Cyclopropyl Group: An Excited-State Aromaticity Indicator?

Article abstract of DOI:10.1002/chem.201701404

The cyclopropyl (cPr) group, which is a well-known probe for detecting radical character at atoms to which it is connected, is tested as an indicator for aromaticity in the first ππ* triplet and singlet excited states (T₁ and S₁). Baird's rule says that the π-electron counts for aromaticity and antiaromaticity in the T₁ and S₁ states are opposite to Hückel's rule in the ground state (S₀). Our hypothesis is that the cPr group, as a result of Baird's rule, will remain closed when attached to an excited-state aromatic ring, enabling it to be used as an indicator to distinguish excited-state aromatic rings from excited-state antiaromatic and nonaromatic rings. Quantum chemical calculations and photoreactivity experiments support our hypothesis; calculated aromaticity indices reveal that openings of cPr substituents on [4n]annulenes ruin the excited-state aromaticity in energetically unfavorable processes. Yet, polycyclic compounds influenced by excited-state aromaticity (e.g., biphenylene), as well as 4nπ-electron heterocycles with two or more heteroatoms represent limitations.

Full text of DOI:10.1002/chem.201701404

A Journal of
Accepted Article
Title: The Cyclopropyl Group: An Excited State Aromaticity Indicator?
Authors: Rabia Ayub, Raffaello Papadakis, Kjell Jorner, Burkhard Zietz,
and Henrik Ottosson
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The Cyclopropyl Group: An Excited State Aromaticity Indicator?
Rabia Ayub †‡, Raffaello Papadakis†‡, Kjell Jorner†‡, Burkhard Zietz,‡ and Henrik Ottosson†‡*
† Department of Chemistry - BMC, Uppsala University, Box 576, 751 23 Uppsala, Sweden.
‡ Department of Chemistry - Ångström Laboratory Uppsala University, Box 523, 751 20
Uppsala, Sweden.
Abstract: The cyclopropyl (cPr) group, a well-known probe for radical character at atoms to
which it is connected, is tested as an indicator for aromaticity in the first ππ* triplet and
singlet excited states (T1 and S1). Baird’s rule tells that the -electron counts for aromaticity
and antiaromaticity in the T1 and S1 states are opposite to Hückel’s rule in the ground state
(S0). Our hypothesis is that the cPr group, as a result of Baird’s rule, will remain closed when
attached to an excited state aromatic ring, enabling it to be used as an indicator to distinguish
excited state aromatic rings from excited state antiaromatic and nonaromatic ones. Quantum
chemical calculations and photoreactivity experiments support our hypothesis; calculated
aromaticity indices reveal that openings of cPr substituents on [4n]annulenes ruin the excited
state aromaticity in energetically unfavorable processes. Yet, polycyclic compounds
influenced by excited state aromaticity (e.g., biphenylene), as well as 4n-electron
heterocycles with two or more heteroatoms represent limitations.
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TOC image
Introduction
Is there a fundamental difference in the photoreactivities of [4n+2]- and [4n]annulenes? In
their electronic ground states (S0) annulenes with 4n+2 and 4n -electrons have drastically
different reactivities; benzene is exceptionally reluctant to break up its aromatic cycle while
cyclobutadiene (CBD) and cyclooctatetraene (COT) either very rapidly or readily undergo a
range of reactions.[1 ] If there is also a large reactivity difference between [4n+2]- and
[4n]annulenes in their excited states, how can it be explained?
The excited state (anti)aromaticity (ES(A)A) concept has recently gained
increased attention,[2,3] although it was first applied in the mid-60s by Dewar and Zimmerman
to rationalize allowed and forbidden pericyclic reactions (both thermal and photochemical) in
terms of transition state aromaticity and antiaromaticity, respectively.[4,5] The usage of the
concept to structures that are minima on excited state surfaces stems from 1972 when Baird
used perturbation molecular orbital theory to show that [4n+2]annulenes are antiaromatic in
their lowest ππ* triplet states (T1) while [4n]annulenes are aromatic.[6,7] Today, Baird’s rule
has been confirmed through numerous quantum chemical studies,[2] and it has been found to
also apply to the lowest singlet excited state (S1) of small annulenes.[8-11]
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Wan and co-workers pioneered the usage of excited state aromaticity (ESA) in
an experimental context by concluding that the driving force for photolysis of fluoren-9-ol is
the formation of an aromatic 4π cationic species in the excited state.[12] Ottosson, Kilså, and
co-workers showed experimentally that the ES(A)A concept can be used to rationalize
substituent related variations in the excitation energies of the T1 and S1 states of various
fulvenes.[13] Recently, explicit spectroscopic evidence for Baird’s rule in the excited states
was given by Kim, Osuka and co-workers who investigated [26]- and [28]hexaphyrins known
to be, respectively, aromatic and antiaromatic in their S0 states.[14,15]
Based on Baird's rule one can conclude that excited state antiaromatic
[4n+2]annulenes will photoreact rapidly while [4n]annulenes should be photochemically inert
and resemble [4n+2]annulenes in their S0 states. Indeed, the excited state antiaromatic
character of the benzene ring can be used to identify and develop new photoreactions,[16,17]
and one can apply the ES(A)A concept to reanalyze a series of earlier findings.[2] E.g.,
Paquette and co-workers observed that 1,2-dialkylcyclooctatetraenes are photostable in
acetone solution since only starting material was recovered after 100 hours of irradiation,[18]
a
photostability in line with T1 aromaticity. Indeed, computational studies have revealed that T1
aromaticity goes with energy gain and the opposite for T1 antiaromaticity.[19-21] Now, is there
a structural moiety that indicates whether a molecule is aromatic, or not, in its T1 and S1
states?
The cyclopropyl (cPr) group indicates radical character by ring-opening when
attached to a radical center (Scheme 1),[22] and also when attached to singlet and triplet
diradicals.[23,24] The rate of ring-opening of the cyclopropylcarbinyl radical (1) is 6.7 x 107 s-1,
corresponding to a lifetime of 14.9 ns, and the reaction leads to the 3-butenyl radical.[25-27]
The calculated activation and reaction free energies for ring-opening of 1 at CBS-RAD level
are 7.2 and -3.0 kcal/mol, respectively,[28] while the experimentally reported activation energy
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is 5.9 kcal/mol.[ 29 , 30 ] Moreover, gas phase photolysis studies of cyclopropylbenzene
performed both with λ = 214 and 254 nm irradiation have revealed that the Cα-Cβ bond of the
cPr group is highly photolabile.[31,32] Yet, we argue that it will remain closed when attached to
a [4n]annulene stabilized by aromaticity in its T1 state as its ring-opening will ruin the cyclic
(Baird-aromatic) delocalization, explained in a curve-crossing diagram depicting the energy
changes of two triplet diradical structures localized to either the COT ring or the C-C bond
of the cPr group (Figure 1A). In contrast, when attached to T1 antiaromatic rings the cPr
group should open particularly easily as its opening will alleviate antiaromaticity (Figure 1B).
Yet, since the cPr group opens when next to a radical, and also a radical pair with triplet
multiplicity, it will not differentiate between T1 antiaromatic and nonaromatic rings. Instead,
it should specifically identify T1 state aromatic cycles. Moreover, as Baird’s rule applies to
the S1 state we argue that the cPr group may also function for S1 state aromaticity.
Scheme 1: Ring-opening of the cyclopropylcarbinyl radical (1).
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Figure 1: Curve-crossing diagram for the ring-opening of cyclopropylCOT (A) and
cyclopropylbenzene (B) in their T1 states in dependence of the C-C bond distance of the cPr
group. The dissociating C-C bond and the corresponding two same-spin electrons of the cPr
group are displayed in red. The (anti)aromaticity of the annulene is represented by A =
aromatic, AA = antiaromatic, and NA = nonaromatic. Aromatic structures have low relative
energies, nonaromatic intermediate and antiaromatic high energies. The aromatic structures
are composites of several valence bond structures.
Three criteria should be fulfilled; (i) the cPr group must be a substituent on the
potentially excited state aromatic cycle, (ii) the excitation must be localized to this cycle, and
(iii) decay to the S0 state must not be faster than ring-opening of the cPr group. The last
requirement is complex since the persistence of the cPr group in a photochemical context
depends on the activation barrier for its ring-opening vs. the rate for radiative and non-
radiative decay processes as well as competing photochemical reactions.
We report on experimental studies of cPr substituted benzene, COT,
naphthalene and biphenylene, whereby the excited state lifetimes of the parent compounds are
important. The T1 state lifetimes of these compounds are longer by factors 103 – 105 [33-36]
(Table S1) than the lifetime of 1 (14.9 ns). Thus, the cPr ring-opening will not be restricted by
T1 state lifetimes. The situation is different in the S1 state where the lifetimes of benzene and
naphthalene are 28 – 34 ns and 96 - 105 ns, respectively.[34] The corresponding lifetime of
COT is not reported, but for biphenylene it is merely 0.23 ns,[34] leading to the question if cPr
ring-opening in the S1 state of a cPr-substituted biphenylene will occur before it has decayed
to the S0 state.
One can argue that several different photoreactions (e.g., carbon-halogen bond
dissociation and olefin Z/E-photoisomerizations)[2,3] can be used to identify excited state
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aromatic compounds. But as those structural units have either lone-pairs, leading to n*
states, or additional -orbitals that influence ground and/or excited states we find the cPr
group to be more suitable as a potential excited state aromaticity indicator, although its scope
and limitations must be resolved. In an applied context it can be noted that the cPr group is an
often found unit in drug molecules.[37] Our present study indicates in which -conjugated
structural environments this group will be stable to light, information of potential use for drug
design.
Results and Discussion
To determine if the cPr group can distinguish a T1 state aromatic cycle from one which is T1
antiaromatic or nonaromatic we first used quantum chemical computations to examine the T1
state potential energy surfaces (PESs) for cPr ring-opening of compounds 1 – 15 as well as
their spin density distributions. We further calculated the S1 state PESs of cyclopropylbenzene
(10) and cyclopropylCOT (11). We excluded cyclopropylCBD as CBD is reported to be only
weakly T1 aromatic.[38,39] Experimentally we studied the photostabilities of 10, 11, 2-cyclo-
propylnaphtalene (13), and 2-cyclopropylbiphenylene (15), both upon direct and sensitized
irradiation in presence of methanol as trapping agent. Subsequently, we used quantum
chemical computations to assess changes in (anti)aromaticity along the T1 PESs of 8 – 15, and
3
we explored how the findings extend to the * states of the heterocyclic compounds 16 –
31.
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Figure 2: The all-carbon compounds investigated; the cyclopropylcarbinyl radical (1), 1-
cyclopropylcyclohexene (2), cyclopropylcyclohexa-1,3-dienes (3 and 4), cyclopropylcyclo-
octa-1,3,5-trienes (5 - 7), the cyclopentadienyl cation and anion (8 and 9),
cyclopropylbenzene (10), cyclopropylCOT (11), 1-cyclopropylnaphthalene (12), 2-
cyclopropylnaphthalene (13), 1-cyclopropylbiphenylene (14) and 2-cyclopropylbiphenylene
(15).
Nonaromatic reference compounds: The cyclopropylcarbinyl radical (1) and
compounds 2 – 7 are nonaromatic references against which 8 – 15 are evaluated. At
UB3LYP/6-311G(d,p) level the activation free energy for ring-opening of 1 in its doublet
ground state is 7.1 kcal/mol and the reaction energy is -5.0 kcal/mol (Figure 3), in agreement
with previously computed and experimental values.[28-30] For 2 – 7 in their T1 states the
calculated activation energies are 6.1 – 21.1 kcal/mol, and the reactions are exergonic by 1.3 –
21.0 kcal/mol. Noteworthy, there is a good correlation (R2 = 0.931, Figure 4) between the
activation energies of 1 – 7 and the spin densities at the C atoms to which the cPr groups are
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attached. For similar plots using Mulliken (R2 = 0.941) and NPA (R2 = 0.916) spin densities,
see the Supporting Information.
Figure 3: T1 (D0 for 1) state potential energy surface diagrams for the cyclopropyl ring-
openings of 1 - 7 at UB3LYP/6-311G(d,p) level.
Figure 4: Activation free energies of cPr ring-opening in dependence of the spin density
(QTAIM) at the C atom at which the cPr group is attached, with a least-squares fit of the data
for the nonaromatic reference compounds 1 - 7. Positive values represent excess of -spin
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density, negative values excess of -spin density. Open triangles for nonaromatic, filled
squares for compounds 9, 10, 12, and 13, and filled circles for 8, 11, 14, and 15.
cPr-Substituted annulenic compounds 8 – 11 in the T1 state: Now, are the
activation energies higher for the T1 aromatic compounds than for the nonaromatic references,
and is it the opposite for T1 antiaromatic ones? Also, are the reaction energies more
endergonic (exergonic) for the T1 aromatic (antiaromatic) compounds than for the references?
The activation energies for 8 and 11 with 4n-electron cycles are higher (16 – 18 kcal/mol,
Figure 5) than all except one reference (6), while those of 9 and 10 are much smaller (1 – 2
kcal/mol). Moreover, the reaction energies are strongly endergonic for 8 and 11 while they are
markedly exergonic for 9 and 10.
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Figure 5: T1 state potential energy surface diagrams for cyclopropyl ring-openings of 8 - 11 at
the UB3LYP/6-311G(d,p) level.
Noteworthy, the T1 state cPr ring-opening reactions of 8 – 11 are all adiabatic
according to intrinsic reaction coordinate (IRC) calculations as the transition states are
smoothly connected to both reactants and products (Figures S53-S56). The IRC plots closely
resemble the T1 PES diagrams of Figure 5. Moreover, the vertically excited T2 state computed
with TD-UB3LYP//UB3LYP along the T1 state IRC paths of 10 and 11 reveal relationships
between the T1 and T2 states (Figures S61- S62) that resemble the qualitative curve-crossing
diagrams of Figure 1. At the TS structures of 10 and 11, the T2 states are calculated to be,
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respectively, 26.7 kcal/mol (1.16 eV) and 42.4 kcal/mol (1.84 eV) above the T1 states. The
same picture results at CASPT2//B3LYP level where the energy differences are 1.51 and 1.70
eV, respectively (Figures S63- S64). With regard to the T1 state minimum geometries of 10
and 11 the benzene ring in 10 is best described as antiquinoid as drawn in Figure 1B,[40] while
the COT ring in 11 is nearly octagonal as depicted in Figure 1A with CC bonds length in
range 1.398 – 1.414 Å.
Do the activation energies for cPr opening reflect the number of -electrons in
the annulenic cycles? In a T1 aromatic cycle the two unpaired same-spin -electrons will be
delocalized leading to low spin density per C atom, and accordingly, a lowered propensity for
cPr ring-opening. Additionally, we find that the activation barrier is linked to the number of
-electrons of the ring (4n or 4n+2) because for the two (4n+2)-electron compounds 9 and
10 the activation energies are well below the regression line for the nonaromatic references (-
6.1 and –7.7 kcal/mol, Figure 4 and Table S2). Oppositely, for the 4n-electron compound 11
the activation energy is 3.4 kcal/mol above the line, while for 8 it is situated on. However, the
activation energy of 8 it likely reduced because the two C-C bonds are significantly
elongated (1.571 Å) at the T1 state minimum. Indeed, when combined with results of cPr-
substituted heterocycles (vide infra) our findings suggest that there is a drive to alleviate T1
antiaromaticity of 4n+2 -electron cycles and a resistance to give up T1 aromaticity of 4n
cycles.
cPr-Substituted polycyclic compounds 12 – 15 in the T1 state: Naphthalene is
antiaromatic in its T1 state,[16] and we now find the cPr ring-openings of 12 and 13 to be
exergonic (Figure 6) but less so than for 10. Moreover, the activation energies are higher (8 –
12 kcal/mol) than that of 10 and resemble those of 1 - 7. The activation energy of 13 is higher
than for 12, and our calculations show that the spin density at the C atom to which the cPr
group is attached has an influence on the activation barrier because a higher spin density is
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observed for C1 in 12 (0.558) than for C2 in 13 (0.167). Yet, for both 12 and 13 the activation
energies are lower by ~4 kcal/mol when compared to the nonaromatic reference line, again
revealing an additional driving force for cPr ring-opening when compared to that predicted
exclusively from the spin density (Table S2).
Figure 6: T1 state potential energy surface diagrams for cyclopropyl ring-openings of 12 - 15
at UB3LYP/6-311G(d,p) level.
Biphenylene is an "aromatic chameleon" compound (Figure 7) as it can adapt to
different aromaticity rules; Hückel’s rule in the S0 state and Baird’s rule in the T1 and S1
states.[2,41-43] For the cPr substituted biphenylenes 14 and 15 the ring-opening reactions in the
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T1 states are modestly exergonic (Figure 6). Yet, the activation energy of 14 is even higher
than that of 11. The activation energy of 15, on the other hand, is 14.4 kcal/mol, slightly lower
than reported for the T1 state Z/E-photoisomerization of 3-(prop-1-enyl)perylene (15.7
kcal/mol), a reaction that progressed slowly at ambient temperature.[44] When compared to the
non-aromatic 2 – 7, compounds 14 and 15 displayed less exergonic ring-opening reactions,
and the activation energies are high. Thus, the T1 PESs of 14 and 15 resemble those of the
4n-electron species 8 and 11 more than those of the (4n+2)-electron compounds 9 and 10,
suggesting 12-electron circuits in the T1 states of 14 and 15. Indeed, for 14 the activation
energy is 3.8 kcal/mol higher than expected had it been nonaromatic (Figure 4), but for 15 the
activation energy is predicted as were it nonaromatic.
Figure 7: Aromatic resonance structures of biphenylene showing the “aromatic chameleon”
characteristics of this compound in its S0 vs. T1 and S1 states.
Computed S1 state PESs of 10 and 11: We also computed the reaction and
activation free energies of 10 and 11 in the S1 states at CASPT2/ANO-RCC-
VTZP//CASSCF/6-31G(d) level using, respectively, (8in8) and (10in10) active spaces. The
benzene ring in the calculated S1 state structure of 10 resembles that earlier found for
benzene,[45] and the relaxation of 10 from the Franck-Condon region should resemble that of
benzene.[ 46 ] Moreover, it has earlier been concluded that the D8h symmetric COT is a
collecting point on the S1 state surface,[47] and also 11 in the S1 state has a nearly octagonal
COT ring.
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The reaction free energies for ring-opening of the cPr group are 12.7 kcal/mol
for 10 and 54.3 kcal/mol for 11 at MS-CASPT2/ANO-RCC-VTZP level (Figure 8). The
CASPT2 calculations reveal that the S1 and S2 states of 10 become degenerate, but only after
the transition state structure (Figure S63). Moreover, the activation free energy for cPr ring-
opening of 10 in the S1 state is 13.4 kcal/mol, i.e., 11.2 kcal/mol higher than in the T1 state at
(U)B3LYP/6-311G(d,p) level. For 11, the transition state for the ring-opening was not
possible to locate, likely due to a degeneracy between the S2 and S3 states close to the
transition state regions (see Figures S67-S69). Instead, using a linear interpolation approach
we estimate the activation energy at 68.0 kcal/mol, much higher than for the T1 state. Yet,
despite the fact that both ring-opening reactions are endergonic, the much higher endergonic
reaction energy of 11 than of 10 shows a trend that lends support to our hypothesis also in the
S1 state; loss of S1 state aromaticity seems to be a particularly unfavorable process. For
mappings of the higher excited states of 10 and 11 see the Supporting Information.
Figure 8: The S1 state PESs of 10 and 11 at the CASPT2/ANO-RCC-VTZP//CASSCF/6-
31G(d) level, with the reference energies being the energies of the ring-closed species in their
S1 states. For 11, a linear interpolation method is used for finding the transition state. Active
spaces and occupation numbers are described in the Supporting Information (Tables S3-S7).
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Experimental studies of 10, 11, 13 and 15: Compounds 11, 13 and 15 were
prepared by a slight modification of a procedure by Paquette and co-workers (for synthetic
details see the SI).[18] However, the yields of cyclopropanation decreased gradually when
going from COT to benzene (Scheme 2), and only starting material was recovered when
bromobenzene was used. Yet, 10 is commercially available.
Scheme 2: Synthesis of cyclopropyl substituted compounds.
Compound 10 has its first UV absorption at 274 nm, and upon irradiation of a
14.5 mM solution of 10 in methanol with λ = 254 nm for two hours it formed the ring-opened
methoxy adduct 10-MeOHad (Scheme 3). Continuous monitoring of the reaction with GC-MS
showed that 10 has photodecomposed completely after twelve hours (Figure 9A). The
formation of 10-MeOHad reached a photostationary state after ten hours, but the conversion
to 10-MeOHad is merely 3% according to GC-MS. Long-term irradiation (24 h) gave only
polymers according to spectral analysis (see Figures S13-S18). This polymer formation
progresses via 10-MeOHad as supported by irradiation of separately prepared 10-MeOHad
leading to yellowish polymers (see Figures S23-S28 for NMR and UV-Vis spectra, and
photos of reaction tubes). Since benzene has an intersystem crossing quantum yield (ISC) of
0.25,[48] the photodegradation of 10 likely arises from its T1 state, or from both the S1 and T1
states as a substantial difference in yields of the photodecomposition products was observed
when a solution of 10 was irradiated with and without oxygen present (Figure 9B).
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Scheme 3: Photoreaction of 10 with MeOH.
Figure 9: (A) Concentration of 10 as a function of irradiation time with inset showing the
formation of the adduct (10-MeOHad) formed between 10 and methanol, and (B) a
comparison of the increase in concentration of 10-MeOHad when oxygen is present and when
not.
Direct irradiation of an 11 mM solution of 13 in methanol at λ = 254 nm for 24
hours, and continuous monitoring with GC-MS, revealed that its decomposition is slower than
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that of 10 (see Figures S36 – S40). As naphthalene has an ISC of 0.75 [49] the process likely
progresses in the T1 state. The ring-opened adduct (13-MeOHad) appears after seven hours
and reaches a maximum after eleven hours (to a conversion of merely <1%). Compound 13,
which should be labeled as T1 antiaromatic based on both previous findings for
naphthalene[16] and our computations (vide infra) has decomposed fully after 24 hours. Here it
should be noted that the molar absorptivity of naphthalene (~3500 M-1cm-1) is more than an
order of magnitude higher than that of benzene (~215 M-1cm-1), yet, the rate of cPr ring-
opening is considerably slower in 13 than in 10 (Figure S41). Thus, the difference in the
observed rate of cPr ring-opening is not related to the difference in absorptivity but most
likely due to the higher activation barrier for cPr opening in 13.
Our hypothesis as well as computations predict a drastically different reactivity
of 11 when compared to 10 and 13. Indeed, when 11 was irradiated for 24 hours in presence
of methanol at 254 nm only starting material was recovered (Scheme 4). As COT has a very
[35]
low ISC
this finding applies to the S1 state, and it is in line with the high calculated S1
state activation barrier of 11 (Figure 8) or short S1 lifetime. Yet, 11 can be excited to the T1
state since efficient energy transfer from triplet pyrene and anthracene to COT takes place.[35]
Still, 11 is recovered unreacted when irradiated at 300 nm in presence of triplet sensitizers,
and we conclude that the cPr ring is not opened because an intermediate would have been
trapped by MeOH. This low reactivity is in line with the observation by Paquette and co-
workers that dialkyl-COTs in presence of acetone are persistent to photolysis.[16,18] Our data
show that even an alkyl substituent which normally is labile to (di)radical character remains
unaffected when COT is irradiated. This is a strong indication that the cyclopropyl group can
identify excited state aromatic cycles. Yet, what is the situation for more complex polycyclic
molecules influenced by excited state aromaticity, e.g., biphenylene?
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Scheme 4: Photoreactions of 11 with MeOH, with or without sensitizer.
Indeed, there is literature support for photochemical persistence of
cyclopropylbiphenylene derivatives because Wu and co-workers synthesized such species by
a photochemical route ( = 254 nm).[50] The UV absorption spectrum of 15 shows a major
absorption at λ = 255 nm and a small band at around 300-350 nm (see Figure S50),
resembling the published spectrum of biphenylene.[51] Interestingly, no ring-opening was
observed upon direct irradiation of a 16 mM solution at λ = 254 in presence of methanol, not
even after 24 hours of irradiation. However, this lack of photoreactivity can be connected to
the short S1 state lifetime (0.23 ns) [25] when compared to the lifetime of cyclopropylcarbinyl
radical (14.9 ns). [52-54,36] Moreover, as the activation energy for cPr ring-opening in the S1
state likely is equally high or higher than in the T1 state, and as the ISC of biphenylene is low
(ISC ≤ 0.01),[52] it is presumable that photoexcited 15 decays to the S0 state before the cPr
group can open. This reveals a limitation of the cPr group as an excited state aromaticity
indicator.
When naphthalene was used as a triplet sensitizer in fivefold excess 15 was fully
decomposed after 14 h, however, also the concentration of naphthalene decreased
continuously in this process (Figures S43 – S45). In contrast, only starting material is
recovered if we irradiate a 5 mM solution of 15 in MeOH at 254 nm for 24 hours in presence
of Xe, known to increase the spin-orbit coupling and intersystem-crossing due to the heavy
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atom effect.[55] According to our calculations the cPr group of 15 opens over a barrier of 14.4
kcal/mol, possible to overcome in the T1 state but only slowly, resembling the Z/E-
photoisomerization of 3-(prop-1-enyl)perylene.[44] This combined suggests that 15 is
photostable when the reaction is performed under constant supply of Xe.
Changes in excited state (anti)aromaticity upon cPr ring-opening: To what
extent are the shapes of the T1 state PESs for cPr ring-openings of 8 – 15 connected to
changes in (anti)aromaticity? We first compared the potentially T1 aromatic 8 and 11 against
the potentially T1 antiaromatic 9 and 10 using HOMA (harmonic oscillator model of
aromaticity) and ACID (anisotropy of the induced current density) plots, and subsequently
analyzed the polycyclic 12 – 15. Changes in S1 state (anti)aromaticity in 10 and 11 were only
assessed via changes in CC bond lengths.
3
3
3
The HOMA values of 8-closed and 11-closed are both positive, and for 11-
closed it corresponds to a strongly aromatic COT cycle (Figure 10). Similarly, the ACID plots
show that both compounds have diatropic (aromatic) ring-currents. Cyclopropyl ring-opening,
3
3
giving 8-open and 11-open, leads to structures with lowered HOMA values and loss of the
diatropic ring-currents according to the ACID plots. This reveals loss of T1 aromaticity. In
3
3
contrast, for 9-closed and 10-closed, which have 6-electron cycles, the HOMA values are
negative indicating antiaromatic character (Figure 10), and this is supported by paratropic
3
3
(antiaromatic) ring-currents. Upon cPr ring-opening, leading to 9-open and 10-open,
respectively, the compounds go from antiaromatic to aromatic; in particular the HOMA of 310
3
3
3
3
increases by 1.308 to 0.861. Taken together, 8 and 11 versus 9 and 10 display opposite
changes in their (anti)aromatic characters upon cPr ring-opening. This connects well with the
shapes of the T1 PESs; in 8 and 11 T1 aromaticity is lost in the endergonic cPr ring-openings
while 9 and 10 alleviate T1 antiaromaticity in strongly exergonic processes.
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Figure 10: ACID plots of 38 – 311 at (U)B3LYP/6-311+G(d,p)//(U)B3LYP/6-311G(d,p) level
(for larger images see the Supporting Information) and HOMA values at the (U)B3LYP/6-
311G(d,p) level. Black clockwise arrows represent diatropic (aromatic) ring-currents and red
counter-clockwise arrows paratropic (antiaromatic) ring-currents. A = aromatic, NA = non-
aromatic and AA = antiaromatic.
3
3
For cPr-substituted naphthalenes 12-closed and 13-closed, the HOMA(peri)
values, i.e., the HOMA values based on the CC bonds of the perimeter, suggest weakly
aromatic character while the ACID plots show paratropic ring-currents (Figure 11). Yet, both
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3
3
HOMA and ACID reveal that cPr ring-opening, leading to 12-open and 13-open, is linked
to antiaromaticity relief and aromaticity gains in line with the exergonic reaction energies of
Figure 6.
3
3
Figure 11: ACID plots of 12 – 15 at (U)B3LYP/6-311+G(d,p)//(U)B3LYP/6-311G(d,p)
level (for large images see the Supporting Information) and HOMA values at (U)B3LYP/6-
311G(d,p) level. Black clockwise arrows in the ACID plots represent diatropic (aromatic)
ring-currents and red counter-clockwise arrows represent paratropic (antiaromatic) ring-
currents. The HOMA values for the perimeters are indicated as HOMA(peri). A = aromatic,
NA = non-aromatic and AA = antiaromatic.
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3
3
The perimeters of 14-closed and 15-closed are influenced by Baird-
aromaticity according to both HOMA (HOMA(peri) = 0.754 and 0.721, respectively) and
ACID plots displaying diatropic ring-currents, in line with biphenylene being an aromatic
chameleon (Figure 7). This T1 aromaticity is disrupted upon ring-opening, but as the
compounds are polycyclic the (anti)aromatic features of the ring-opened isomers are complex.
Moreover, and opposite to 8 and 11, the process is neither particularly exergonic nor
endergonic since 314-open and 315-open can adopt some local (Hückel-)aromatic character in
the six-membered rings. Clearly, polycyclic molecules pose limitations to the usage of the cPr
group as an excited state aromaticity indicator.
Finally, in the S1 state we only consider 10 and 11. In 10-closed all CC bond
lengths in the benzene ring are nearly equal (1.431 - 1.441 Å) while upon ring-opening they
become alternating single and double bonds (1.364 – 1.461 Å, see Figure S70 for plots of
bond length alternation). The significant CC bond elongation in 10-closed is noteworthy and
could be a collective response which alleviates a strongly antiaromatic character at the
vertically excited S1 state structure. In the S1 state of 11-closed the CC bonds in the COT ring
are found within 1.404 – 1.417 Å, and the bond length alternation in 11-open (1.395 – 1.423
Å) is also small when compared to that in 10-open (see Figure S71).
cPr-Substituted heterocycles with 4n or 4n+2 -electrons: Many heterocyclic
compounds are aromatic in their S0 states,[56] and can be T1 and S1 state antiaromatic provided
these states are of * instead of n* character. However, as heteroatoms have different
electronegativities than carbon, excited state antiaromaticity can be attenuated through
electron density redistributions. Moreover, electronegativity differences and/or poor size
matches between the p-AOs of heteroatoms and those of carbons can weaken the -
conjugation and aromaticity.[57] Accordingly, both (4n+2)- and 4n-electron heterocycles
may display properties that resemble those of the T1 nonaromatic 2 – 7. We examined a
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selection of heterocyclic compounds with cPr substituents at the various positions and with
* T1 states. We excluded 2- and 3-cyclopropylpyridine and 2-cyclopropylthiophene as their
T1 states are of nπ* character. Moreover, we did not consider S1 state processes as this part of
the study explores to what extent the nature of the heterocycles (4n vs. (4n+2)) influences
the activation and reaction energies. Are there similar effects in the T1 states of cPr substituted
heterocycles as in compounds 8 - 11?
The cPr substituted 6-electron heterocycles 26 - 31 showed highly exergonic
cPr ring-opening reactions (Figure 12), but less so than 10, indicating weakened T1
antiaromaticity. Among the cPr substituted heterocycles with 4n π-electrons (16 – 25) nearly
all had endergonic reaction energies. However, 16 and 18 have exergonic ring-opening
reactions, likely due to poor heteroatom-carbon -overlap yielding T1 nonaromatic
compounds. Among the cPr-substituted azepins (19 - 21) and oxepins (23 - 25), the oxepins
have 2 - 5 kcal/mol less endergonic reactions. Interestingly, the N-cyclopropyl substituted
4n-electron compounds 17 and 22 have considerably higher reaction energies than their
carbon substituted isomers.
With regard to the activation energies it can first be noted that the N-
cyclopropylated compounds have significantly higher activation barriers than those with the
cPr group attached at a C atom. Here, we focus on the latter isomers. The activation energies
of all compounds with 6-electron cycles, except 28, have similar or slightly higher barriers
to cPr ring opening than 10. Importantly, all 6-electron compounds with cPr substituents
attached to a C atom have activation energies which are lower by 4 - 5 kcal/mol than the
nonaromatic reference line (Figure 14 and Table S2). The situation is different for the 8-
electron azepins 19 – 21 as they have activation barriers in the range 16 - 22 kcal/mol, and
those of oxepins 23 - 25 are 14 – 22 kcal/mol. On the other hand, the 8-electron compounds
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16 and 18 have activation barriers similar to those of the nonaromatic 1 – 7, revealing that
when T1 aromaticity is attenuated, the cPr group will open.
Now, combining the activation energies of the heterocyclic compounds 16 – 31
with those of the all-carbon species 8 – 15 it becomes clear that species with (4n+2)-electron
cycles generally have lower activation barriers than had they been nonaromatic (Figure 14).
Conversely, the 4n-electron species have higher barriers than estimated from the
nonaromatic references.
Figure 12: T1 state Gibbs free energies of reaction of cyclopropyl ring opening of cyclopropyl
substituted heterocycles with either 4n or 4n+2 -electrons.
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Figure 13: Activation free energies at the (U)B3LYP/6-311G(d,p) level for cyclopropyl
substituted heterocycles with 4n and 4n +2 π-electrons in the T1 state.
Figure 14: Activation free energies of cPr ring-opening of heterocycles 16 – 31 and all-
carbon compounds 8 – 15 plotted against the spin density (QTAIM) at the C atom at which
the cPr group is attached. The dashed line displayed is the regression in the least-squares fit of
the data for nonaromatic reference compounds 1 – 7. Positive spin density values represent
excess of -spin density, negative values excess of -spin density. Filled circles for 16 – 25
and squares for 26 - 31. Empty circles and squares for all-carbon T1 aromatic and T1
antiaromatic compounds, respectively.
Conclusions and Outlook
When a cyclopropyl substituted annulene is irradiated the effect on the cyclopropyl group is
strongly determined by the excited state character of the annulene. The cPr group is known to
act as a radical probe due to its tendency to ring-open when next to radicals and
diradicals.[23,24] Yet, our hypothesis is that it remains closed when attached to an annulene
which is T1 and S1 state aromatic as its ring-opening will ruin the ESA character. Indeed,
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through comparison with nonaromatic compounds we reveal that cPr substituted 4n-electron
annulenes and heterocycles have T1 state activation barriers for C-C cleavage of the cPr
group where 1.6 – 6.0 kcal/mol result from resistance to loose T1 aromaticity (Figure 14). In
contrast, compounds with (4n+2)-electron cycles have activation barriers that are lower by
1.7 – 7.7 kcal/mol than had they been nonaromatic. This reveals a drive to alleviate T1
antiaromaticity.
Our computations show that 4n-electron heterocyclic compounds with one
heteroatom (e.g., azepins and oxepins) will keep the cPr group closed. With several
heteroatoms in the ring the T1 aromatic character is weakened due to attenuated -orbital
overlap, and as a result, the latter species have calculated T1 PESs resembling those of T1
nonaromatic molecules. Polycyclic compounds influenced by excited state aromaticity are
also complex since parts of the polycyclic moieties can adopt (Hückel-)aromaticity in the cPr
ring-opened isomers, leading to greater stabilizations than what is the case for the
corresponding isomers of those with monocyclic 4n-electron units.
At this point it should be stressed that the cPr group differentiates excited state
aromatic cycles from excited state antiaromatic and nonaromatic ones. A separate probe needs
to be identified for the excited state antiaromatic cycles, one where antiaromaticity lowers the
activation energy to such an extent that it exclusively ring-opens for excited state antiaromatic
cycles. We postulate that cyclopentyl or cyclohexyl groups have this ability, yet, such studies
will be reported separately.
Finally, from an applications perspective our study outlines in which -
conjugated structural environments the cPr group leads to light-sensitive vs. light-insensitive
compounds, findings of potential use in pharmaceutical chemistry as the cPr group is
frequently found in drug molecules.[37
]
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Materials and Methods
All chemicals required for the synthesis were purchased from Sigma Aldrich (> 97% purity)
and used without further purifications. Compounds 11, 13 and 15 were synthesized while 10
was purchased from Sigma Aldrich (> 99.0%). All solvents (n-heptane and methanol) used
for photosolvolysis were anhydrous. Distilled pentane was used for coloumn chromatography
and recrystallization. De-ionized water was used during synthesis. NMR spectra were
recorded on Agilent MR (1H-NMR at 399.97 MHz, 13C-NMR at 100.58 MHz). 1H-NMR and
13C-NMR spectra were referenced against CDCl3 at 7.26 ppm and 77.16 ppm, respectively.[58]
Photoreactions were monitored with the Gas Chromatography – Mass Spectrometry (GC-
MS). Split-injection (2μL injection volume; Split Ratio: 100:1; 250 oC inlet temperature; Flow
Rate: 120 mL/min) was used for injecting samples. The starting temperature of the column
o
o
oven was 70 C (0.5 min equilibration time) and the ending temperature was 320 C. The
temperature rate was set to 20 oC/min resulting in a 12.5 min total run time. Helium was used
as a carrier gas (flow rate: 1.2 mL/min). The column used was an Aligent 19091S-433: 325
oC: 30 m x 250 μm x 0.25 μm (front SS-inlet: He; out: vacuum). Masspectrometer: Source
temperature: 250 oC, Quad-temperature 150 oC. Varian Cary 50 UV-visible spectrometer was
used for recording the UV-Visible spectra in between 200 – 800 nm wavelength range.
Elemental analysis of compound 15 was recorded at Eurofins Mikro kemi AB, Uppsala.
An RPR-100 Rayonet Photochemical Chamber Reactor was used for
photostability and photosolvolysis study. Two different sets of lamps were used depending on
the excitation wavelength of the experiment: a set of 16 UV lamps at 2537 Å with a total
power of 35 W or a set of 16 UV lamps at 3000 Å with total power of 35 W. Photoreactions
were performed on two different scales; 15 mL quartz cylindrical tubes (RQV-5: Rayonet; Ø
13 mm) were used for the medium-scale photoreactions and for the large-scale photoreactions
cylinders made of quartz with 185 mL capacity (RQV-118: Rayonet; Ø 20 mm) were used.
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Computational details
Most of the quantum chemical calculations were performed at the (U)B3LYP hybrid density
functional theory with the Pople basis sets 6-31G(d)[59-61] and 6-311G(d,p)[62] using Gaussian
09 revision D.01.[63] Frequency calculations were carried out at the same level of theory to
confirm stationary points with no imaginary frequencies. All transition states were confirmed
by intrinsic reaction coordinate (IRC) calculations.[64] The Harmonic oscillator model of
aromaticity (HOMA) was used as a structural index of aromaticity and values were calculated
at the (U)B3LYP/6-311G(d,p) level.[65] For polycyclic molecules, HOMA(peri) values based
on the CC bonds of the perimeter of whole molecules are also considered. Positives values
close to one correspond to aromatic compounds, negative to antiaromatic compounds, and
values closed to zero correspond to nonaromatic compounds. The Anisotropy of the Induced
Current Density (ACID) was used for visualizing electron delocalization and ring currents.[66]
ACID plots were generated with the ACID 2.0.0 program[67] using the Continuous Set of
Gauge Transformations (CGST) method at the B3LYP/6-311+G(d,p) level.[68] The MOLCAS
8.1 quantum chemistry program package[69] was used to run CASSCF[70] and CASPT2[71]
calculations with the ANO-RCC-VTZP[72] basis set. Compounds 10 and 11 were optimized in
the S1 state with CASSCF/6-31G(d) using state-average calculations of the two and three
lowest singlet excited states using an active space of (8,8) and (10,10), respectively. The
transition state (TS) of 10 was also confirmed by IRC analysis. For 11, the TS was found by
1
1
linear interpolation in internal coordinate method between the 11-closed and 11-opened
optimized structures. The electronic energies were calculated by MS-CASPT2/ANO-RCC-
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VTZP at the CASSCF/6-31G(d) optimized geometries. Frequency calculations were
performed at CASSCF/6-31G(d) level to confirm the true minima and the transition states.
Atomic spin densities were calculated according to the Mulliken,[ 73 ] Natural Population
Analysis (NPA)[74] and the Quantum Theory of Atoms in Molecules (QTAIM)[75] schemes,
with Gaussian09, NBO6[76] and Multiwfn 3.3.8 (using a grid spacing of 0.10 Bohr),[77]
respectively.
Acknowledgements: We are grateful to the Erasmus Mundus EXPERTS III program for PhD
scholarship to R.A., the Wenner-Gren Foundations, and the Swedish Research Council (grant
2015-04538) for financial support. Moreover, H.O. thanks Joakim Bergman and Per-Ola
Norrby, AstraZeneca Gothenburg, for stimulating discussions on the cyclopropyl group in
pharmaceutical chemistry. We also thank the SNIC (Swedish National Infrastructure for
computing) through NSC (National Supercomputer Center), Linköping, and UPPMAX,
Sweden for generous allotment of computer time.
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[3] R. Papadakis, H. Ottosson, Chem. Soc. Rev. 2015, 44, 6472-6493.
[4] M. J. S. Dewar, Tetrahedron Suppl. 1966, 22, Supplement 8, 75-92.
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[6] N. C. Baird, J. Am. Chem. Soc. 1972, 94, 4941-4948.
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