Effects of the Distance between Radical Sites on the Reactivities of Aromatic Biradicals

Article abstract of DOI:10.1021/acs.joc.0c00658

Coupling of the radical sites in isomeric benzynes is known to hinder their radical reactivity. In order to determine how far apart the radical sites must be for them not to interact, the gas-phase reactivity of several isomeric protonated (iso)quinoline-and acridine-based biradicals was examined. All the (iso)quinolinium-based biradicals were found to react slower than the related monoradicals with similar vertical electron affinities (i.e., similar polar effects). In sharp contrast, the acridinium-based biradicals, most with the radical sites farther apart than in the (iso)quinolinium-based systems, showed greater reactivities than the relevant monoradicals with similar vertical electron affinities. The greater distances between the two radical sites in these biradicals lead to very little or no spin-spin coupling, and no suppression of radical reactivity was observed. Therefore, the radical sites can still interact if they are located on adjacent benzene rings and only after being separated further than that does no coupling occur. The most reactive radical site of each biradical was experimentally determined to be the one predicted to be more reactive based on the monoradical reactivity data. Therefore, the calculated vertical electron affinities of relevant monoradicals can be used to predict which radical site is most reactive in the biradicals.

Full text of DOI:10.1021/acs.joc.0c00658

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Article
Effects of the Distance Between Radical Sites
on the Reactivities of Aromatic Biradicals
Duanchen Ding, Hanning Jiang, Xin Ma, John J. Nash, and Hilkka I. Kenttämaa
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00658 • Publication Date (Web): 01 Jun 2020
Downloaded from pubs.acs.org on June 5, 2020
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Effects of the Distance Between Radical Sites on the
Reactivities of Aromatic Biradicals
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Duanchen Ding, Hanning Jiang, Xin Ma, John J. Nash, and Hilkka I. Kenttämaa*
Department of Chemistry, Purdue University, 560 Oval Drive,
West Lafayette, Indiana, 47907
*
Corresponding author: Professor Hilkka I. Kenttämaa, Email: hilkka@purdue.edu,
Telephone: +1 (765) 494−0882.
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ABSTRACT: Coupling of the radical sites in the isomeric benzynes is known to hinder their radical
reactivity. In order to determine how far apart the radical sites must be for them not to interact, the
gas-phase reactivity of several isomeric protonated (iso)quinoline-and acridine-based biradicals was
examined. All the (iso)quinolinium-based biradicals were found to react slower than related
monoradicals with similar vertical electron affinities (i.e., similar polar effects). In sharp contrast,
the acridinium-based biradicals, most with the radical sites farther apart than in the
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(iso)quinolinium-based systems, showed greater reactivities than the relevant monoradicals with
similar vertical electron affinities. The greater distances between the two radical sites in these
biradicals lead to very little or no spin-spin coupling, and no suppression of radical reactivity was
observed. Therefore, the radical sites can still interact if they are located on adjacent benzene rings
and only after being separated further than that does no coupling occur. The most reactive radical
site of each biradical was experimentally determined to be the one predicted to be more reactive
based on the monoradical reactivity data. Therefore, the calculated vertical electron affinities of
relevant monoradicals can be used to predict which radical site is most reactive in the biradicals.
?
N
H
N
H
N
H
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INTRODUCTION
σ-Type carbon-centered aromatic biradicals, including the three benzynes (ortho-, meta- and
para-) and their analogs, have been studied for decades for their potential applications in various
fields, including organic synthesis and anticancer therapeutics.1-8 Due to the difficulty of cleanly
and simultaneously generating two radical sites that are not adjacent to each other in solution, mass
spectrometers have been used to study numerous gas-phase aromatic biradicals with a chemically
inert charged site.5,7,8 These biradicals are generated from protonated diiodo- or iodonitroprecursors
by using collision-activated dissociation to homolytically cleave off iodo atoms and/or nitro goups.
In most cases, the charged site has been demonstrated to influence reactions like a strongly electron-
withdrawing substituent, without directly participating in the reactions.9
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In previous studies, several factors have been elucidated that control the chemical behavior of
the types of mono- and biradicals described above. For instance, the (calculated) vertical electron
affinity (EA ) of the radical site(s) plays a significant role in controlling the reaction efficiencies of
v
polar mono- and biradicals.5,7,9-11 The reactivities of a series of quinolinium-based monoradicals
1
1
toward cyclohexane and allyl iodide have been reported to increase with increasing EA (Table 1).
v
A relatively high EA helps stabilize a polar resonance structure of the transition state for radical
reactions, which has been proposed to increase reactivity.7,9,12 Specifically, for monoradicals, the
v
natural logarithm of the H atom abstraction reaction efficiency has been reported to linearly correlate
9
with the (calculated) EA . It should be noted here that based on recent literature, a designated local
v
electric field created by charged functional groups can influence reaction rates via field effects and
the alignment of the field parallel to the reacting center causes the greatest effect.13 However,
although monoradicals q2 and q6 have very different orientations between the N-H polar bond and the
radical orbital (aligned for q2 but orthogonal for q6), which suggest that q2 should experience much
stronger field effects, these radicals yield exactly the same products with the same branching ratios and
also react at the same efficiency with both cyclohexane and allyl iodide. These results suggest that the
relative orientation of the most polar bond and the radical orbital does not play a major role in the systems
studied here. This may be due to the delocalization of the charge in these systems as the field effects have
a
b
c
Table 1. Reaction Efficiencies and Observed Reactions With Branching Ratios for
Quinolinium-based Monoradicals Upon Interaction with Cyclohexane and Allyl Iodide, and
d
11
Calculated Vertical Electron Affinities (EA )
v
Monoradicals
N
H
N
H
N
H
N
H
N
H
N
H
q1
q4
q5
q6
q2
q3
EA
v
(eV)
6.30
5.59
5.06
4.74
4.89
5.51
H abs
100%
H abs
100%
H abs
100%
H abs
100%
H abs
100%
H abs
100%
Cyclohexane
Efficiency = 36%
I abs
Allyl abs
Efficiency = 14%
Efficiency = 3%
Efficiency = 1%
I abs
Allyl abs
Efficiency = 1%
Efficiency = 12%
I abs
Allyl abs
85%
15%
I abs
94%
6%
I abs
97%
3%
93%
7%
I abs
Allyl abs
92%
8%
96%
4%
Allyl abs
Allyl abs
Allyl Iodide
Efficiency = 64%
Efficiency = 54%
Efficiency = 38%
Efficiency = 30%
Efficiency = 25%
Efficiency = 56%
a
Percentage of collisions that lead to reaction; k /k (reaction rate constant / calculated collision
exp coll
b
c
rate constant) × 100. abs = abstraction. Branching ratios of primary reactions were determined by
dividing the abundance of the product ion by the sum of the abundances of all product ions.
d
Calculated at the CASPT2/CASSCF(12,11)/cc-pVTZ//UB3LYP/cc-pVTZ level of theory.
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been proposed to be weaker in more delocalized ions. Furthermore, they have also been proposed to be
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weaker for ions with a localized radical site, which applies to the systems discussed here.
Additional parameters control the reactivities of related biradicals. For example, most of the
reported biradicals have singlet ground states.7,11,14 In the transition states of radical reactions of
biradicals, some extra energy (i.e., compared to a monoradical) is required to partially uncouple the
two nonbonding electrons.15 The extra energy required has been proposed to be related to the
magnitude of the singlet-triplet splitting (ΔES-T), which reflects the strength of the spin-spin
coupling between the two radical sites.7,11,14 For example, ortho-benzyne has been measured to
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have a ΔES-T of −37.5 kcal mol (the negative sign indicates a singlet ground state), which indicates
very strong spin-spin coupling that should prevent radical reactivity.4,16 Indeed, a quinolinium-based
ortho-benzyne, the 2-pyridyl cation (see Chart 1), has been reported not to undergo radical
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reactions. In contrast, the 4,5-didehydroisoquinolinium cation (i1; Chart 2), which has a calculated
−
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8,14
ΔES-T of –1.3 kcal mol , shows relatively high radical reactivity. In addition to (or in place of)
N
Chart 1. The 2-pyridyl cation.
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N
N1
H
H
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H
N
H
N
H
N
H
N
H
N
H
N
H
q1
q2
q3
q4
q5
q6
N
H
N
H
N
H
N
N
H
N
H
H
q7
q8
q9
q10
q11
q12
N
N
N
H
N
H
N
N
H
H
H
H
q13
q14
q15
q16
i1
i2
N
N
N
H
N
H
H
H
a1
a2
a3
a4
N
N
N
N
H
H
H
H
a5
a6
a7
a8
Chart 2. Numbering schemes for quinolinium, isoquinolinium, and acridinium systems, and the
mono- and biradicals studied.
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EA and ΔES-T, the reactivities of meta-benzynes have been demonstrated to depend on at least three
v
different reactivity-controlling parameters, i.e., the enthalpy required to distort the minimum energy
dehydrocarbon atom separation to the separation of the transition state and the ΔES-T and EA values
v
at the dehydrocarbon atom separation of the transition state.7
The orientations of the nonbonding orbitals and the distances between them in benzynes have
been shown to affect their spin-spin coupling strength6,18 and thereby their reactivity.4,5 However,
the effects of these parameters on the reactivity of other related biradicals have not been studied. In
an effort to determine how far apart the two radical sites must be for them not to interact at all, a
series of (iso)quinolinium- and acridinium-based biradicals (Chart 1) were generated (from the
precursors shown in Chart 3) and allowed to react with cyclohexane and allyl iodide in the gas phase
in a quadrupole ion trap mass spectrometer. Related monoradicals have been reported to react with
these reagents in the gas phase via simple radical pathways – H or I atom abstraction,
respectively.10,11,14 A kinetic reactivity study was carried out and the results were compared with
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8,11,14
those obtained for related monoradicals and those previously reported
for (iso)quinolinium-
based biradicals. The experiments were complemented by quantum chemical calculations.
NO2
NO2
I
O2N
N
I
N
I
O2N
I
N
I
N
I
N
I
q8a
q9a
q10a
q11a
q12a
I
I
NO2
I
N
I
N
N
N
I
I
q16a
q13a
q14a
q15a
I
I
I
N
N
N
I
N
a1a
a2a
a3a
a4a
I
I
I
I
I
I
I
I
N
N
N
N
a5a
a6a
a7a
a8a
Chart 3. Precursors for quinolinium- and acridinium-based radicals used in this study.
RESULTS AND DISCUSSION
The experimental design that was chosen for the comparison of the relative reactivities of
different biradicals, or more accurately, the relative activation enthalpies (∆H‡act) of reactions of
different biradicals, is as follows. The efficiencies of H or I atom abstraction reactions by charged
biradicals from cyclohexane or allyl iodide, respectively, were determined by multiplying the
measured total reaction efficiencies (number of reactive collisions divided by the number of all
collisions) with the measured branching ratios of the H or I atom abstraction reaction to obtain a
measure of the rate of the radical reaction vs the rate of dissociation back to reactants. These radical
-1
reactions are highly exothermic (for example, -16 kcal mol for abstraction of a H atom by biradical
q13 (Chart 2) at either radical site from cyclohexane, as calculated at the (U)M06-2X//6-
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11++G(d,p) level of theory; the corresponding Gibbs free energy calculated at the same level of
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theory is -18 kcal mol ) and irreversible (see Figure 1 for a schematic of a Brauman double-well
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Figure 1. Brauman double-well potential energy surface for H atom abstraction by a charged
+
●
monoradical ( R ) from a hypothetical H atom donor HX in the gas phase. Two reactions are
depicted, one with a higher ∆H‡act and another one with a lower ∆H‡act (red color).
1
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potential energy surface ). Therefore, the measured relative H and I atom abstraction efficiencies
reflect the relative ∆H‡ of these reactions.
act
(Iso)Quinolinium-based biradicals. The observed reactions and the reaction efficiencies
measured for the (iso)quinolinium-based biradicals upon interactions with cyclohexane and allyl
iodide, along with the calculated EA and ΔE values of the biradicals, are shown in Table 2. The
v
S-T
11
data for the 2,4-didehydroquinolinium cation (q7) have been reported previously (the same results
were obtained in this study). The EA and ΔE values of the 4,6-didehydroquinolinium (q13) and
4,7-didehydroquinolinium (q14) cations have been calculated before.10 In the same study, their
reaction efficiencies with cyclohexane were determined to be 2% and 4%, respectively.10 Quite
v
S-T
different results were obtained in this study (Table 2). The exact reason for this discrepancy is not
known at this time but the values reported here were found to be highly reproducible, which was
not true for the previously reported values.
Similar to the quinolinium-based monoradicals (Table 1), all biradicals reacted via predomi-
nant (primary) H atom abstraction with cyclohexane (followed by abstraction of a second H atom
from a different cyclohexane molecule in a secondary reaction). Additional, mostly slow, reactions
-
that were observed include hydride abstraction from cyclohexane by the biradical (H abs; Table 2),
formation of a stable adduct between the biradical and cyclohexane (addition), and nominal addition
of cyclohexane to the biradical followed by elimination of a H atom (addition-H) (Scheme 1).
hydride
or
abstraction
product
N
H
N
H
N
H
H
H
H
H
-
H
H
N
H
N
H
N
H
H atom abstraction
product
adduct
addition - H
product
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Scheme 1. Different reaction pathways for biradical q7 and cyclohexane.
Upon reactions with allyl iodide, most of the biradicals showed I atom abstraction (followed
by a second I atom abstraction from a different allyl iodide molecule) as the major reaction, which
is consistent with the behavior observed for the monoradicals. The abstraction of two H atoms from
cyclohexane and two I atoms from allyl iodide confirmed the presence of two radical sites for each
biradical.
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Surprisingly, most biradicals showed a larger proportion of allyl group abstraction than the
monoradicals (the same observation was made for the acridinium-based biradicals; see below), and
the meta-benzyne, q7, para-benzyne, q16, and the 2,8-didehydroquinolinium cation, q11, exhibited
dominant allyl group abstraction. This behavior is not characteristic for meta- and para-benzynes
as not all meta- and para-benzynes described in the literature show similar behavior.20,21 It should
also be noted that the ions expected to be q11 may, in fact, be a mixture of isomers. When the
monoradical precursor of this biradical, the 8-dehydro-2-iodoquinolinium cation, is subjected to
CAD to generate the second radical site, the H atom at N−1 may migrate to C−8 to ultimately form
20
an ortho-benzyne isomer of q11. A similar type of rearrangement has been reported for the
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Table 2. Total Reaction Efficiencies, Observed Reactions With Branching Ratios, and H
c
and I Atom Abstraction Efficiencies for Quinolinium-based Biradicals Upon Interaction
e
with Cyclohexane and Allyl Iodide, Together With the Calculated Vertical Electron
Affinities (EA ) and Singlet-Triplet Splittings (ΔES-T) of the Biradicals
v
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Biradicals
N
H
N
H
N
H
N
H
N
H
q11
N
H
q9
q10
q7
q8
q12
6
.21
EA
v
(eV)
6.39
0.3
6.37
6.31
6.38
5.61
-1.1
f
(at DAS 2.3 Å)
ΔES – T
−26.4
ΔE2.3 : 8.5 kcal mol−1
−
−0.7
−2.6
−0.8
−
1
(kcal mol )
g
H abs
° H abs
Addition – H 42%
Addition 8%
50%
H abs 87%
2° H abs
H abs
2° H abs
88%
H abs
2° H abs
Addition
74%
H abs
2° H abs
Addition
71%
10%
H abs
2° H abs
64%
2
Addition
9%
4%
Addition
9%
3%
21%
4%
Addition
28%
8%
−
−
−
−
H abs
H abs
H abs
Addition – H 13%
H abs
Cyclohexane
−
H abs
6%
Efficiency = 0.4%
H abs eff. = 0.2%
Efficiency = 36%
H abs eff. = 31%
URI = 52%
Efficiency = 34%
H abs eff. = 30%
URI = 55%
Efficiency = 30%
H abs eff. = 22%
URI = 66%
I abs
2° I abs
Efficiency = 31%
H abs eff. = 22%
URI = 85%
Efficiency = 9%
H abs eff. = 6%
URI = 78%
h
e
Allyl abs
° I abs
I abs
° allyl abs
83%
I abs
63%
31%
I abs
2° I abs
Allyl abs
2° I abs
64%
55%
Allyl abs
2° I abs
59%
I abs
2° I abs
Allyl abs
Adduct
77%
2
2° I abs
Allyl abs
2° I abs
9%
33%
Allyl abs
2° I abs
36%
Allene abs 21%
I abs 21%
2° I abs
10%
7%
2
Allene abs 8%
2° Allyl abs
Allene abs 7%
Efficiency = 80%
I abs eff. = 50%
URI = 53%
Allene abs 4%
2° Allyl abs
Allene abs 9%
Efficiency = 76%
I abs eff. = 42%
URI = 73%/
Allene abs 3%
Allyl Iodide
Efficiency = 0.9%
I abs eff. = 0.08%
Efficiency = 80%
I abs eff. = 51%
URI = 57%
Efficiency = 63%
I abs eff. = 13%
URI = 86%
Efficiency = 55%
I abs eff. = 42%
URI = 63%
Biradicalsi
N
H
N
H
N
N
N
N
H
q13
H
H
q15
H
q16
i2
q14
i1
EA
v
(eV)
5.67
5.68
5.56
-8.3
5.50
5.70
5.53
-8.1
ΔES – T
(
−
1.1
78%
−0.3
−4.2
-1.3
−
1
kcal mol )
H abs
° H abs
Addition
H abs 85%
2° H abs
Addition
H abs 51%
2° H abs
Addition
H abs 99%
2° H abs
Addition
2 x H abs
H abs 35%
2° H abs
46%
19%
H abs 49%
2° H abs
2 x H abs
Addition
Efficiency = 2%
H abs eff. = 1%
2
16%
5%
12%
3%
32%
7%
1%
30%
21%
−
−
−
Cyclohexane H abs
H abs
H abs
Addition
Efficiency = 13%
H abs eff. = 10%
URI = 52%
Efficiency = 15%
H abs eff. = 13%
URI = 54%
Efficiency = 8%
H abs eff. = 4%
URI = 76%
Efficiency = 1%
H abs eff. = 1%
URI = 47%
Allyl abs
2° I abs
Efficiency = 18%
H abs eff. = 7%
I abs
81%
I abs
2° I abs
79%
I abs
2° I abs
76%
80%
I abs
2° I abs
58%
I abs
2° I abs
92%
2
° I abs
Allyl abs
15%
Allyl abs
2° I abs
17%
Allyl abs
2° I abs
22%
Allene abs 15%
I abs
2° Allyl abs
2° Allyl abs
Allene abs 8%
2
° I abs
5%
Allene abs 42%
Allyl Iodide
Allene abs 4%
Efficiency = 53%
I abs eff. = 43%
URI = 48%
Allene abs 4%
Efficiency = 54%
I abs eff. = 43%
URI = 48%
Allene abs 2%
Efficiency = 42%
I abs eff. = 32%
URI = 83%
Efficiency = 4%
I abs eff. = 0.2%
URI = 92%
Efficiency = 42%
I abs eff. = 24%
Efficiency = 41%
I abs eff. = 38%
a
%
collisions that lead to reaction; k /k (reaction rate constant/calculated collision rate constant)
exp coll
b
c
×
100. abs = abstraction. H and I atom abstraction efficiencies calculated by multiplying the total
reaction efficiency with the branching ratio of H atom abstraction from cyclohexane or I atom abst-
o
raction from allyl iodide. 2 H (or I or allyl) abs implies that this H abs is a secondary reaction of
the product shown just above. The identity of the primary product that produced each secondary
product was deduced from the rate plots prepared for all studied reactions. When not clear, each pri-
d
mary product ion was isolated and its reactions examined. Branching ratios of primary reactions
were determined by dividing the abundance of the product ion by the sum of the abundances of all
e
product ions. ΔE values calculated at the CASPT2/CASSCF(12,12)/cc-pVTZ//UB3LYP/cc-
S-T
pVTZ level of theory; EA values calculated at the CASPT2/CASSCF(13,12)/cc-pVTZ//UB3LYP/
v
f
g
cc-pVTZ level of theory. DAS = dehydrocarbon atom separation. ΔE is defined as the energy
2.3
required for the meta-benzyne to reach the transition state geometry with a DAS of 2.3 Å from the
h
minimum-energy geometry of the (ground) singlet state (ref. 7). URI = unreactive isomer; the
structures of the unreactive isomers are unknown in most cases; the percentage of URI was
i
determined from the rate plots at long reaction times. Data for i1 and i2 from ref. 14.
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analogous 5-iodo-8-dehydroquinolinium monoradical that partially undergoes migration of the H
atom at N−1 to C−8 upon the second CAD step. Elimination of the I atom then results in a mixture
of isomers: the 5,8-didehydroquinolinium cation and its ortho-isomer. This mixture showed major
allyl abstraction instead of I atom abstraction upon reaction with allyl iodide.20
Perhaps not surprisingly, no correlations were found between the reactivities (i.e., reaction
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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3
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5
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5
5
6
0
1
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5
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0
efficiencies) of the biradicals studied here and either their ΔES-T or EA values (individually)
v
(Figures 1, 2 and S1). This was the case when comparing either the total reaction efficiencies for
cyclohexane and allyl iodide, or the reaction efficiencies for H atom abstraction from cyclohexane
7
or I atom abstraction from allyl iodide. Indeed, the radical reactivity of meta-benzynes has been
shown to depend on at least three variables: (1) the energy required to distort the minimum energy
dehydrocarbon atom separation to the separation of the transition state and (2) the ΔES-T and (3) the
EA values at the dehydrocarbon atom separation of the transition state (dehydrocarbon atom
v
separation of 2.3 Å). Only the reactivity of q7 (a meta-benzyne) would be expected to be affected
by distortion energy, but both EA and ΔES-T, and possibly additional factors, should influence the
v
reactivities of all the other biradicals studied here.
Most of the studied biradicals showed lower total reaction efficiencies relative to the
monoradicals with a similar EA . For example, the 4,8-didehydroquinolinium cation (q15) is less
v
reactive toward cyclohexane and allyl iodide (efficiencies = 8% and 42%, respectively; Table 2)
than the related monoradicals, q2 (efficiencies = 14% (cyclohexane) and 54% (allyl iodide)) and q6
(efficiencies = 12% (cyclohexane) and 56% (allyl iodide); Table 1), which have EA values (5.59
v
eV and 5.51 eV, respectively; Table 1) similar to that for q15 (EA : 5.56 eV; Table 2). The reduced
v
reactivity of the (ground) singlet state of biradical q15 is attributed to spin-spin coupling that reduces
the radical reactivity of the (ground) singlet-state biradical compared to analogous
monoradicals.22,23 The extent of this radical reactivity reducing effect was initially proposed to be
related to the magnitude of ΔES-T, and this has since been found to be true in many cases.5,7,22,23 For
example, biradical q12, which was calculated to have a similar EA (5.61 eV) as biradical q15 (5.56
v
-1
eV) but substantially smaller ΔES-T (−1.1 kcal mol ), reacts somewhat faster than q15 (ΔES-T: −8.3
-1
kcal mol ) with both cyclohexane and allyl iodide (efficiencies = 9% vs. 8% (cyclohexane), and 55%
vs. 42% (allyl iodide) for q12 and q15, respectively; Table 2).
There were a few exceptions, though, as some biradicals exhibited greater reactivity toward
allyl iodide than the related monoradicals with a similar EA . For example, the 2,7-
v
−
1
didehydroquinolinium cation (q10), with a ΔES-T of −2.6 kcal mol , was expected to be less reactive
1
1
toward allyl iodide than the related monoradical q1, which has an almost identical calculated EA
v
(6.30 eV) as the biradical q10 (6.31 eV). However, biradical q10 was found to be more reactive
toward allyl iodide (total reaction efficiency = 76%) than q1 (total reaction efficiency = 64%; Table
2). This is likely due to the existence of another relatively fast reaction pathway for the biradical,
abstraction of an allyl group, which occurs at a higher rate (36% branching ratio) than for the
monoradical (15% branching ratio). In fact, almost all biradicals showed a smaller branching ratio
for I atom abstraction and a greater branching ratio for allyl group abstraction from allyl iodide than
the relevant monoradicals. This was especially notable for those biradicals that have a radical site
at C−2 (Table 2). This finding suggests that allyl iodide may coordinate with these specific biradicals
by forming a hydrogen bond between the iodine atom and the proton bound to the N atom, which
would hinder I atom abstraction but facilitate allyl abstraction by the adjacent radical site. A similar
finding was made for the related monoradicals: the monoradical that most efficiently abstracts an
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allyl group is the only one (q1) with the radical site next to the protonated nitrogen atom (Table 1).
It should also be noted here that allyl abstraction involves addition of a (bi)radical to the C=C double
bond in allyl iodide, which is a fundamentally different reaction from I atom abstraction. It is
possible that spin-spin coupling in biradicals hinders this reaction less than atom abstraction
reactions. We are exploring this issue further.
0
1
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9
0
In order to examine the efficiencies of specific reactions (i.e., H atom and I atom abstractions),
the H and I atom abstraction efficiencies (total efficiency × branching ratio of atom abstraction) for
cyclohexane and allyl iodide were plotted as a function of the (calculated) EA for a series of
v
(iso)quinolinium-based mono- and biradicals (Figures 1 and 2; note that only those biradicals that
underwent major I atom abstraction were included in the I atom abstraction plot).11,14 The
monoradicals showed a linear correlation for both reactions (Figures 1 and 2; note that
corresponding plots of the natural logarithm of the H or I atom abstraction efficiency versus EAv
(data not shown) gave fits almost as good). While a correlation between the natural logarithm of H
9
atom abstraction efficiency and EA for related monoradicals has been published previously, no
v
correlations have been reported for I atom abstraction reactions of radicals similar to those described
here.
Finally, it is noteworthy that all of the (iso)quinolinium-based biradicals lie below the trend
lines fit for the monoradicals (Figures 1 and 2). Based on the fact that the calculated EA values of
v
all the biradicals are higher than those for the corresponding monoradicals, the biradicals might be
expected to be more reactive than the monoradicals. However, it appears that spin-spin coupling
between the two radical sites may be responsible for the lower observed reactivity of the biradicals.
Figure 1. The efficiency of H atom abstraction from cyclohexane by (iso)quinolinium-based mono-
1
1
14
14
and biradicals versus the (calculated) EA of the radical site(s). The data for q1 – q7, i1, and i2
v
1
0
have been reported previously. The EA of q13 and q14 have been calculated previously. The data
v
2
for the monoradicals (only; red boxes) were fit to a linear trend line (R = 0.95).
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Figure 2. The efficiency of I atom abstraction from allyl iodide versus the (calculated) EA of the
v
radical site(s) for those (iso)quinolinium-based mono- and biradicals that underwent a major I atom
1
1
14
14
abstraction. The data for q1 – q7, i1, and i2 have been reported previously. The EA of q13
v
and q14 have been calculated previously.10 16 The data for the monoradicals (only; red boxes) were
2
fit to a linear trend line (R = 0.76).
Acridinium-based radicals. Because all of the (iso)quinolinium-based biradicals showed
stabilizing interactions between the two radical sites that lowered their reactivities compared to the
analogous monoradicals (Figures 1 and 2), several acridinium-based mono- and biradicals (a1–a8)
were studied as they allow greater distances between the radical sites and, therefore, should have
little to no spin-spin coupling (Table 3). Just like the quinolinium-based monoradicals, the acridi-
nium-based monoradicals a1–a4 exclusively undergo H atom abstraction from cyclohexane and
predominant I atom abstraction from allyl iodide. Also like the quinolinium-based monoradicals,
the H and I atom abstraction efficiencies measured for the acridinium-based monoradicals were
found to be linearly correlated with their (calculated) EA (Figures 3 and 4).
v
Surprisingly, however, the reactivities of monoradicals a1–a4 (Table 3) were found generally
to be slightly lower than those for the related quinolinium-based monoradicals q2–q5 (Table 1)
despite their nearly identical EA . For example, the 9-dehydroacridinium cation (a1; EA : 5.63 eV)
v
v
reacts with cyclohexane and allyl iodide at efficiencies of 4% and 40%, respectively, while the
related quinolinium-based monoradical, the 4-dehydroquinolinium cation (q2; EA : 5.59 eV),
v
showed total reaction efficiencies of 14% toward cyclohexane and 54% toward allyl iodide. The
reasons for this behavior are not obvious.
The acridinium-based biradicals a5–a8 predominantly underwent either one or two H atom
abstractions as the primary reactions with cyclohexane and predominant I atom abstraction with
allyl iodide (followed by a second I atom abstraction from another allyl iodide molecule; Table 3).
The abstraction of two H atoms from cyclohexane and two I atoms from allyl iodide confirmed the
presence of two radical sites for each biradical.
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a
b
c
Table 3. Total Reaction Efficiencies and Observed Reactions With Branching Ratios, and
d
H Atom and I Atom Abstraction Efficiencies for Acridinium-Based Mono- and Biradicals
e
Upon Interaction With Cyclohexane and Allyl Iodide, and Calculated Vertical Electron
Affinities (EA ) and Singlet-Triplet splittings (ΔES-T)
v
N
H
N
H
a4
0
1
2
3
4
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7
8
9
0
1
2
3
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Monoradicals
N
H
a1
N
H
a2
a3
EA
v
(eV)
5.63
5.06
H abs 100%
4.74
4.90
H abs
100%
H abs
100%
H abs
100%
Cyclohexane
Efficiency = 4%
Efficiency = 0.8%
Efficiency = 0.3%
I abs
Allyl abs
Efficiency = 0.4%
I abs
Allyl abs
97%
3%
I abs
Allyl abs
98%
2%
94%
6%
I abs
Allyl abs
93%
7%
Allyl Iodide
Efficiency = 40%
I abs eff. = 39%
Efficiency = 33%
I abs eff. = 32%
Efficiency = 27%
I abs eff. = 25%
Efficiency = 29%
I abs eff. = 27%
N
H
N
H
a8
Biradicals
N
H
N
H
a6
a7
a5
EA
ΔES–T
(kcal mol )
v
(eV)
5.76
5.18
5.07
0.0
5.05
+0.1
−
0.6
−0.1
−
1
H abs
2
Adduct
72%
20%
8%
H abs
62%
32%
6%
H abs
2 x H abs
Adduct
79%
18%
3%
H abs
78%
16%
5%
x H abs
2 x H abs
Adduct
2 x H abs
Adduct
Cyclohexane
Efficiency = 9%
H abs eff. = 7%
Efficiency = 3%
H abs eff. = 1.9%
URI = 48%
Efficiency = 2%
H abs eff. = 1.6%
URI = 37%
I abs
2° I abs
Efficiency = 2%
H eff. = 1.6%
URI = 45%
f
URI = 71%
I abs
81%
19%
I abs
2° I abs
78%
79%
I abs
2° I abs
82%
2
° I abs
Allyl abs
2° I abs
Allyl abs
2° I abs
22%
Allyl abs
2° I abs
21%
Allyl abs
2° I abs
18%
Allyl Iodide
Efficiency = 43%
I abs eff. = 35%
URI = 75%
Efficiency = 35%,
I abs eff = 27%
URI = 16%
Efficiency = 37%
I abs eff. = 29%
URI = 11%
Efficiency = 34%
I abs eff. = 28%
URI = 16%
a
Percentage of collisions that lead to reaction; k /k (reaction rate constant / calculated collision
exp coll
b
o
rate constant) × 100. abs = abstraction. 2 H (or I or allyl) abs implies that this H abs is a secondary
reaction of the product shown just above. The identity of the primary product that produced each
secondary product was deduced from the rate plots prepared for all studied reactions. When not clear,
each primary product ion was isolated and its reactions examined. Branching ratios of primary
reactions were determined by dividing the abundance of the product ion by the sum of the
abundances of all product ions. H and I atom abstraction efficiencies calculated by multiplying the
total reaction efficiency with the branching ratio of H atom abstraction from cyclohexane or I atom
abstraction from allyl iodide. EA values calculated at the UB3LYP/aug-cc-pVTZ//UB3LYP/cc-
pVTZ level of theory; ΔE values calculated at the UB3LYP/cc-pVTZ//UB3LYP/cc-pVTZ level
c
d
e
v
S-T
f
of theory. URI = unreactive isomer; the structures of the unreactive isomers are unknown in most
cases; the percentage of URI was determined from rate plots.
Benzannelation of the quinolinium-based biradical q13 to give the acridinium-based biradical,
a5 (the only acridinium-based biradical studied where the positioning of the two radical sites is
analogous to any of the (iso)quinolinium-based biradicals), resulted in a slight decrease in the
magnitude of the singlet-triplet splitting (q13 and a5 have calculated ΔES-T values of –1.1 and –0.6
-1
kcal mol , respectively; Tables 2 and 3), a slight increase in (calculated) EA (5.67 and 5.76 eV,
v
respectively), and a slight decrease in the total reaction efficiencies (cyclohexane = 13% and 9%,
respectively; allyl iodide = 53% and 43%, respectively). However, the three acridinium-based
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Figure 3. The efficiency of H atom abstraction from cyclohexane by acridinium-based mono- and
biradicals versus the (calculated) EA of the radical site(s). The data for the monoradicals (only; red
v
2
boxes) were fit to a linear trend line (R = 0.92).
4
0
Monoradicals
Biradicals
N
H
a1
38
36
N
H
34
a2
3
2
N
N
H
a5
H
a4
30
N
28
N
H
a7
H
a3
26
2
N
H
R = 0.97
N
24
H
a8
a6
4.6
4.8
5.0
5.2
5.4
5.6
5.8
Calculated Vertical Electron Affinity (eV)
Figure 4. The efficiency of I atom abstraction from allyl iodide by acridinium-based mono- and
biradicals versus the (calculated) EA of the radical site(s). The data for the monoradicals (only; red
v
2
boxes) were fit to a linear trend line (R = 0.97).
biradicals with greater separations between their radical sites have smaller ΔES-T (ranging from –
-1
0.1 to +0.1 kcal mol ; Table 3), smaller EA (5.05–5.18 eV) and lower reactivity (for cyclohexane,
v
2
–3% total reaction efficiency) than 10 of the 12 (iso)quinolinium-based biradicals studied. The
smaller ΔES-T and EA values are due to a greater distance between the radical sites, and between
v
the radical sites and the protonated nitrogen atom, respectively. For biradicals a6–a8, therefore, it
appears that the lowering of EA is primarily responsible for their lower reactivity (i.e., compared
v
to the (iso)quinolinium-based biradicals) since lowering of ΔES-T (less spin–spin coupling) would
be expected to lead to higher reactivity.
As the number of carbon-carbon bonds between the two radical sites increases in the
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acridinium-based biradicals from a5 to a8 (3, 5, 6 and 7 bonds, respectively), the calculated ΔES-T
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was found to systematically become more positive (−0.6, –0.1, 0.0and +0.1 kcal mol , respectively;
Table 3). Such a correlation does not exist for the (iso)quinolinium-based biradicals, which is likely
due to the very different nonbonding orbital orientations in these systems, which strongly influence4-
6
spin–spin coupling. It is also noteworthy that the orientation of the nonbonding orbitals in biradical
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a7 might, in fact, be expected to lead to relatively weak through-bond spin-spin coupling (via a
-1
“
W”-type arrangement like that in q10); however, the calculated ΔES-T (0.0 kcal mol ) suggests that
the distance between the two radical sites is too large for any significant spin-spin interaction (at
least at the DFT level of theory used here to calculate ΔES-T). Thus, based on the ΔES-T values, most
of the acridinium-based biradicals should behave like they contain two isolated radical sites, which
should result in equal or greater reactivity than for the monoradicals with a similar EA . Indeed, the
v
total reaction efficiencies of a7 and a8 for cyclohexane (both 2%; Table 3) are greater than that of
monoradical a2 (efficiency 0.8%) with a similar EA (5.06 eV) as a7 and a8 (5.07 and 5.05 eV,
v
respectively). Total reaction efficiencies for allyl iodide are similar or slightly greater than that of
the monoradical a2 (a7, a8 and a2: total reaction efficiencies are 37%, 34% and 33%, respectively).
On the other hand, although the magnitude of ΔES-T for biradical a5 is calculated to be the largest
-1
among the acridinium-based biradicals (–0.6 kcal mol ), it showed the highest reactivity toward
both cyclohexane and allyl iodide (Table 3). This can be attributed to its relatively high EA (5.76
v
eV; EA of the other biradicals range from 5.05 eV to 5.18 eV).
v
In order to examine the efficiencies of specific reactions, the efficiency of H atom abstraction
from cyclohexane was plotted as a function of the (calculated) EA for all the acridinium-based
v
mono- and biradicals (Figure 3). In this plot, the data for the biradicals (a5–a8) lie above the
monoradical trend line (Figure 3) as opposed to below it as observed for the related
(iso)quinolinium-based biradicals (Figure 1). This suggests somewhat greater reactivities for the
acridinium-based biradicals than the related monoradicals, which is likely due to the very weak, to
absent, spin-spin coupling between the radical sites in a5–a8. Therefore, when the radical sites are
located on benzene rings that are not adjacent to each other, they do not appear to interact. A
different result was obtained for I atom abstraction from allyl iodide. In the plot (Figure 4), the data
for the acridinium-based biradicals lie below the monoradical trend line. The reasons for this
difference are not known at this time.
Identification of the most reactive radical site in the biradicals. Among all the previously
reported biradicals of the type discussed here, the radical site that reacts first has only been
experimentally identified for one biradical, the 4,5-didehydroisoquinolinium cation (i1), that first
8
abstracts a H atom from cyclohexane at the radical site C−4. In order to identify the radical site that
reacts first for the other studied biradicals, the products of the quinolinium-based biradicals q7 –
q16 formed upon abstraction of a H atom from cyclohexane (MS/MS experiments) were isolated in
the ion trap and allowed to undergo further reactions for 300 ms with cyclohexane (MS/MS/MS
experiments). The MS/MS/MS spectra were compared with MS/MS spectra measured for authentic,
isomeric monoradicals collected on the same instrument on the same day (Figure 5) in order to
identify the structures of the unknown monoradicals. For all biradicals containing a radical site at
C−2 (q7 - q11), this site was found to react first as none of the unknown monoradical products
showed the same relative abundances of ions m/z 129 and m/z 130 as authentic 2-
dehydroquinolinium cation (q1). Moreover, each of the MS/MS/MS spectra measured for the
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Figure 5. (a–j) MS/MS/MS spectra measured after 300 ms reaction with cyclohexane for the
isolated H abstraction products (m/z 129) of quinolinium-based biradicals, q7–q16; (k–p) MS/MS
spectra measured after 300 ms reaction with cyclohexane for the isolated, authentic monoradicals,
q1–q6. The major product is the H atom abstraction product (m/z 130). The ions of m/z 161, 147,
1
33, and 105 are assigned as background oxygen adduct, background water adduct, oxygen adduct
that has lost CO, and oxygen adduct that has lost two molecules of CO, respectively. In this case,
then, both of the C−4 and C−8 radical sites in q15 may undergo the first H atom abstraction. In
summary, the radical site that reacts first for each biradical is the one predicted to be more reactive
based on the reactivities of the authentic monoradicals (whose reactivities correlate with their EAv).
The ratios of the peaks m/z 129 and m/z 130 are provided in the bottom left part of each mass
spectrum.
unknown monoradicals was similar to the MS/MS spectrum measured for the expected authentic
monoradical, thus confirming that the radical site at C−2 reacted first and that the resulting
monoradical had the expected structure (e.g., the MS/MS/MS spectrum measured for the
monoradical reaction product of q7 (with radical sites at C−2 and C−4) is similar to that measured
for q2 (C−4 radical site)). For q16 (with radical sites at C−5 and C−8), the radical site at C−8 is
more reactive, again as expected based on the monoradical reactivities (Table 1).
Similarly, the biradicals with a radical site at C−4 (q12–q14) reacted first at the C−4 radical
site with cyclohexane (Figure 5). These results are consistent with the results previously reported
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for the 4,5-didehydroisoquinolinium cation (i1; see above). However, the 4- and 8-
dehydroquinolinium cations (q2 and q6) have very similar reactivity toward cyclohexane (and allyl
iodide; Table 1). The MS/MS/MS spectrum measured for the H atom abstraction product of the 4,8-
didehydroquinolinium cation (q15, Figure 5i) resembles both of those measured for q2 and q6.
The radical site that reacts first for the acridinium-based biradical, a5, was identified
experimentally as described above for the quinolinium-based biradicals. As shown in Figure 6, the
H atom abstraction product of a5 formed upon reaction with cyclohexane showed relatively low
reactivity, which is similar to the behavior of the related monoradical, a3. This result indicates that
the first H abstraction occurs at the radical site at C−9 of a5, which is consistent with the
observations described above for the quinolinium-based systems for which the radical site predicted
to be more reactive based on related monoradical reactivities reacts first. Unfortunately, similar
experiments for biradicals a6–a8 were inconclusive because the related monoradicals a2–a4 display
similar and low reactivity toward cyclohexane.
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170
180
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m/z
200
220
Figure 6. (a) MS/MS/MS spectrum measured after 500 ms reaction with cyclohexane for the H atom
abstraction product of a5 (m/z 179); (b, c) MS/MS spectra measured for the authentic monoradicals a1
and a3, respectively. The product ions arise from H atom abstraction (m/z 180), background oxygen
addition (m/z 211) and background oxygen addition followed by elimination of carbon monoxide (m/z
1
83). Note that the virtually identical spectra, (a) and (c), indicate that the H atom abstraction product of
a5 is a3.
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CONCLUSIONS
A linear correlation was identified for all studied monoradicals for the H atom and I atom
abstraction efficiencies from cyclohexane and allyl iodide, respectively, as a function of the
(
calculated) EA of the monoradicals. As opposed to H atom abstraction efficiency, I atom
v
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abstraction efficiency has not been previously correlated with any reactivity-controlling factor for
related radical systems. The acridinium-based monoradicals were found to be slightly less reactive
than the related (iso)quinolinium-based monoradicals in spite of similar EA values.
v
The reactivities of the (iso)quinolinium-based biradicals were found not to correlate
individually with either their ΔES–T or EA . values, as they are likely to depend on both and possibly
v
also on other yet unidentified variables. However, plots of the efficiencies of H and I atom
abstraction from cyclohexane and allyl iodide, respectively, as a function of the (calculated) EAv
for the various (iso)quinolinium-based mono- and biradicals showed that all of the biradicals lie
below the trend line for the monoradicals, hence showing lower reactivity than the monoradicals.
In sharp contrast, the acridinium-based biradicals displayed slightly greater reactivity toward
cyclohexane than the related monoradicals. Therefore, when the two radical sites in these biradicals
are farther apart than in the same or in two adjacent aromatic rings (with one exception), the radical
sites appear not to interact and, as a result, no suppression of radical reactivity was observed. Indeed,
based on the (very small) calculated ΔES-T values, most of the acridinium-based biradicals should
behave like they contain two individual monoradicals. Moreover, a plot of the efficiencies of H
atom abstraction from cyclohexane as a function of the (calculated) EA for the acridinium-based
v
mono- and biradicals revealed slightly greater reactivity for the biradicals. However, the acridinium-
based biradicals did not show greater reactivity than the relevant monoradicals in I atom abstraction
reactions, possibly due to competing reactions that were not accounted for.
Most of the acridinium-based biradicals have greater separations between their radical sites
than the (iso)quinolinium-based biradicals, and they all have smaller ΔES-T and smaller EA values
v
due to the greater distance between the radical sites, and between both radical sites and the
protonated nitrogen atom. The reduction of both of these reactivity-controlling factors explains the
generally lower total reaction efficiencies compared to the (iso)quinolinium-based biradicals.
For each biradical examined, the radical site that reacts first was found to be the same site that
is predicted to be more reactive based on the reactivities of authentic monoradicals. Because the
reactivity of the monoradicals reflects their (calculated) EA values, calculation of the EA values
v
v
for the relevant monoradicals enables the prediction of the more reactive radical site in such
biradicals.
EXPERIMENTAL SECTION
Quinolinium-based monoradicals q1–q6, biradical q7, and isoquinolinium-based biradicals i1
and i2 have been studied previously.11,14 The precursors (Chart 3) for quinolinium-based radicals
q1–q9, q12–q14, and q16 were synthesized as described in the literature.10,24 Precursors for
quinolinium-based biradicals q10, q11 and q15 and acridinium-based monoradicals a1–a8 were
synthesized as described below. All other chemicals were purchased from Sigma-Aldrich and used
without further purification.
The reactivity and kinetic studies were performed using a previously reported approach.10,11
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Briefly, radical precursors were protonated using an atmospheric pressure chemical ionization
(APCI) source of a linear quadrupole ion trap (LQIT) mass spectrometer coupled with a reagent
2
5
inlet manifold described previously. The ions were transferred into the ion trap. The desired ions
were isolated by ejecting all the unwanted ions from the trap. Collision-activated dissociation (CAD)
was used to cleave off iodine atom(s) and/or a nitro group from the protonated (bi)radical precursors
to generate the desired radical site(s). The protonated radicals were isolated and allowed to react
with the neutral reagent for a variable period of time before all ions were ejected from the ion trap
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and detected. The reagent was injected into the heated manifold at a flow rate of 5 μL h . The
evaporated reagent was mixed with helium buffer gas and introduced into the ion trap.10
Kinetic data for the reactions were collected to identify the primary and secondary reaction
products and to determine second-order reaction rate constants. The measured second-order reaction
rate constants (see Supporting Information) were divided by calculated collision rate constants
(k /kcoll; see Supporting Information) to give reaction efficiencies (i.e., the percentage of collisions
exp
leading to a reaction). The collision rate constants were calculated using a parameterized trajectory
theory.26
1
13
Syntheses (all synthesis schemes and H and C NMR spectra are provided in SI)
2
-Iodo-7-nitroquinoline (q10a). 2-Chloro-7-nitroquinoline (30 mg, 0.14 mmol) was
dissolved in anhydrous acetonitrile. Acetyl chloride (31 mg, 0.39 mmol) and anhydrous sodium
iodide (180 mg, 1.20 mmol) were added into the solution. The solution was refluxed in an oil bath
for 24 h under argon. After cooling to room temperature, the solution was diluted with
dichloromethane and washed with sodium carbonate and sodium sulfite, consecutively. The solvent
was removed under low pressure. 3 mg of the residue was purified through a reversed phase C18
preparative HPLC column (50:50 water/acetonitrile to 5:95 water/acetonitrile) to yield a white solid
1
product. H NMR (800 MHz, chloroform-d) δ 8.98 (s, 1H), 8.37 (d, J = 8.9 Hz, 1H), 7.98 (d, J =
13
1
8
.9 Hz, 1H), 7.94 (d, J = 8.5 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H). C{ H} NMR (201 MHz, CDCl )
3
δ 148.4, 148.3, 136.5, 135.0, 130.2, 129.5, 125.0, 121.7, 120.8. HRMS (APCI), calcd. for
+
C H N O I: 300.9474 [M+H] , found: 300.9451.
9
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2
2
2
-Chloro-8-nitroquinoline (s1). 1 mL of concentrated nitric acid and 4 mL of concentrated
sulfuric acid were mixed, and 645 mg of 2-chloroquinoline (3.92 mmol, purchased from Sigma-
Aldrich), was added. The solution was stirred under room temperature for 12 h, then poured on ice
and neutralized with 33% ammonium hydroxide solution until a pH of 7. The precipitated solid was
filtered and purified by silica column chromatography (5:95 ethyl acetate/hexanes) to yield 2-
chloro-5-nitroquinoline (226 mg, 28%) and 2-chloro-8-nitroquinoline (378 mg, 46%) as light
1
yellow solid. H NMR (400 MHz, chloroform-d) δ 8.20 (d, J = 8.6 Hz, 1H), 8.09 (dd, J = 7.6, 1.4
Hz, 1H), 8.04 (dd, J = 8.3, 1.4 Hz, 1H), 7.64 (dd, J = 8.2, 7.6 Hz, 1H), 7.54 (d, J = 8.6 Hz, 1H). The
1H NMR is consistent with literature.27
8
-Amino-2-chloroquinoline (s2). 2-Chloro-8-nitroquinoline (300 mg, 1.44 mmol) and iron
powder (252 mg, 4.46 mmol) were mixed in 4.5 mL of methanol and cooled to 0 °C. While stirring,
1.5 mL of concentrated hydrochloric acid was added dropwise. The solution was allowed to warm
to room temperature and stirred for 5 min, then neutralized with sodium carbonate until pH of 9.
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The mixture was extracted with dichloromethane (three times, 20 mL each) and dried with
anhydrous sodium sulfate. A silica column pretreated with 1% triethylamine hexanes solution was
used to purify the product (1:9 ethyl acetate/hexanes). The product was a yellow solid (143 mg,
1
5
6%). H NMR (400 MHz, chloroform-d) δ 8.00 (d, J = 8.6 Hz, 1H), 7.36 – 7.31 (m, 2H), 7.13 (dd,
1
3
1
J = 8.1, 1.3 Hz, 1H), 6.94 (dd, J = 7.6, 1.3 Hz, 1H), 4.88 (s, 2H). C{ H} NMR (101 MHz, CDCl )
3
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δ 147.9, 143.1, 138.9, 137.6, 127.7, 127.4, 122.3, 115.6, 111.2. HRMS (APCI), calcd. for C H N Cl:
9
8
2
+
1
79.0376 [M+H] , found: 179.0361, 181.0332.
2
-Chloro-8-iodoquinoline (s3). 8-Amino-2-chloroquinoline (129 mg, 0.72 mmol) was
dissolved in a mixture of 3 N hydrochloric acid (5 mL) and methanol (5 mL) and cooled to 0 °C.
Into this solution, 1.3 mL of sodium nitrite solution (172 mg, 2.50 mmol) was slowly added. The
reaction was stirred at 0 °C for 10 min. 174 mg of copper(I) iodide dispersed in 2.2 mL of water
was added into the solution, followed by addition of 1.1 mL of 57% hydroiodic acid. After 5 min,
the reaction mixture was poured onto ice and neutralized with sodium carbonate. The solution was
extracted by dichloromethane (three times, 20 mL each) and dried with anhydrous sodium sulfate.
A silica column pretreated with 1% triethylamine hexanes solution was used to purify the product
1
(
1:9 ethyl acetate/hexanes). The product was a pale white solid (80 mg, 40%). H NMR (400 MHz,
chloroform-d) δ 8.33 (dd, J = 7.4, 1.3 Hz, 1H), 8.04 (d, J = 8.5 Hz, 1H), 7.79 (dd, J = 8.1, 1.3 Hz,
1
3
1
1
H), 7.40 (d, J = 8.5 Hz, 1H), 7.27 (dd, J = 8.1, 7.4 Hz, 1H). C{ H} NMR (101 MHz, CDCl ) δ
3
151.9, 147.1, 141.0, 139.4, 128.3, 128.0, 127.3, 123.4, 101.4. HRMS (APCI), calcd. for C H NICl:
9
6
+
2
89.9234 [M+H] , found: 289.9211, 291.9186.
2,8-Diiodoquinoline (q11a). 2-Chloro-8-iodoquinoline (80 mg, 0.28 mmol), anhydrous
sodium iodide (428 mg, 2.85 mmol) and copper(I) iodide (5 mg, 0.026 mmol) were charged in a
Schlenk tube. The tube was subjected to vacuum and refilled with argon three times. 0.6 mL of 1,4-
dioxane containing 8 mg of N,N’-dimethyl-1,2-cyclohexanediamine (0.056 mmol) was added into
the Schlenk tube and sealed. The solution was stirred in an oil bath at 110 °C. After three days, the
solution was cooled to room temperature, quenched with 1 mL of 33% ammonium hydroxide and
extracted with dichloromethane (three times, 2 mL each). The solution was dried with anhydrous
sodium sulfate and purified using a silica column pretreated with 1% triethylamine hexanes solution
(1:9 ethyl acetate/hexanes). The product was then recrystallized in a mixture of dichloromethane
1
and hexanes, yielding as white solid (16 mg, 15%). H NMR (400 MHz, chloroform-d) δ 8.32 (dd,
1
3
1
J = 7.4, 1.2 Hz, 1H), 7.77 – 7.73 (m, 2H), 7.67 (d, J = 8.4 Hz, 1H), 7.29 – 7.24 (m, 1H). C{ H}
NMR (101 MHz, CDCl ) δ 148.6, 140.5, 137.3, 133.1, 128.6, 128.1, 127.6, 120.1, 102.1. HRMS
3
+
(
APCI), calcd. for C H NI : 381.8590 [M+H] , found: 381.8567.
9
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2
4
-Chloro-8-nitroquinoline (s4). 3 mL of concentrated nitric acid and 12 mL of concentrated
sulfuric acid were mixed, and 1.00 g of 4-chloroquinoline (6.11 mmol, purchased from Sigma-
Aldrich), was added. The solution was stirred under room temperature for 1 h, then poured onto ice
and neutralized with 33% ammonium hydroxide solution until at pH of 7. The precipitated solid
was filtered and purified by flash column chromatography (1:9 ethyl acetate/hexanes) to yield 4-
chloro-5-nitroquinoline (216 mg, 17%) and 4-chloro-8-nitroquinoline (774 mg, 61%) as white
1
solids. H NMR (400 MHz, chloroform-d) δ 8.93 (d, J = 4.7 Hz, 1H), 8.47 (dd, J = 8.5, 1.4 Hz, 1H),
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.07 (dd, J = 7.5, 1.4 Hz, 1H), 7.73 (dd, J = 8.6, 7.5 Hz, 1H), 7.65 (d, J = 4.7 Hz, 1H). The H NMR
is consistent with literature.28
8
-Amino-4-chloroquinoline (s5). 4-Chloro-8-nitroquinoline (270 mg, 1.29 mmol) and iron
powder (217 mg, 3.84 mmol) were mixed in 4 mL of methanol and cooled to 0 °C. While stirring,
1.5 mL of concentrated hydrochloric acid was added dropwise. The solution was allowed to warm
to room temperature and stirred for 1 h, then neutralized with sodium carbonate until at pH of 9.
The mixture was extracted with dichloromethane (three times, 20 mL each) and dried with
anhydrous sodium sulfate. A silica column pretreated with 1% triethylamine hexanes solution was
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used to purify the product (1:9 ethyl acetate/hexanes). The product was a yellow solid (212 mg,
1
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2%). H NMR (400 MHz, chloroform-d) δ 8.60 (d, J = 4.6 Hz, 1H), 7.52 (dd, J = 8.4, 1.3 Hz, 1H),
.46 (d, J = 4.6 Hz, 1H), 7.41 (dd, J = 8.4, 7.5 Hz, 1H), 6.97 (dd, J = 7.5, 1.3 Hz, 1H), 5.03 (s, 2H).36
7
1
3
1
C{ H} NMR (101 MHz, CDCl ) δ 146.4, 144.2, 142.4, 139.0, 128.3, 127.0, 121.5, 112.1, 110.7.
3
+
HRMS (APCI), calcd. for C H N Cl: 179.0376 [M+H] , found: 179.0365, 181.0337.
9
8
2
4-Chloro-8-iodoquinoline (s6). 8-Amino-2-chloroquinoline (212 mg, 1.19 mmol) was
dissolved in 5 mL of 3 N hydrochloric acid and cooled to 0 °C. Into this solution, 123 mg sodium
nitrite (1.78 mmol) in 1 mL water was slowly added. The reaction was stirred at 0 °C for 10 min.
2
72 mg of copper(I) iodide (1.42 mmol) dispersed in 2 mL of water was added into the reaction
mixture followed by addition of 1.5 mL of 57% hydroiodic acid. After 5 min, the reaction mixture
was poured onto ice and neutralized with sodium carbonate. The solution was extracted by
dichloromethane (three times, 20 mL each) and dried with anhydrous sodium sulfate. A silica
column pretreated with 1% triethylamine hexanes solution was used to purify the product (1:9 ethyl
1
acetate/hexanes). The product was a pale white solid (130 mg, 39%). H NMR (800 MHz,
chloroform-d) δ 8.91 (d, J = 4.7 Hz, 1H), 8.43 (d, J = 7.8 Hz, 1H), 8.28 (d, J = 7.8 Hz, 1H), 7.59 (d,
1
3
1
J = 4.7 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H). C{ H} NMR (201 MHz, CDCl ) δ 150.6, 147.9, 143.0,
3
+
1
41.2, 128.7, 127.0, 125.2, 122.0, 103.6. HRMS (APCI), calcd. for C H NICl: 289.9234 [M+H] ,
9 6
found: 289.9210, 291.9183.
4,8-Diiodoquinoline (q15a). 4-Chloro-8-iodoquinoline (100 mg, 0.36 mmol) was dissolved in
anhydrous acetonitrile. Acetyl chloride (84 mg, 1.13 mmol) and anhydrous sodium iodide (535 mg,
3
.57 mmol) were added into the solution. The solution was refluxed in an oil bath for 24 h under
argon. After cooling to room temperature, the solution was diluted with dichloromethane and
washed with sodium carbonate and sodium sulfite consecutively. The solvent was removed under
low pressure. The residue was purified with a silica flash column (1:9 ethyl acetate/hexanes) to give
1
a white solid product (106 mg, 77%). H NMR (400 MHz, chloroform-d) δ 8.54 (d, J = 4.5 Hz, 1H),
13
1
8
.38 (dd, J = 7.4, 1.3 Hz, 1H), 8.07 – 8.00 (m, 2H), 7.33 (dd, J = 8.4, 7.4 Hz, 1H). C{ H} NMR
(
101 MHz, CDCl ) δ 150.5, 146.6, 141.1, 133.5, 133.0, 130.6, 129.0, 112.0, 103.6. HRMS (APCI),
3
+
calcd. for C H NI : 381.8590 [M+H] , found: 381.8572.
9
6
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General procedure to synthesize mono- and diiodoacridines. Most of the substituted
acridines were obtained by reduction of synthesized 9(10H)-acridone derivatives. Substituted
acridone (0.24 mmol) was mixed with anhydrous tetrahydrofuran (THF, 2 mL) and borane-THF
solution (1M, 0.27 mL) in a Schlenk tube under argon. The mixture was heated in an oil bath to
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00°C and stirred for 1 h. After cooling to room temperature, the mixture was poured into an iron(III)
chloride solution (121 mg anhydrous in 10 mL ethanol and 2 mL water) and stirred in an oil bath at
50°C for 30 min. The reaction was quenched with saturated sodium bicarbonate solution and
extracted with dichloromethane (three times, 20 mL each). The solution was dried with anhydrous
sodium sulfate and concentrated under reduced pressure. The residue was purified using silica
column chromatography (5% ethyl acetate in hexanes).
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-((3-Iodophenyl)amino)benzoic acid (s7). 2-Chlorobenzoic acid (2.34 g, 15.0 mmol) and 3-
iodoaniline (3.27 g, 14.9 mmol), potassium carbonate (2.05 g, 14.9 mmol), copper(II) sulfate (15
mg, 0.094 mmol), copper(I) iodide (45 mg, 0.24 mmol), copper powder (42 mg, 0.66 mmol) and
water (15 mL) were mixed in a round bottom flask and stirred in an oil bath at 100°C for 12 h. The
black solution was filtered hot and washed with 20 mL of water. The filtrate was neutralized with
excess of acetic acid, during which light grey solid precipitated. The solid was collected after
+
1
another filtration (1.12 g, yield 22%). (+)APCI-MS: m/z: 340 [M+H] . H NMR (800 MHz,
Methanol-d ) δ 8.01 (dd, J = 8.0, 1.7 Hz, 1H), 7.59 (t, J = 1.9 Hz, 1H), 7.42 – 7.38 (m, 2H), 7.28
4
(dd, J = 8.5, 1.1 Hz, 1H), 7.24 (ddd, J = 8.1, 2.2, 0.9 Hz, 1H), 7.10 (t, J = 7.9 Hz, 1H), 6.83 (ddd, J
13
1
=
8.1, 7.0, 1.1 Hz, 1H). C{ H} NMR (201 MHz, CD OD_SPE) δ 170.3, 146.6, 142.7, 133.7, 132.0,
3
1
31.5, 130.6, 129.4, 120.0, 117.8, 114.0, 113.3, 93.8.
1- and 3-iodoacridones (s8 and s9). 2-((3-Iodophenyl)amino)benzoic acid (501 mg, 1.48
mmol) was dissolved in concentrated sulfuric acid (6 mL) and stirred in an oil bath at 100°C for 3
h. The solution was poured on 30 g ice and a greenish grey solid precipitated. The solid was filtered
and washed with massive amounts of water, followed by 5 mL 0.2% ammonium hydroxide solution.
The solid was vacuum dried and used without further purification.
1- and 3-iodoacridines (a2a and a4a). The product from the above step was used as described in the
generalprocedure. 1-Iodoacridine(16mg, yield3.5%)and3-iodoacridine(11mg, yield2.4%)werecollectedas
pale yellow solid.
1
1
-iodoacridine. H NMR (800 MHz, Chloroform-d) δ 8.99 (s, 1H), 8.27 (d, J = 8.7 Hz, 1H),
8.24 (d, J = 8.7 Hz, 1H), 8.15 (d, J = 7.0 Hz, 1H), 8.11 (d, J = 8.3 Hz, 1H), 7.85 (dd, J = 8.4, 6.6
1
3
1
Hz, 1H), 7.61 (dd, J = 8.7, 6.6 Hz, 1H), 7.49 (dd, J = 8.7, 7.0 Hz, 1H). C{ H} NMR (201 MHz,
CDCl ) δ 149.6, 148.8, 141.1, 137.0, 131.1, 130.9, 130.6, 129.0, 128.4, 128.1, 127.5, 126.4, 98.7.
3
+
HRMS (APCI), calcd. for C H NI: 305.9780 [M+H] , found: 305.9757.
1
3
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1
3
-Iodoacridine. H NMR (800 MHz, Chloroform-d) δ 8.76 – 8.73 (m, 2H), 8.23 (d, J = 8.7 Hz,
1
H), 8.00 (d, J = 8.3 Hz, 1H), 7.83 (t, J = 7.7 Hz, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.73 (dd, J = 8.7,
2.2 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H). 13C{ H} NMR (201 MHz, CDCl ) δ 149.3, 149.3, 138.6,
1
3
1
36.3, 134.3, 131.0, 129.5, 129.1, 128.3, 126.8, 126.2, 125.3, 97.1. HRMS (APCI), calcd. for
+
C H NI: 305.9780 [M+H] , found: 305.9752.
1
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2-Iodoacridone (s10). Acridone (226 mg, 1.16 mmol) was dissolved in 5 mL glacier acetic
acid and iodine chloride (207 mg, 1.28 mmol) was added dropwise. The solution was refluxed in an
oil bath for 4 h and then cooled to room temperature. The product was collected through filtration
as a brown solid and washed with water. The insoluble solid was used without further purification.
+
HRMS (APCI), calcd. for C H NOI: 321.9729 [M+H] , found: 321.9708.
1
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-Iodoacridine (a3a). 2-Iodoacridone obtained from above synthesis was treated as described
1
in the general procedure to give the product as an orange solid (127 mg, yield 36%). H NMR (400
MHz, Chloroform-d) δ 8.65 (s, 1H), 8.42 (d, J = 1.4 Hz, 1H), 8.21 (d, J = 8.9 Hz, 1H), 8.00 (d, J =
1
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.5 Hz, 1H), 7.97 (t, J = 1.2 Hz, 2H), 7.84 – 7.78 (m, 1H), 7.60 – 7.53 (m, 1H). C{ H} NMR (101
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+
9
1.2. HRMS (APCI), calcd. for C H NI: 305.9780 [M+H] , found: 305.9758.
13 9
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-Chloroacridine (s11). Acridone (118 mg, 0.61 mmol) was dissolved in 3 mL of
phosphorus(V) oxychloride and refluxed in an oil bath for 12 h. After cooling to room temperature,
the solvent was removed under reduced pressure. The residue was neutralized with cold 1M sodium
hydroxide solution, during which a solid was formed. After filtration, the solid was washed with
water and a small amount of methanol and then vacuum dried to yield the product as a yellow solid
1
(
73 mg, yield 56%). H NMR (400 MHz, Chloroform-d) δ 8.44 (dd, J = 8.8, 1.4 Hz, 2H), 8.23 (dt,
J = 8.8, 1.3 Hz, 2H), 7.82 (ddd, J = 8.8, 6.6, 1.4 Hz, 2H), 7.64 (ddd, J = 8.8, 6.6, 1.2 Hz, 2H).
1
3
1
C{ H} NMR (101 MHz, CDCl ) δ 206.9, 148.9, 130.5, 129.7, 126.8, 124.6, 124.2. HRMS (APCI),
3
+
calcd. for C H NCl: 214.0424 [M+H] , found: 214.0407, 216.0383.
1
3
9
9
-Iodoacridine (a1a). 9-Chloroacridone (73 mg, 0.34 mmol), sodium iodide (525 mg, 3.5
mmol), copper(I) iodide (14 mg, 0.073 mmol), N,N’-dimethyl-1,2-cyclohexane diamine (22 mg,
.15 mmol) and 1,4-dioxane (1 mL) were charged into a Schlenk tube. The solution was stirred in
0
an oil bath at 110°C for 48 h. After cooling, the reaction was quenched with 1 mL 10 wt.%
ammonium hydroxide solution and extracted with dichloromethane (three times, 10 mL each). The
organic layer was washed with brine and the solvent was removed under reduced pressure. After
1
recrystallization in ethyl acetate, the product was obtained as a yellow solid (19 mg, yield 18%). H
NMR (400 MHz, Chloroform-d) δ 8.34 (dt, J = 8.8, 1.3 Hz, 2H), 8.19 (dt, J = 8.7, 1.2 Hz, 2H), 7.79
ddd, J = 8.8, 6.6, 1.3 Hz, 2H), 7.64 (ddd, J = 8.9, 6.6, 1.2 Hz, 2H). 13C{ H} NMR (101 MHz,
1
(
CDCl ) δ 148.5, 132.9, 130.4, 129.8, 129.8, 127.7, 120.0. HRMS (APCI), calcd. for C H NI:
3
13
9
+
3
05.9780 [M+H] , found: 305.9759.
2
,9-Diiodoacridine (a5a). 2-Iodoacridone (73 mg, 0.23 mmol) was treated in the same manner
as above to produce 9-chloro-2-iodoacridine (s12) as a pale white solid. The product was used
+
without further purification. (+)APCI-MS: m/z: 322 [M+H] . 9-Chloro-2-iodoacridine was further
converted to the 2,9-diiodoacridine as described above to give the product as yellow solid (11 mg,
1
yield 11%). H NMR (800 MHz, Chloroform-d) δ 8.78 (d, J = 1.9 Hz, 1H), 8.34 (d, J = 8.8 Hz, 1H),
8.18 (d, J = 8.6 Hz, 1H), 8.00 (dd, J = 9.0, 1.9 Hz, 1H), 7.92 (d, J = 9.1 Hz, 1H), 7.84 (dd, J = 8.6,
13
1
6
1
.5 Hz, 1H), 7.67 (dd, J = 8.8, 6.5 Hz, 1H). C{ H} NMR (201 MHz, CDCl ) δ 148.8, 147.2, 141.7,
3
39.1, 133.1, 131.4, 131.3, 130.9, 130.0, 130.0, 128.4, 118.1, 94.2. HRMS (APCI), calcd. for
+
C H NI : 431.8746 [M+H] , found: 431.8731.
13
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2
1
,7- and 2,6-dibromoacridines (s16 and s17). 5-Bromo-2-((3-bromophenyl)amino)benzoic
acid (s13) was synthesized using the same method as for 2-((3-iodophenyl)amino)benzoic acid. No
NMR spectrum was collected due to its poor solubility. The crude product was vacuum dried and
used as it was to produce 1,7- and 2,6-dibromoacridones (s14 and s15) in the same manner as 1-
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and 3-acridones. The total yield of the two steps was 25%. The mixture of the products was reduced
as described in the general procedure to give pure 1,7- (yield 7%) and 2,6-dibromoacridine (yield
10%), both as light-yellow solids.
1
1
,7-Dibromoacridine. H NMR (800 MHz, Chloroform-d) δ 9.04 (s, 1H), 8.26 (d, J = 2.2 Hz,
1
H), 8.19 (d, J = 8.7 Hz, 1H), 8.12 (d, J = 9.2 Hz, 1H), 7.89 – 7.84 (m, 2H), 7.65 (dd, J = 8.8, 7.1
1
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Hz, 1H). C{ H} NMR (201 MHz, CDCl ) δ 149.3, 147.7, 135.2, 134.7, 130.9, 130.5, 130.2, 130.0,
3
+
1
29.6, 127.7, 126.2, 122.0, 120.5. HRMS (APCI), calcd. for C H NBr : 335.9023 [M+H] , found:
13 8 2
3
35.8998, 337.8978, 339.8956.
1
2
,6-Dibromoacridine. H NMR (800 MHz, Chloroform-d) δ 8.67 (s, 1H), 8.44 (d, J = 1.9 Hz,
1H), 8.18 (d, J = 2.2 Hz, 1H), 8.10 (d, J = 9.2 Hz, 1H), 7.88 (d, J = 8.9 Hz, 1H), 7.86 (dd, J = 9.2,
1
3
1
2
1
.1 Hz, 1H), 7.65 (dd, J = 8.9, 1.8 Hz, 1H). C{ H} NMR (201 MHz, CDCl ) δ 149.3, 147.8, 135.1,
3
34.5, 131.7, 131.2, 130.2, 129.9, 129.3, 127.3, 125.3, 125.2, 120.2. HRMS (APCI), calcd. for
+
C H NBr : 335.9023 [M+H] , found: 335.9003, 337.8998, 339.8991
1
3
8
2
1
,7- and 2,6-diiodoacridines (a6a and a8a). 1,7- and 2,6-dibromoacridines were treated
similarly as 9-chloroacridine but with double amounts of reagents and doubled reaction time to give
,7-diiodoacridine (yield 44%) as a pale yellow solid and 2,6-diiodoacridine (yield 58%) as a yellow
solid.
1
1
1
,7-Diiodoacridine. H NMR (800 MHz, Chloroform-d) δ 8.89 (s, 1H), 8.56 (d, J = 1.9 Hz,
1H), 8.22 (dt, J = 8.7, 1.0 Hz, 1H), 8.18 (dd, J = 7.0, 1.0 Hz, 1H), 8.04 (dd, J = 9.1, 1.9 Hz, 1H),
1
3
1
8
1
.00 (d, J = 9.1 Hz, 1H), 7.52 (dd, J = 8.7, 7.0 Hz, 1H). C{ H} NMR (201 MHz, CDCl ) δ 149.1,
3
48.1, 139.9, 139.6, 137.7, 137.1, 131.4, 130.6, 130.5, 128.9, 128.3, 98.6, 92.2. HRMS (APCI),
+
calcd. for C H NI : 431.8746 [M+H] , found: 431.8722.
1
3
8
2
1
2
,6-Diiodoacridine. H NMR (800 MHz, Chloroform-d) δ 8.72 (dt, J = 1.5, 0.6 Hz, 1H), 8.64
(d, J = 1.1 Hz, 1H), 8.43 (dt, J = 1.9, 0.6 Hz, 1H), 8.01 (dd, J = 9.1, 1.9 Hz, 1H), 7.96 (dt, J = 9.2,
1
3
1
0.7 Hz, 1H), 7.81 (dd, J = 8.8, 1.6 Hz, 1H), 7.74 (dt, J = 8.8, 0.6 Hz, 1H). C{ H} NMR (201 MHz,
CDCl ) δ 149.5, 147.8, 139.4, 138.7, 136.9, 135.0, 134.9, 131.1, 129.1, 128.2, 125.4, 97.7, 91.9.
3
+
HRMS (APCI), calcd. for C H NI : 431.8746 [M+H] , found: 431.8724.
1
3
8
2
2,7-Diiodoacridone (s18). Acridone (100 mg, 0.51 mmol) was dissolved in 5 mL glacier acetic
acid and iodine chloride (249 mg, 1.53 mmol) was added dropwise. The solution was refluxed for
6
h. The mixture was filtered while hot. The insoluble solid was washed with hot acetic acid (three
times, 10 mL each). The remaining yellow solid was vacuum dried to give the product (134 mg,
yield 59%). The insoluble product was used without further purification. HRMS (APCI), calcd. for
+
C H NOI : 447.8695 [M+H] , found: 447.8675.
1
3
8
2
2
,7-Diiodoacridine (a7a). 2,7-Diiodoacridone (105 mg) was treated as described in the general
1
procedure to produce 2,7-diiodoacridine as a yellow solid (41 mg, yield 40%). H NMR (800 MHz,
Chloroform-d) δ 8.55 (s, 1H), 8.45 (d, J = 1.9 Hz, 2H), 8.02 (dd, J = 9.1, 1.9 Hz, 2H), 7.96 (d, J =
9.1 Hz, 2H). 13C{ H} NMR (201 MHz, CDCl ) δ 147.8, 139.2, 136.9, 133.4, 131.1, 128.1, 92.2.
1
3
+
HRMS (APCI), calcd. for C H NI : 431.8746 [M+H] , found: 431.8717.
1
3
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Molecular geometries for all species were optimized at the density functional (DFT) level of
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calculations used the gradient-corrected exchange functional of Becke, which was combined with
32
the gradient-corrected correlation functional of Lee, Yang and Parr (B3LYP). All DFT geometries
were verified to be local minima by computation of analytic vibrational frequencies, and these
(unscaled) frequencies were used to compute zero-point vibrational energies (ZPVE) and 298 K
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thermal contributions (H298 – E ). All DFT calculations for the mono- and biradicals employed an
0
unrestricted formalism. Total spin expectation values for Slater determinants formed from the
optimized Kohn-Sham orbitals did not exceed 0.761 and 2.022 for doublet (monoradicals) and
triplet (biradical) states, respectively. For singlet biradicals, the DFT “wave function” was allowed
to break spin symmetry by using an unrestricted formalism.33 Total spin expectation values for
Slater determinants formed from the optimized Kohn-Sham orbitals in these cases ranged between
0.907 and 1.022, except for q7 (0.000).
To improve the molecular orbital calculations for the (iso)quinolinium-based systems, dynamic
electron correlation was also accounted for by using multi-reference second-order perturbation
theory34,35 (CASPT2) for multi-configurational self-consistent field (MCSCF) reference wave
functions; these calculations were carried out for the DFT optimized geometries. The MCSCF
3
6
calculations were of the complete active space (CASSCF) variety and included (in the active space)
the full -space for each molecule and, for each of the mono- and biradicals, the nonbonding 
orbital(s). Some caution must be applied in interpreting the CASPT2 results since this level of theory
3
7
is known to suffer from a systematic error proportional to the number of unpaired electrons. Thus,
the electronic energies are of the CASPT2/CASSCF(m,n)/cc-pVTZ//UB3LYP/cc-pVTZ variety
(where m is the number of active electrons and n is the number of active orbitals), and estimates of
the thermodynamic quantities, E and H298, are derived by adding to these electronic energies ZPVE
0
and the sum of ZPVE and (H298 – E ), respectively, where the latter are derived from the DFT
0
calculations. Note that similar calculations for the acridinium-based systems were not possible due
to their size.
In order to compute vertical electron affinities (EA ) for the mono- and biradicals, single-point
v
calculations (CASPT2/CASSCF(m,n)/cc-pVTZ for the (iso)quinolinium-based systems;
UB3LYP/aug-cc-pVTZ30,38 for the acridinium-based systems), using the UB3LYP/cc-pVTZ
optimized geometry for each radical, were also carried out for the states that are produced when a
single electron is added to the nonbonding  orbital (or one of the two such orbitals) of each
3
9
molecule. Thus, for the monoradicals (doublet ground states) these calculations were carried out
for (zwitterionic) singlet states, whereas for the biradicals (singlet ground states) calculations were
carried out for (zwitterionic) doublet states.40
All CASPT2/CASSCF and DFT calculations were carried out with the MOLCAS 8.041 48 and
42
Gaussian 09 electronic structure program suites, respectively.
ASSOCIATED CONTENT
Supporting Information. Plots of reaction efficiencies vs. S-T splittings of biradicals, calculated
collision rate constants and measured second-order reaction rate constants for mono- and biradicals,
synthesis schemes, NMR spectra, computational details. The Supporting Information is available
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free of charge on the ACS Publications website.
ACKNOWLEDGEMENTS
We are grateful to the National Science Foundation (CHE-1464712) for financial support.
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REFERENCES
(
1)
Alam, A. Md. The Advances and Applications of Arynes and Their Precursors to Synthesize
the Heterocyclic Compounds: A Review. Am. J. Heterocycl. Chem. 2017, 3, 47–54.
Romeo, R.; Giofre, S. V.; Chiacchio, M. A. Synthesis and Biological Activity of Unnatural
Enediynes. Curr. Med. Chem. 2017, 24, 3433–3484.
(2)
(3)
Wender, P. A.; Jeon, R. Bromoacetophenone-Based Photonucleases: Photoinduced
Cleavage of DNA by 4‘-Bromoacetophenone−Pyrrolecarboxamide Conjugates. Org. Lett.
1
999, 1, 2117–2120.
(
(
(
4)
5)
6)
Wenk, H. H.; Winkler, M.; Sander, W. One Century of Aryne Chemistry. Angew. Chem. Int.
Ed. 2003, 42, 502–528.
Williams, P. E.; Jankiewicz, B. J.; Yang, L.; Kenttämaa, H. I. Properties and Reactivity of
Gaseous Distonic Radical Ions with Aryl Radical Sites. Chem. Rev. 2013, 113, 6949–6985.
Wenthold, P. G.; Squires, R. R.; Lineberger, W. C. Ultraviolet Photoelectron Spectroscopy
of the o-, m-, and p-Benzyne Negative Ions. Electron Affinities and Singlet−Triplet
Splittings for o-, m-, and p-Benzyne. J. Am. Chem. Soc. 1998, 120, 5279–5290.
Gao, J.; Jankiewicz, B. J.; Reece, J.; Sheng, H.; Cramer, C. J.; Nash, J. J.; Kenttämaa, H. I.
On the Factors That Control the Reactivity of meta-Benzynes. Chem. Sci. 2014, 5, 2205–
(7)
(8)
(9)
2
215.
Vinueza, N. R.; Archibold, E. F.; Jankiewicz, B. J.; Gallardo, V. A.; Habicht, S. C.; Aqueel,
M. S.; Nash, J. J.; Kenttämaa, H. I. Reactivity of the 4,5-Didehydroisoquinolinium Cation.
Chem. – Eur. J. 2012, 18, 8692–8698.
Jing, L.; Nash, J. J.; Kenttämaa, H. I. Correlation of Hydrogen-Atom Abstraction Reaction
Efficiencies for Aryl Radicals with Their Vertical Electron Affinities and the Vertical
Ionization Energies of the Hydrogen-Atom Donors. J. Am. Chem. Soc. 2008, 130, 17697–
1
7709.
(10) Max, J. P.; Ma, X.; Kotha, R. R.; Ding, D.; Milton, J.; Nash, J. J.; Kenttämaa, H. I. Reactivity
of Organic σ,σ,σ,σ,σ-Pentaradicals. Int. J. Mass Spectrom. 2019, 435, 280–290.
(
11) Kotha, R. R.; Yerabolu, R.; Ding, D.; Szalwinski, L.; Ma, X.; Wittrig, A.; Kong, J.; Nash, J.
J.; Kenttämaa, H. I. Spin–Spin Coupling Between Two meta–Benzyne Moieties In a
Quinolinium Tetraradical Cation Increases Their Reactivities. Chem. – Eur. J. 2019, 25,
4
472–4477.
(12) Donahue, N. M.; Clarke, J. S.; Anderson, J. G. Predicting Radical−Molecule Barrier Heights:
The Role of the Ionic Surface. J. Phys. Chem. A 1998, 102, 3923–3933.
(13) Ciampi, S.; Darwish, N.; Aitken, H. M.; Diez-Perez, I.; Coote, M. L. Chem. Soc. Rev. 2018,
7, 5146-5164.
4
(
14) Vinueza, N. R.; Jankiewicz, B. J.; Gallardo, V. A.; LaFavers, G. Z.; DeSutter, D.; Nash, J.
J.; Kenttämaa, H. I. Reactivity Controlling Factors for an Aromatic Carbon-Centered σ,σ,σ-
Triradical: The 4,5,8-Tridehydroisoquinolinium Ion. Chem. – Eur. J. 2016, 22, 809–815.
2
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 28
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
15) Logan, C. F.; Chen, P. Ab Initio Calculation of Hydrogen Abstraction Reactions of Phenyl
Radical and p-Benzyne. J. Am. Chem. Soc. 1996, 118, 2113–2114.
(16) Stiles, M.; Miller, R. G.; Burckhardt, U. Reactions of Benzyne Intermediates in Non-Basic
Media. J. Am. Chem. Soc. 1963, 85, 1792–1797.
(17) Gozzo, F. C.; Eberlin, M. N. 2-Pyridyl and 2-Pyrimidyl Cations:ꢀ Stable o-Hetarynium Ions
in the Gas Phase. J. Org. Chem. 1999, 64, 2188–2193.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
18) Wierschke, S. G.; Nash, J. J.; Squires, R. R. A Multiconfigurational SCF and Correlation-
Consistent CI Study of the Structures, Stabilities, and Singlet-Triplet Splittings of o-, m-,
and p-Benzyne. J. Am. Chem. Soc. 1993, 115, 11958–11967.
(19) Barfknecht, A. T.; Dodd, J. A.; Salomon, K. E.; Tumas, W.; Brauman, J. I. Pure Appl. Chem.
984, 56, 1809-1818.
1
(
(
(
20)
Ma, X.; Jin, C.; Wang, D.; Nash, J. J.; Kenttämaa, H. I. Relative Reactivities of Three
Isomeric Aromatic Biradicals with a 1,4‐Biradical Topology Are Controlled by Polar
Effects. Chem. – Eur. J. 2019, 25, 6355–6361.
21) Jankiewicz, B. J.; Vinueza, N. R.; Kirkpatrick, L. M.; Gallardo, V. A.; Li, G.; Nash, J. J.;
Kenttӓmaa, H. I. Does the 2,6-Didehydropyridinium Cation Exist? J. Phys. Org. Chem.
2
013, 26, 707–714.
22) Logan, C. F.; Chen, P. T. Ab initio Calculations of Hydrogen Abstraction Reactions of Phenyl
Radical and p-Benzyne, J. Am. Chem. Soc. 1996, 118, 2113–2114.
(23) Roth, W. R.; Hopf, H.; Wasser, T.; Zimmerman, H.; Werner, C. 1,4-Didehydronaphthalin.
Liebigs Ann. 1996, 1691–1695.
(
24) Kotha, R. R. Gas-Phase Reactivity Studies of Charged Quinoline Polyradicals by Using
Distonic Ion Approach and Linear Quadrupole Ion Trap Mass Spectrometry, and
Mechanistic Studies on Metal-Promoted Self-Assembly of Collagen Mimetic Peptides. Ph.D.
Thesis, Purdue University, 2017.
(25) Habicht, S. C.; Vinueza, N. R.; Archibold, E. F.; Duan, P.; Kenttämaa, H. I. Identification
of the Carboxylic Acid Functionality by Using Electrospray Ionization and Ion-Molecule
Reactions in a Modified Linear Quadrupole Ion Trap Mass Spectrometer. Anal. Chem. 2008,
8
0, 3416–3421.
(26) Su, T.; Chesnavich, W. J. Parametrization of the Ion–Polar Molecule Collision Rate
Constant by Trajectory Calculations. J. Chem. Phys. 1982, 76, 5183–5185.
(
27) Pedron, J.; Boudot, C.; Hutter, S.; Bourgeade-Delmas, S.; Stigliani, J.-L.; Sournia-Saquet,
A.; Moreau, A.; Boutet-Robinet, E.; Paloque, L.; Mothes, E.; Laget, M.; Vendier, L.; Pratviel,
G.; Wyllie, S.; Fairlamb, A.; Azas, N.; Courtioux, B.; Valentin, A.; Verhaeghe, P. Novel 8-
Nitroquinolin-2(1H)-ones as NTR-Bioactivated Antikinetoplastid Molecules: Synthesis,
Electrochemical and SAR Study. Eur. J. Med. Chem. 2018, 155, 135–152.
https://doi.org/10.1016/j.ejmech.2018.06.001.
(28) Lee, J. A.; Roh, E. J.; Oh, C.-H.; Lee, S. H.; Sim, T.; Kim, J. S.; Yoo, K. H. Synthesis of
Quinolinylaminopyrimidines
Antiproliferative Activity against Melanoma Cell Line. J. Enz. Inh. Med.l Chem. 2015, 30
4), 607–614. https://doi.org/10.3109/14756366.2014.958082.
and
Quinazolinylmethylaminopyrimidines
with
(
(29) Zhang, Y.; Guo, X.; Jia, L.; Xu, S.; Xu, Z.; Zheng, L.; Qian, X. Substituent-Dependent
Fluorescent Sensors for Zinc Ions Based on Carboxamidoquinoline. Dalton Trans.s 2012,
4
1 (38), 11776–11782. https://doi.org/10.1039/c2dt31139a.
2
6
ACS Paragon Plus Environment

Page 27 of 28
The Journal of Organic Chemistry
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6
7
8
9
(
30) Dunning, T. H. Gaussian Basis Sets for Use in Correlated Molecular Calculations. I. The
Atoms Boron Through Neon and Hydrogen. J. Chem. Phys. 1989, 90, 1007–1023.
(31) Becke, A. D. Density-functional Exchange-Energy Approximation With Correct
Asymptotic Behavior. Phys. Rev. A 1988, 38, 3098–3100.
(
32) Lee, C. T.; Yang, W. T.; Parr, R. G. Development of the Colle-Salvetti Correlation-Energy
Formula Into a Functional of the Electron Density. Phys. Rev. B, 1988, 37, 785–789.
33) (a) Polo, V.; Kraka, E.; Cremer, D. Some Thoughts About the Stability and Reliability of
Commonly Used Exchange-Correlation Functionals – Coverage of Dynamic and
Nondynamic Correlation Effects. Theor. Chem. Acc. 2002, 107, 291–303. (b) Gräfenstein,
J.; Hjerpe, A. M.; Kraka, E.; Cremer, D. An Accurate Description of the Bergman Reaction
Using Restricted and Unrestricted DFT: Stability Test, Spin Density, and On-Top Pair
Density. J. Phys. Chem. A 2000, 104, 1748–1761. (c) Cramer, C. J. Bergman, Aza-Bergman,
and Protonated Aza-Bergman Cyclizations and Intermediate 2,5-Arynes: Chemistry and
Challenges to Computation. J. Am. Chem. Soc. 1998, 120, 6261–6269. (d) Gräfenstein, J.;
Kraka, E.; Cremer, D. Density Functional Theory for Open-Shell Singlet Biradicals. Chem.
Phys. Lett. 1998, 288, 593–602. (e) Crawford, T. D.; Kraka, E.; Stanton, J. F.; Cremer, D.
Problematic p-Benzyne: Orbital Instabilities, Biradical Character, and Brojen Symmetry. J.
Chem. Phys. 2001, 114, 10638–10650.
1
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7
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0
(
(
(
(
(
34) Andersson, K.; Malmqvist, P.-Å.; Roos, B. O.; Sadlej, A. J.; Wolinski, K. Second-Order
Perturbation Theory With a CASSCF Reference Function. J. Phys. Chem. 1990, 94, 5483–
5
488.
35) Andersson, K. Different Forms of the Zeroth-Order Hamiltonian in Second-Order
Perturbation Theory With a Complete Active Space Self-Consistent Field Reference
Function. Theor. Chim. Acta 1995, 91, 31–46.
36) Roos, B. O.; Taylor, P. R.; Siegbahn, P. E. M. A Complete Active Space SCF Method
(CASSCF) Using a Density Matrix Formulated Super-CI Approach. Chem. Phys. 1980, 48,
1
57–173.
37) Andersson, K.; Roos, B. O. Multiconfigurational Second-Order Perturbation Theory: A Test
of Geometries and Binding Energies. Int. J. Quantum Chem. 1993, 45, 591–607.
(38) Kendall, R. A.; Dunning, T. H.; Harrison, R. J. Electron Affinities of the First-Row Atoms
Revisited. Systematic Basis Sets and Wave Functions. J. Chem. Phys. 1992, 96, 6796–6806.
(39) Note that, for these calculations, we are computing the electron affinity of the radical site
not the electron affinity of the molecule.
(
40) Because the mono- and biradicals studied here contain a formal positive charge on the
nitrogen atom, the state that is produced when an electron is added to the nonbonding orbital
of any one of these species is formally zwitterionic; that is, it contains localized positive ()
and negative () charges.
(
41) (a) MOLCAS 7.4: Aquilante, F.; De Vico, L.; Ferré, N.; Ghigo, G.; Malmqvist, P.-°A.;
Neogrády; Pedersen, T. B.; Pitonak, M.; Reiher, M.; Roos, B. O.; Serrano-Andrés, L.; Urban,
M.; Veryazov, V.; Lindh, R. J. Comp. Chem. 2010, 31, 224–247. (b) Code Development:
Veryazov, V.; Widmark, P.-O.; Serrano- Andrés, L.; Lindh, R. Roos, B. O. Int. J. Quant.
Chem. 2004, 100, 626–635. (c) MOLCAS 7: Karlstrőm, G.; Lindh, R.; Malmqvist, P.-°A.;
Roos, B. O.; Ryde, U.; Veryazov, V.; Widmark, P.-O.; Cossi, M.; Schimmelpfennig, B.;
Neogrády, P.; Seijo, L. Comp. Mat. Sci. 2003, 28, 222–239.
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42) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J.
R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.;
Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada,
M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.;
Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, Jr., J. A.; Peralta, J. E.; Ogliaro, F.; Bearpark,
M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Keith, T.; Kobayashi, R.;
Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.;Cossi,
M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.;Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli,
C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.;
Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, O.; Foresman, J. B.;
Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian, Inc., Wallingford CT, 2013.
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