High resolution mass spectrometry in studies of stereochemistry effect on fragmentation of epimeric derivatives of azabicycloalkane

Burlingame, A. L.

Schnoes, H. K.

Smith, D. H.

English

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https://ntrs.nasa.gov/search.jsp?R=19660025339 2020-03-16T20:16:45+00:00Z
High Resolution Mass Spectrometry
in Molecular Structure and Stereochemical Studies
Effect of Stereochernistry on the Fragmentation
of Epimeric Derivativea of Azabicycloalkanesl
by 066629^^
D. H. Smith, " H. K. Schnoes, and A. L. Burlingame
	 C I AO
Department of Chemistry and Space Sciences Laboratory,
University of California, Berkeley 	 )	 Q
3 i tmr) , 5A recent study by A. L. Burlingame, H. 0. House and co-workers n2 l ed an
examination of possible correlations that might be drawn between the low resolution
mass spectra and the structures and stereochemistry of a series of related azabicyclo-
alkanes, This work concluded that the stereochemistry about the bridgehead carbon
atom could be determined by examining the relative intensities of molecular ion minus
a hydrogen (M-1) peaks between epimeric pairs and, in some cases, namely the
secondary alcohols and ethers, the relative intensities of m/e 44 and 58.
The peak at M-1 was shown to arise from loss of a hydrogen atom from a carbon
atom adjacent to nitrogen. With reference to Figure 1, it may be noted that there
exists considerable 1, 3-diaxial interaction between the substituent on the bridgehead
carbon and the axial hydrogens (labeled Ha) on the carbons adjacent to nitrogen. Loss
of one of these axial hydrogens from a molecular ion results in relief of some of this
interaction plus the formation of a stable immonium ion as illustrated. Indeed, it was
found that the epimer with the larger substituent oriented toward nitrogen displayed
the larger M-1 peak, and thus this fragmentation proves useful in determining stereo-
chemistry about the bridgehead.
The fragmentations of secondary alcohols or ethers mentioned above leading to
m/e 44 and 58 are more complicated processes, but also proved useful in elucidating
stereochemistry. These processes are summarized in Figure 2. Cleavage of an
a-5 carbon bond in both epimers yields an immonium ion that can be pictured as
structure A. From this molecular ion it was demonstrated that two different re-
arrangement rpocesses take place dependent on the stereochemistry of the bridgehead.
In the case of the 8-epimer, with the hydroxyl group oriented toward nitrogen, a
rearrangement that may be pictured as shown in structure B yields a fragment ion at
m/e 44, with the composition C ZH6N, while a similar rearrangement pictured in
structure B' for the a-epimer yields a fragment ion at m/e 58, of composition C3H8N.
High resolution mass spectra of representative members of the series were
determined employing a Mattauch-Herzog double focusing instrument (CEC type 21-110)
with photoplate recording. Subsequent data acquisition and reduction employing our
automatic plate scanning system and the computer facilities of the Lawrence Radiation
Laboratory verified the compositions of the peaks discussed above in the initial paper,
but, more importantly, proved invaluable in elucidating certain features of the
fragmentation patterns of epimeric pairs. These epimers displayed fragmentation
patterns that were quite different in many respects. For example, several peaks in
the mass spectrum of one epimer were missing entirely in the spectrum of the other
c-imer, and there were, in certain regions of the spectra, marked intensity
differences between the two epimers other than those mentioned above.
The first pa'r of epimers provides an illustrative example of the generalizations
noted in the low resolution studies. The compound, as drawn, has a six-membered
ring to the left and is a secondary alcohol. The distribution of peaks in the hydro-
carbon and oxygen containing plots 4 is quite similar for the epimers. Figure 3
represents the nitrogen and nitrogen-oxygen containing plots for the same epimers.
The molecular ion has the composition CggH1i7NO For the $-epimer, with OH
oriented toward nitrogen, the M-1 peak C gH 16NO , is larger than that of the a-epimer,
with the hydrogen (less bulky than OH) oriented toward nitrogen. Also, exactly as
noted before, the peak at C2H6H is larger than that of C3H8N for the 5-epimer, while
the intensity ratio is effectively reversed in the C/H N plot of the a-epimer. There is
one more feature of this set of spectra that has significance to the following discussion,
and that is the presence of relatively intense peaks in the C/H N plot of the 8-epimer at
C9H15N and CgH14N, representing loss of the elements of H2O and H30 respectively,
from the molecular ion. These peaks are virtually absent in the C/H N plot of the
corresponding epimer.
The next pair of epimers provides perhaps the most graphic exair ► ples of the
dependence of the fragmentation pattern on stereoc • heniistry. Again, the C/11 and
C/H O plots are quite similar with the exception of a much larger C6Nc, fr,tgnient ion
in the spectrum of the a-epimer, which has the phenyl group oriented toward nitrogen.
This presumably arises from the 1, 3 diaxial interactions noted above; interactions
that are considerably more pronounced for phenyl versus OH.
Figure 4, however, which contains the C/11 N and C/11 N O plots for the same
pair, displays marked differences. In particular, one may note the larger M-1 peak
for the a-epimer at C 1 5 H30NO, as expected; the presence of peaks in the lower
C/H N O plot, at CgH15N O (peak D') and C61i8NO (peak E') that are absent in the
C/H N O plot of the S-epinier; the larger M-H2O and M-1I3O peaks in the C/11 N plot of
the S-epimer at C15H19N (peak D) and C15H18N; and finally the presence of an intense
peak at C 121112N (peak E) in the S-epimer that is entirely absent in the C/H N plot of
the cx-epimer. These differences can be explained quite readily if the fragmentation is
assumed to proceed as shown in Figure 5. In both epimers the fragmentation proceeds
either with loss of a hydrogen followed by lo.-- of the group oriented toward nitrogen,
or a single step elimination of the elements of H2O or C6H6 inthe 8- and a-epimers
respectively. In the case of the S-epimer tlii; process yields the fragnient ion D
C1511 19 N, a much more favorable process than in the cY- epimer, while in the case of
the ce-epimer, a peak at C 9 H 15NO (peak D' ►
 results. Elimination of a C3H7 radical as
shown, to aromatize the system, from both of these fragments, yields C 12H 12N
(peak E) for the S-epimer, and CH8NO (peak E') for the a-epimer. Thus this rather
straightforward fragmentation sceme, dependent entirely on stereochemistry, is
sufficient to account for the more obvious dissimilarities between the two spectra.
Also of interest are the fragmentation patterns of the 8- and a-epimers of a
compound similar to that discussed above, but with a seven-membered ring instead of
six. The pairs of C/H and C/H O plots are virtually identical, but again as above,
there exist several marked dissimilarities in the pairs of C/H N and C/H N O plots
presented in Figure 6 (note peaks F, F', G, G', H, H'). These differences can be
explained assuming a mechanism exactly as that discussed above. With reference to
Figure 7, the more intense M-H2O and M-1430 peaks at C16H L 1N and C16H2ON
(peaks F) in the spectrum of the E-epimer are due to the more facile elimination of
these elements from the molecular ion, C16H23NO, of the S-epimer. In the spectrum
of the a-epimer, however, elimination of the ele-inents of C6H6 or C6H7 initially from
the molecular ion yields the peaks at C10F117NO and ClOH 1 6NO (peaks F'). In this
case, both fragments F and F' can eliminate either a propyl or butyl radical to yield
C13H14N (peak G) or C12H12N (peak H) in the S-epimer, or C7HIONO (peak G') or
C6H8NO (peak H') in the a-epimer. These peaks are unique for each compound with
the exception of peak H and a very light elimination of H2O and H3O in the a-epimer.
There exists a small peak at C12F12N in the c,-epimer's spectrum also, but the
fragmentation process leading to this ion is obviously less favorable.
As the substituent on the bridgehead becomes less and less large compared to
OH, the above processes become less clearly resolved. One can, however, still
easily discern that these fragmentations are occurring, as may be seen in Figure 8.
This epimeric pair has a methyl group on the bridgehead. The O/H and C/H O plots
are again similar although there are several intensity differences. The C/H N and
C/H N O plots as presented in Figure 8 again display a stereochemical influence on the
fragmentation similar to those discussed above. The M-H 2O and M-H 3 O peaks are
more pronounced for the S-epimer. Loss of a propyl radical in this epimer as above
yields a distinct difference in the intensity of the C 7 HION peak as compared to the
a-epimer. Loss of a methyl group to yield a fragment ion with the composition
C9H 1 6NO is more favorable for the a-epimer. It is important to n-te. however, that
loss of a three carbon fragment in this spectrum in a mechanism analogous to those
shown above to yield an ion of composition C6H8NO is neitht.r a unique nor a dominant
process. This may result from the fact that loss of a hydrogen radical from the
molecular ion followed by loss of CH3 or a single step process of loss of CH:} is
apparently not a favorable process.
The net results of this study may be summarized as follows:
1. M-1 is larger for the epimer with a larger substituent oriented toward
nitrogen.
2. Fragmentation proceeds with loss of the substituent oriented toward
nitrogen to yield a C/H N fragment ion in the S-epimers or a C/11 N O
fragmentation for the a-epimers.
3. Other differences in the C/H N and C/H N O plots may be explained by loss
of an appropriate aliphatic radical from the ions in No. 2 above.
In summary, then, the techniques of high resolution mass spectrometry combined
with heteroatomic plotting for data presentation have made possible elucidation of
important fragmentation processes in the azabicycloalkane series studied; processes
that are entirely dependent on stereochemical influences.
FOOTNOTES
1) This work has been supported in part by a grant from the National Aeronautics and
{	 Space Administration, NsG 101.
2) NASA Predoctoral Trainee, 1965-67.
3) W. M. Bryant, III, A. L. Burlingame, H. O. House, C. G. Pitt, and B. A.
Tefertiller, J. Org . Chem., in press.
4) For detailed discussion of heteroatomic plotting presentation of high resolution
mass spectral data, see A. L. Burlingame and D. H. Smith, Tetrahedron Letters,
in press.
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High resolution mass spectrometry in molecular structure and stereochemical studies - Effect of stereochemistry on the fragmentation of epimeric derivatives of azabicycloalkanes

High resolution mass spectrometry in molecular structure and stereochemical studies - Effect of stereochemistry on the fragmentation of epimeric derivatives of azabicycloalkanes

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