Continues)

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Compound 1n 1p HRMS Error (ppm) Calcd. HRMS Elemental comp. Error (ppm) Elemental comp. 69.0708 72.0820 258.1177 194.1551 71.0740 109.1013 93.0692 91.0533 79.0561 77.0390 67.0551 65.0392 43.0551 41.0387 3.9 13.2 0.8 16.8 1.6 4.8 1.2 7.5 10.4 C8H13 C7H9 C7H7 C6H7 C6H5 C5H7 C5H5 C3H7 C3H5 91.0548 79.0548 77.0391 65.0391 43.0548 41.0391 91.0542 79.0554 77.0399 65.0405 43.0568 41.0414 6.3 7.9 10.1 21.1 46.4 56.0 5.4 9.4 5.1 3.1 7.0 C5H9 C4H10N C12H20NO3S C12H20NO C4H9N 69.0704 106.0657 243.1623 69.0713 106.0643 243.1642 12.7 13.0 7.8 C5H9 C7H8N C16H21NO C7H7 C6H7 C6H5 C5H5 C3H7 C3H5

Table 2. (Continued)

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Cation

Calcd.

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69.0704 72.0813 258.1164 194.1545 71.0735

MR. 3 5 6 8 10 11 12, 13 14 15 16 17 18 19 24 25 27 28/8e 29 31 32 34 35 36 37 38 [C9H13O] ([MX]) [C8H14N] [C8H13] [C7H9] [C7H7] [C6H7] [C6H5] [C4H8O] [C5H7] [C5H6] [C5H5] [C3H7] [C3H5]

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109.1017 93.0704 91.0548 79.0548 77.0391 67.0548 65.0391 43.0548 41.0391

E. Teso Vilar et al.

EI-MS studies of bridgehead-substituted norbornan-2-ones

O
C N 1i
4 5 3 7 2

O
C N 7i

O
C N

O H 8i-k

O
O

O
O OR 7j,k

O
O OR

OR 1j,k

Scheme 2. Formation of 7 and 8 from 1ik. corresponding to the radical cation 5 is only observed in those compounds bearing an electron-withdrawing substituent (CO, CN or SO2) at the bridgehead position which stabilizes the radical center better than the cationic one. Thus, for compounds 1im a-cleavage of the C(1)C(2) bond, which can only be directed by the ketonic carbonyl group, becomes an important process which leads exclusively to distonic ion 4 with charge location at C(2). In contrast, for those compounds in which the bridgehead heteroatomic substituent (O, N, I) can straightforwardly stabilize the positive charge at C(1) by the M effect, the fragment ion 5 is absent. In other words, for those compounds, the homolytic C(1)C(2) a-cleavage is only directed by the heteroatomic substituent, and not by the carbonyl group, leading exclusively to radical cation 7, with charge location at C(1). Path C1, starting from the radical cation 7, involves a 1,4-hydrogen rearrangement from C(7) to C(2) and concomitant homolytic C(3)C(4) bond cleavage, with the loss of the tertiary radical C4H7O, to give the cyclopentenyl ion 8 ([M71]) which is an important fragment ion in the spectra of compounds bearing an heteroatomic substituent at C(1) with a M effect, such as 1ah. The [M71] ion is the base peak (together with the ion at m/z 69) in the mass spectra of fenchone[8] and the second most important ion in the mass spectrum of camphenilone.[8] An alternative route to the formation of cation 8, in the case of compounds 1eh, is path C2 involving elimination of CO from 7 followed by 1,3-H rearrangement in iso-6 and concomitant C(3)C(4) bond cleavage with the loss of the isopropyl radical. The possibility of the formation of iso-6 (the precursor of 8), in the case of compounds 1eh, by loss of CO from iso-2, cannot be discounted. However, taking into account the powerful stabilizing ability of the nitrogen atom, a-cleavage of the C(1)C(2) bond in 1eh seems to be the predominant process. Both fragmentation paths C1 and C2 are supported by the precursor ion scan spectra of 8, in compounds 1a, b, d, f, h, that show connectivity between 8, iso-6 (for compounds 1f,h) and/or the molecular ion. Constant neutral loss spectra recorded for compounds 1b, d, and fh, set to monitor a loss of 71 Da, corresponding to the radical C4H7O, provide additional evidence for fragmentation path C1. Fragment ion 8 is absent in the spectra of compounds 1lp, where the bridgehead substituent is the strong electron-withdrawing sulfonyl group (-M and -I effects); however, this ion is present (with low relative abundance) in the spectra of 1ik. Pathway C3 explains the formation of 8 from 5 by loss of a hydrogen atom. However, the precursor ion spectra of 8, carried out with compounds 1i, k, show connectivity between the ions 8, 6 (or iso-6), 5 and, in the case of 1k, the molecular ion, providing evidence not only for fragmentation path C3 but also for paths C1 and C2 involving the formation of 7 as precursor ion. Additional evidence for pathway C1 is provided by the constant neutral loss spectra, recorded for the same compounds, set to monitor a loss of 71 Da. Nevertheless, pathways C1 and C2 in the cases of 1ik are minor processes (see Table 1). Formation of 7ik could be explained by heterolytic C(1)C(2) bond cleavage directed by the carbonyl group at C(2) (Scheme 2). Thus, although the CN, COOH and COOMe groups are electron withdrawing, the positive charge at C(1) in iso-6, 7 and 8 can be partially stabilized by the M effect exerted by these groups towards a strong electronic demand, as occurs in a-carbonyl[19] and a-cyano cations.[20] Path D, a minor process which is only observed in compounds 1d and 1j, k, involves a 1,4-H rearrangement in 7, giving rise to 9, followed by a McLafferty rearrangement with the loss of 2-methylpropanal to give the radical cation 10. Both the precursor ion spectrum of 10 (which shows connectivity between this ion and the molecular ion) and the constant neutral loss spectrum set to monitor a loss of 72 Da (corresponding to C4H8O), recorded for 1d, provide evidence for this pathway. A similar fragmentation pathway has been previously described for camphor and related compounds.[812] In addition to these common fragmentation pathways shown in Scheme 1, depending on the electronic character and the structural nature of the bridgehead substituent, the norbornan-2-ones 1ap undergo other specic fragmentation processes that are discussed in the following sections. Fragmentation of C(1)-O-substituted norbornan-2-ones 1ac The EI fragmentation patterns of C(1)-O-substituted norbornan-2-ones (i.e. triuoromethanesulfonate, acetate and propionate 1a, 1b and 1c, respectively) are very similar. In addition to the fragment ions 3, 8 (Scheme 1) and [C3H5] (Table 1) these compounds show other common fragment

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E. Teso Vilar et al.

C2H4

17a 17b m/z 83

CH2 C O

CO

18 m/z 97

3 m/z 69

12 m/z 83

O 14a m/z 125

O 14b m/z 125

15 C O m/z 55

CO SO2CF3
4 3 2 7 6 1 5

C O CO

RCH C O

a O 11 m/z 153 O O 12 m/z 83 C2H4 HO 13a m/z 83 HO 13b O O

O SO2CF3 1a

CH H R (R = H, Me) 8b, c

O 16 m/z 55

O H (Sch. 1)

O HN 1f C O R O NH

R C O 19 m/z 43 (R = Me) 57 (R = Et) O O

O C O 1b, c O R

Scheme 3. EI fragmentation pathways of 1ac. ions, such as m/z 83 and 55 (see Tables 1 and 2), whose formation from the molecular ions of 1ac is proposed in Scheme 3. However, in the case of 1b and 1c, the most important primary fragmentation, which almost overrides the C(1)C(2) and C(2)C(3) bond cleavages, is the O-acyl cleavage leading to the acylium cation 19 (Scheme 2), which appears as the base peak in the spectra of 1b and 1c (Table 1). Moreover, N-acyl cleavage also constitutes a very important fragmentation path in the case of amide 1f (see Table 1 and Scheme 2). In the case of triuoromethanesulfonate 1a, whose mass spectrum is shown in Fig. 2, the high-resolution spectrum shows that the fragment ion at m/z 83 is a duplet of isobaric ions 12 ([C5H7O], 46%) and 17 ([C6H11], 54%) (Table 2). The fragmentation pathway that can be proposed to explain the formation of 12 from the molecular ion of triuoromethanesulfonate 1a involves a concomitant homolytic cleavage of the OS and C(1)C(2) bonds with the loss of triinate radical to give 11, at m/z 153, followed by elimination of dimethylketene. Formation of the fragment ion 17 can be explained by elimination of CO from 11, leading to 14a, followed by the loss of ketene to give 17a or a related species such as 17b. Alternatively, the ion 12 can be formed by elimination of propene from 14a in an analogous way to the formation of 5 (see Scheme 1). All these proposed pathways leading to the isobaric ions 12 and 17 are supported by CID MS/MS experiments carried out with 1a. Both the precursor ion spectrum of the fragment ion at m/z 83, which shows connectivity between 12/17, 11 and 14a, and the precursor ion spectrum of 14, which shows connectivity between this ion, 11 and the molecular ion, agree with the proposed pathways. Elimination of CO from 14a leads to 18, at m/z 97, which by elimination of ethene yields ion 3 in an alternative way to that proposed in path A (Scheme 1). The precursor ion spectrum of 3 shows connectivity between this ion, 18, 14a, 11 and the molecular ion, providing evidence for these fragmentation pathways. On the other hand, in the case of 1b and 1c the fragment ion 13, a tautomer of 12, arises from 8b and c (see also Scheme 1, path C1) through a 1,3-hydrogen rearrangement from the methylene or methyl groups of the acyl moiety to the bridgehead oxygen atom and concomitant homolytic O-acyl bond cleavage with elimination of the corresponding ketene. This fragmentation pathway is supported by the precursor ion spectrum of 13, recorded for 1b, which shows connectivity between 13, 8b and the molecular ion. The constant neutral loss spectrum of 1b set to monitor a loss of 42 Da,

Figure 2. EI mass spectrum of 1a.

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EI-MS studies of bridgehead-substituted norbornan-2-ones spectrum of 1a. In the case of the acetate 1b, however, only ion 15 is present. Another alternative path for the formation of 15 in the case of 1a is the loss of CO from the cyclopentanic ring of 11, leading to 14b (isomer of 14a), followed by loss of dimethylketene. These two competitive pathways for the formation of 15 and 16 are supported by the precursor ion spectrum of the fragment ion at m/z 55, carried out with 1a, that shows connectivity between this ion, 14b and 12 (or 13). In addition, the product ion spectra of 12 and 14 show connectivity between 12 and 15/16 and between 14, 18, 12/ 17, 3 and 15/16, respectively. The formation of 15 from 12 in the case of the acetate 1b is also supported by both the precursor ion spectrum of 15, that shows connectivity between the two ions, and the product ion spectra of 13. Fragmentation of amino compounds 1eg The mass spectra of the amino compounds 1eg are quite different from those displayed by the other compounds, indicating that the nitrogen atom plays an important role in their fragmentation pathways. The fragmentation patterns

Figure 3. EI mass spectrum of 1f. corresponding to ketene, is also in agreement with the proposed fragmentation pathway. Losses of CO and ethene from 12 lead, respectively, to the isobaric ions 15 (C4H7, 61%) and 16 (C3H3O, 39%) (see Table 2), at m/z 55, which constitute the base peak in the
RCH C O

O NH H CHR 8f,g

NH2 8e m/z 82

CH3

C2H4

(7f,g) O H C3H7
(Sch.1, path C2) (Sch.1, path C1)
4 5 7 1 6

NH2 26e CO

NH2 27 m/z 110 H H

NH2 28 m/z 82

3 2

O X

O 7e-g

(X = NH2) NH2 iso-6e NH2 20 NH2 21a NH2 22a

CO

(X = NHCOR)

RCH C O

O NH H NH CHR H iso-6f,g (R = H or Me)

O NH CHR H 23

O CHR

NHCOCH2R

NH2 21b

NH2 22b

HN NHCOCH2R O

H NH2

H O O NH 7f,g CH2R 29a R = H: m/z 98 R = Me: m/z 112 O NH CH2R 29b O NH O

CHR NH2 24 25 R = H: m/z 99 m/z 57 R = Me: m/z 113 RCH C O O NH CH2R 29c

CH2R

Scheme 4. EI fragmentation pathways of 1eg.

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E. Teso Vilar et al. of 1eg are almost identical (allowing for the mass differences due to the substituents shifts) and clearly dominated by the base peak at m/z 57, whose elemental composition is C3H7N by high-resolution measurements (see Table 2). As common features, no molecular ion is observed and the highest mass peak appearing in their mass spectra is the [M28] fragment ion, which is absent in most compounds. In the case of the acetamide 1f the acylium ion 19 (see Scheme 3) is the second most abundant fragment ion. Loss of CO from 7eg (see Scheme 1) together with the powerful stabilizing ability of the nitrogen atom is the determining factor for the fragmentation pathways of these compounds. Figure 3 shows the mass spectrum of 1f. The fragmentation pathways which explain the formation of the base peak fragment ion 25 at m/z 57, as well as other signicant ions, are shown in Scheme 4. The product ion spectra of fragment ion iso-6f,g/23, recorded from compounds 1f,g, show connectivity between this ion, iso-6e/26e, 8e-g (see also Scheme 1, path C2), 25, 27 and 28, indicating the possible pathways for the formation of these ions. Thus, loss of CO from the distonic ion 7eg, with charge retention at C(1), resulting from the homolytic C(1)C(2) bond cleavage (a-cleavage) in 1eg (see Scheme 1), gives rise to iso-6eg (iso-6, X NH2, NHCOMe, NHCOEt). The iso-6e ion can be also formed from iso-6f,g by elimination of the corresponding ketene in the case of amides 1f,g. This pathway is supported by the precursor ion spectra of the fragment ion iso-6e/26e at m/z 125, recorded for 1f,g, which show connectivity between this ion and iso-6f,g. The homolytic C(4)C(7) bond cleavage in iso-6e leads to 20, which undergoes a 1,4-hydrogen rearrangement from C(5) to C(7), giving rise to 21. A second 1,4-hydrogen rearrangement from the gem-dimethyl group to C(5) in 21 leads to 22. Elimination of a cycloalkene or diene from 21 or 22, respectively, leads to the base peak 25. Another alternative pathway to 25, in the case of amides 1f, g, involves a homolytic C(4)C(7) bond cleavage in iso-6f, g to give 23. This last ion can be formed by two competitive routes: The rst one involves elimination of the corresponding ketene to give 20, the precursor ion of 25, and the second one involves an analogous pathway to that followed by iso-6e (to give 25), leading to 24, which by elimination of the corresponding ketene gives rise to 25. All the competitive pathways leading to the base peak 25 are supported by the precursor ion spectra of this ion, carried out with compounds 1f,g, that show connectivity between iso-6e-g/23, 24 and 25. On the other hand, the constant neutral loss scan spectra carried out with 1f, set to monitor a loss of 68 Da, show connectivity between the ions iso-6e (isomeric with 20, 21 and 22) and 25. Additional evidence for the transitions iso-6f,g!iso-6e (or 23!20) and 24!25 is provided by the constant neutral loss

CH3

x
30i-k

x
31i,,j

CO
3 2 4 5 7 6 1

x
4i-k

x
6i-k H

3 m/z 69

or (X = CN) CN 32a m/z 134

Scheme 5. EI fragmentation pathways of 1ik.

CN 32b

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EI-MS studies of bridgehead-substituted norbornan-2-ones The difference of 14 m/z units between the fragment ions at m/z 98 and 112 in the spectra of 1f and 1g, respectively, is a clear indication that the N-acyl moiety is present in such ions. Their structures can be attributed to the 2-oxazolidinium ion 29, which is a specic fragment ion in the spectra of 1f, g. The possible pathways which explain its formation, as Scheme 3 shows, involve: (a) elimination of an acyl radical C6H9O from 7f,g by concomitant heterolytic cleavage of the C(4)C(7) and C(5)C(6) bonds assisted by the carbonyl group; (b) elimination of the radical C5H9 from iso-6f, g following a similar process; and (c) loss of a hydrogen atom from 24. Paths (b) and (c) are supported by both the precursor ion spectra of 29, which show connectivity between this ion, iso-6f,g and 24, and the constant neutral loss spectra set to monitor a loss of 69 Da corresponding to the radical C5H9. However, there is no evidence for the direct formation of 29 from the molecular ion of 1f, g. The proposed structure of 29 is speculative; however, as this ion (shifted at m/z 56) is absent in the spectrum of 1e, it can be deduced that the carbonyl group plays an important role in the formation of 29. The mass spectrum of the triuoromethanesulfonamide 1h, as seen in Table 1, shows only very few fragment ions whose formation has been explained in Scheme 1. No other noticeable specic fragmentations have been found for this compound. Fragmentation of C(1)-C-substituted norbornanones 1ik The main fragmentation pathways of 1ik have been explained in Scheme 1. The fragmentations of 1i and 1j, bearing at the bridgehead C(1) position the CN and COOH groups, respectively, are clearly dominated by the fragment ions 3 and 5 (Scheme 1, paths A and B, respectively), which

Figure 4. EI mass spectrum of 1i. spectra set to monitor a loss of 42 Da (for 1f) or 56 Da (for 1g), corresponding to the loss of the ketene RCH C O. The fragment ion at m/z 82 constitutes another important peak in the mass spectra of 1eg. It can be attributed to the isomeric ions 8e, whose formation in the case of amine 1e has been shown in Scheme 1 (paths C1 and C2), and 28. The precursor ion spectra of 8e/28 show connectivity between these ions, iso-6e-g, 8f,g and 27 (formed by loss of a methyl radical from 26e). Therefore, the formation of 8e in the case of amides 1f,g can be explained by elimination of the corresponding ketene from 8f,g (also in agreement with the constant neutral loss spectra of 1f,g set to monitor a loss of 42 or 56 Da, corresponding to the ketene RCH C O) or, alternatively, by the loss of the isopropyl radical from iso-6e (see Scheme 1, path C2). The formation of the 27 ion, precursor of 28, from 26 is supported by the corresponding precursor ion spectra which show connectivity between 27, iso-6e/26e and iso-6f,g.

O SO2
4

R = CH3
3 7 5 6 1

SO2

R H N R R 34 n: m/z 72 o: m/z 58 p: m/z 106 N

R CHR R 33 O

R R C R

O SO2 N

R CH R 35n,o n: m/z 258 o: m/z 244 (1n,o) O

O N R HC R

O S O 1n-p

N H

n: R = Et; R= Me, R= H o: R = H; R, R= Me p: R, R= H; R= Ph SO2

36n,o n: m/z 194 o: m/z 180

(1p) O O HN CH2Ph 37 m/z 243 HC CH3 CH3 m/z 43 or (1o) (1p) SO2NH

R N

SO2H R N C R R 38 n: m/z 71 o: m/z 57

C R R

m/z 91

Scheme 6. EI fragmentation patterns of 1np.

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E. Teso Vilar et al. constitute the base peaks of their spectra, and by the allyl cation at m/z 41. Other specic fragmentation paths are shown in Scheme 5. A possible alternative pathway to the one proposed in Scheme 1 for the formation of the base peak 3 is shown in Scheme 5. It involves concomitant homolytic cleavage of the C(4)C(7) and C(5)C(6) bonds in 6ik with the loss of the allylic radical C3H4X bearing the bridgehead substituent. This fragmentation pathway is conrmed by both the precursor ion spectra of 3, carried out with compounds 1i, k, which show connectivity between this ion, 6i, j and the molecular ion, and the constant neutral loss spectra set to monitor a loss of 94 Da (for 1i) or 127 Da (for 1j) . corresponding to the radical C3H4X. Losses of a hydrogen atom from 6i (only observed in the case of the nitrile 1i to give 32, as well as of a methyl radical from 6ik, are minor processes. Formation of 32 from 6i is supported by the precursor ion spectrum of 32 which shows connectivity between both ions. As an example, the EI mass spectrum of 1i is shown in Fig. 4. the methyl radical in 1n and 1o, leading to 35, is a secondary process. Loss of the methyl radical from the gem-dimethyl group cannot be discounted; however, the absence of the [M15] ion in the spectrum of 1p indicates that this ion probably arises exclusively by a-cleavage in 1n and 1o. Another characteristic process observed in the mass spectra of 1np is the elimination of SO2, either from 35 in the case of 1n and 1o, leading to 36, or from the molecular ion, in the case of 1p, to give 37. The formation of 36 from 35 is supported by the constant neutral loss spectrum set to monitor a loss of 64 Da corresponding to SO2. On the other hand, heterolytic CN bond cleavage in 1n and 1p leads, respectively, to the isopropyl and tropylium cations (Tables 1 and 2). In addition, the formation of radical cation 38 in the case of 1n and 1o can be explained by a concomitant 1,3-hydrogen rearrangement from the N-alkyl substituent to the oxygen atom of the sulfonyl group and homolytic SN bond cleavage with loss of the corresponding sulnic acid. SN bond cleavage with elimination of sulnic acid and sulfonyl radical in the mass spectra of tertiary sulfonamides has been previously described.[21]

Fragmentation of C(1)-S-substituted norbornanones 1lp. The sulfonic acid 1l and sulfonate 1m present very few fragment ions in their mass spectra which are dominated, respectively, by the allyl cation and the fragment ion 3 at m/z 69, whose formation has been explained in Scheme 1 (path A). The formation of the ion 5 ([M70]) is a minor process. No other noticeable ions are present in their spectra. In analogy with the amino compounds 1eg, the fragmentation patterns of the bridgehead sulfonamides 1np present substantial differences from those of the other compounds. The molecular ion is absent and the mass spectra are dominated by nitrogen-containing ions, arising from the NS bond cleavage, which constitute the base peaks of the spectra. The fragmentation pathways are shown in Scheme 6. Figure 5 shows, as an example, the mass spectrum of 1n. The molecular ion of 1np undergoes an homolytic SN bond cleavage with the loss of the sulfonyl radical C9H13O3S leading to 33 which isomerizes to 34, the base peak in the spectra of 1np, through a 1,2-hydride rearrangement to the electron-decient nitrogen atom. This fragmentation pathway is specially favored with regard to others owing to the stabilities of both the immonium ion 34, due to the electron-releasing character of the nitrogen atom, and the lost sulfonyl radical. In contrast, a-cleavage with the loss of

CONCLUSIONS
The present study has allowed us to determine that the structure and electronic character of the bridgehead substituent play an important role in the main EI fragmentation pathways of bridgehead-substituted 3,3-dimethylnorbornan2-ones (bridgehead-substituted camphenylones). In general, the more important and distinctive fragmentation pathways involve homo- or heterolytic C(1)C(2) and C(2)C(3) bond cleavages which lead to distonic radical cations that undergo further rearrangements and fragmentations. In the case of the C(2)C(3) cleavage the charge can be located at either the quaternary center C(3) or the carbonyl group, whereas for the distonic ions resulting from the C(1)C(2) cleavage the charge can be preferentially located at either position depending on the structural nature and electronic properties of the bridgehead substituent. Thus, for compounds bearing at the bridgehead position substituents possessing a M and strong I effect, such as OSO2CF3 (1a), I (1d) and NHSO2CF3 (1h), the fragmentation pattern is clearly dominated by the ion 3 at m/z 69, resulting from the heterolytic C(2)C(3) bond cleavage, whereas the homolytic C(1)C(2) cleavage with charge retention at C(1), which by further rearrangements and fragmentations leads to the ion 8 (Scheme 1, paths C1 and C2), is a secondary process. Exceptions are the acetate 1b and propionate 1c, in which the dominant fragmentation pathway that overrides any others is the O-acyl cleavage. For the amino compounds 1eg, owing to the powerful fragmentation-directing ability of the nitrogen atom, the most important primary fragmentation process is the homolytic C(1)C(2) cleavage with charge location at C(1) which, by further rearrangements and fragmentations, leads to the base peak 25 (Scheme 4) at m/z 57. Paths C1 and/or C2 (see Scheme 1) are also important. As a common feature of compounds 1ah, in which the bridgehead substituent has I and M effects, the C(1)C(2) a-cleavage directed by the carbonyl group leading to the [M-70] radical cation 5 (Scheme 1, paths B1 and B2) is not observed. For compounds 1im, bearing at the bridgehead position substituents with strong I and M effects, in

Figure 5. EI mass spectrum of 1n.

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EI-MS studies of bridgehead-substituted norbornan-2-ones addition to the dominant C(2)C(3) bond cleavage, the fragmentation pattern is also characterized by the radical cation 5 ([M70]) resulting from the initial C(1)C(2) bond a-cleavage directed by the carbonyl group followed by further fragmentations (Scheme 1, paths B1 and B2). These paths lead to the base peak in the case of nitrile 1i and carboxylic acid 1j. However, for 1ik the charge may be partially located at C(1) due to the stabilizing M effect exerted by the CN and COOR groups towards a strong electronic demand. Therefore, paths C1 and C2 cannot be totally excluded. In contrast, for the sulfonamides 1np the main fragmentation pathway involves a homolytic SN bond cleavage, which overrides any others, leading to the corresponding immonium cations.
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Acknowledgements
We gratefully acknowledge the nancial support from the n y Ciencia of Spain (research project Ministerio de Educacio CTQ2007-67103-C02-02/BQU), Universidad Complutense de n Santander-UCM Madrid (PR1/08-15775) and Fundacio (PR34/07-15782). We also want to thank the Mass Spectrom noma of Madrid for etry Service (SIdI) at Universidad Auto their helpful assistance.

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