Journal of the American Chemical Society
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(b) 1ꢀ2ꢀ6ꢀ7ꢀ4; (c) 1ꢀ5NHꢀ2ꢀ3′ꢀ3ꢀ4. Black and blue
phase and in the gasꢀphase is quite evident. Nevertheless, we
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bars denote conformers participating in pathꢀL and pathꢀS, respecꢀ
tively.
showed that products resulting from gasꢀphase and solutionꢀphase
synthesis of isoquinoline are identical, but the particular paths to
such products can be very different.
The computed barriers for pathꢀL and pathꢀS for this step is 23
kcal/mol and 25 kcal/mol, respectively. It is worth noting that
there are two other competing routes, 1NHꢀ2ꢀ3′ꢀ3ꢀ4 (Figure
S8l) and 1NHꢀ2NHꢀ3NHꢀ4 (Figure S8o), which are both
indistinguishable from 1ꢀ2ꢀ3′ꢀ3ꢀ4 by m/z. The initial reacꢀ
tant, 1NH, is more stable than 1 by 28 kcal/mol. However, the
barriers for these two routes are much higher (32 kcal/mol and 47
kcal/mol) because of proton transfer coupled dissociation
(1NHꢀ2), and ring closure of the Nꢀprotonated species
(2NHꢀ3NH).
Other routes with relatively low barriers generally form the
isomeric molecules 6/7 (m/z 148.0747). The reactions that form
these species, 2ꢀ6 and 3ꢀ7, have barriers of 34 kcal/mol and 35
kcal/mol, respectively. Figure 4b shows the energy profile of the
energetically most favorable route in this category:
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: xxxxxxxxxxxxxxx
Experimental section, supplementary notes, solutionꢀphase synꢀ
thesis scheme, tandem mass spectra, energy profiles of different
reaction routes, supporting data of the gasꢀphase Combes and
Friedländer quinoline syntheses. Cartesian coordinates for all
intermediates described in the text and SI.
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AUTHOR INFORMATION
Corresponding Author
1
ꢀ2ꢀ6ꢀ7ꢀ4. The rds 2ꢀ6 in Figure 4b has a barrier height of
34 kcal/mol, which exceeds the rds 3ꢀ4 in Figure 4a by 11
kcal/mol. The transformation 7ꢀ4 also requires 6 kcal/mol more
energy than direct formation of 4 from 3. Here we note that routes
involving the formation of the two isomeric molecules,
Author Contributions
#
These two authors contributed equally.
Notes
The authors declare no competing financial interests.
6
NH/7NH, have much higher barriers due to the formation of
energetically unfavorable intermediates (Figure S8, Table S2).
The differences between these routes become more apparent when
looking at 3NHꢀ7NH and 7NHꢀ4, which suffer from large
barrier heights of 54 kcal/mol and 55 kcal/mol, respectively.
Routes involving the formation of 5/5NH by ethylene loss from
1/1NH (Figure S8) were found to have high energy barriers. For
example, 1ꢀ5NH, 1ꢀ5 and 1NHꢀ5NH have increasing barriers
of 31 kcal/mol, 44 kcal/mol, 54 kcal/mol, respectively. Our calcuꢀ
lations predict that the reactions 1ꢀ5 and 1NHꢀ5NH follow a
ACKNOWLEDGMENT
This work was supported by the Air Force Office of Scientific
Research through Basic Research Initiative grant (AFOSR
FA9550ꢀ16ꢀ1ꢀ0113), National Science Foundation under the CCI
Center for Selective CꢀH Functionalization (CHEꢀ1205646), and
Office of Naval Research (N00014ꢀ14ꢀ1ꢀ0590). DMS is grateful
to the NSF for a graduate fellowship.
1
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previously proposed mechanism. In contrast, we found 1ꢀ5NH
follows a new mechanism (Movie S1) where the ethyl group first
detaches from the protonated ethoxy group, and then attaches to
the nearby imine nitrogen, followed by its detachment again to
form a transition state as shown in Figure 4c. To enable this reacꢀ
tion, 1 needs to be in a Z conformer that places the protonated
ethoxy group and the imine nitrogen in close proximity. Figure 4c
shows the energy profile of the energetically most favorable route
in this category: 1ꢀ5NHꢀ2ꢀ3ꢀ3′ꢀ4. The first step (1ꢀ5NH)
is the rds with a barrier of 31 kcal/mol, which is larger than the
suggested energy profiles in Figure 4a by 8 kcal/mol.
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(
1
(
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In summary, we have shown the syntheses of isoquinoline in the
gas phase by collisional activation of the precursor protonated
species, used in the classic solutionꢀphase PomeranzꢀFritsch synꢀ
thesis of isoquinoline. Proton mobility in the gaseous activated
states of the precursor protonated species resulted in the formation
of the product isoquinoline via a number of intermediates, some
of which cannot be formed in solution. Tandem mass spectromeꢀ
try along with isotope labeling identified these intermediates and
products which assisted in revealing the routes responsible for
gasꢀphase synthesis of isoquinoline. In addition, it was shown that
some of these routes differ significantly from their condensedꢀ
phase counterparts. Unlike the corresponding solutionꢀphase reacꢀ
tions (where the reaction conditions are thermalized and catalytic
proton exchange occurs between intermediates and solvent
(
11) Pruesse, T.; Fiedler, A.; Schwarz, H. J. Amer. Chem. Soc.
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(
6
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(
1
(
(Brønsted–Lowry base)), these gasꢀphase reactions occur under
collisionally excited conditions. Here, energy is deposited in the
protonated molecule by multiple collisions with the inert gas (heꢀ
lium) in the ion trap and proton hopping causes new intermediates
to appear. Therefore, the difference in reactivity in the condensedꢀ
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