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org/joc

Temperature Dependence of Regioselectivity in Nucleophilic

Photosubstitution of 4-Nitroanisole. The Activation Energy Criterion
for Regioselectivity
Gene G. Wubbels,* Hanan Danial, and Danielle Policarpio
Department of Chemistry, University of Nebraska at Kearney, Kearney, Nebraska 68847, United States

[email protected]
Received August 12, 2010

Photosubstitution of the nitro group vs the methoxy group of triplet 4-nitroanisole by hydroxide ion
in water leads to product yields of about 80% 4-methoxyphenol and 20% 4-nitrophenol. The ratio
depends slightly on temperature from 3 to 73
C. The slight temperature variation in the yield ratio is
reproduced almost perfectly with a simple Arrhenius model for a mechanism involving bonding of
hydroxide ion with the triplet state of 4-nitroanisole. The competing transition states have activation
energies of 2.2 and 2.6 kcal/mol, respectively. Correct prediction of regioselectivity can be done for
this case by quantum chemical calculation of the competing triplet transition-state energies, or those
of the corresponding triplet σ-complexes. Other models for aromatic photosubstitution regioselec-
tivity in mechanisms of the SN2Ar* type, such as those based on calculated electron densities,
HOMO/LUMO coefficients, or energy gap sizes, are discussed and shown to be inferior to the
relative activation energies model. The photoreaction in alcohol solvents, claimed by others to
generate the same products as in water and to have an exceedingly large variation of the product ratio
with temperature, may reflect chemical changes other than those reported.

Introduction reaction mechanisms.2-5 It seemed odd that, despite the

long history of attempts to explain the regioselectivity of
When it became clear that photochemical reactions in
nucleophilic aromatic photosubstitution reactions,6-13 no
condensed phases occurred typically from thermally relaxed,
one to our knowledge had examined the utility of relative
electronically excited molecules, pioneering photochemists
suggested that the temperature dependence of reaction rate (5) Gonzales, C.; Pincock, J. Photochem. Photobiol. 2006, 82, 301.
constants from excited states would be governed by the (6) Zimmerman, H. E.; Somasekhara, S. J. Am. Chem. Soc. 1963, 85, 922.
Arrhenius equation.1 Many studies have shown the useful- (7) Cornelisse, J.; Havinga, E. Chem. Rev. 1975, 75, 353.
(8) Epiotis, N. D.; Shaik, S. J. Am. Chem. Soc. 1978, 100, 29.
ness of this model in the investigation of photochemical (9) van Reil, H. C. H. A.; Lodder, G.; Havinga, E. J. Am. Chem. Soc.
1981, 103, 7257.
(10) Mutai, K.; Nakagaki, R.; Tukada, H. Bull. Chem. Soc. Jpn. 1985, 58,
(1) Franck, J.; Rabinowitsch, E. Trans. Faraday Soc. 1934, 30, 120. 2066.
(2) Fischer, E. J. Am. Chem. Soc. 1960, 82, 3249. (11) Cantos, A.; Marquet, J.; Moreno-Ma~ nas, M; Gonzalez-Lafont, A.;
(3) Encina, M. V.; Lissi, E. A.; Lemp, E.; Zanocco, A.; Scaiano, J. C. Lluch, J. M.; Bertran, J. J. Org. Chem. 1990, 55, 3303.
J. Am. Chem. Soc. 1983, 105, 1856. (12) Manickam, M. C. D.; Pitchumani, K.; Srinivasan, C. Proc. Indian
(4) Brozic, J. A.; Crosby, G. A. Coord. Chem. Rev. 2005, 249, 1310. Acad. Sci.(Chem. Sci.) 2003, 115, 273.

7726 J. Org. Chem. 2010, 75, 7726–7733 Published on Web 10/18/2010 DOI: 10.1021/jo1015882
r 2010 American Chemical Society
Wubbels et al.
JOC Article
activation energies. Although it was not aimed directly at this would be expected to generate photoproducts. We now
question, a recent study14 of the temperature dependence of report that the temperature dependence of photosubstitution
regioselectivity of photosubstitution on 4-nitroanisole by regioselectivity in pure water is modest and that alkoxide ion
hydroxide ion, which claimed a large dependence on tem- products are major photoproducts in alcohol solutions.
perature of relative product yields, aroused our interest. A
subsequent report15 added a claim of a large temperature Results
dependence of photosubstitution regiochemistry for the Photolyses of 4-nitroanisole (2.0
10 -4 M) in air-
same photoreaction. saturated 5% acetonitrile/water containing 0.010 M NaOH
Our investigation16 of the element effect of halogen leav- were carried out initially at 313 nm (Scheme 1). We found by
ing groups in nucleophilic aromatic photosubstitution of UV-vis monitoring of the reactions that the absorption of the
2-halo-4-nitroanisoles had shown normal, fast, elementary 4-nitrophenoxide ion (PNPh) product (λmax 400 nm, ε 18,300)
rate constants for the photosubstitutions of the nitro and was easily identifiable, but that of the 4-methoxyphenoxide
methoxy groups of triplet 4-nitroanisole by hydroxide ion in ion (PMPh) product (λmax 306 nm, ε 2920) was obscured by
aqueous solution. These findings for 4-nitroanisole extended absorptions of unknown origin centered at 350 nm.18 This
and agreed with those of the original investigation of these result had been noticed by the original investigators of this
photoreactions.17 That study found that hydroxide ion in reaction,17 who attributed the unknown absorptions to
aqueous media displaced the nitro group and the methoxy degradation of the PMPh product. They found that the
group of triplet 4-nitroanisole in a ratio of about 4:1 at 26 and photoreaction gave the two products shown in Scheme 1
3
C. That photolysis of 4-nitroanisole in solutions of sodium quite cleanly if air was excluded. We confirmed this result,
hydroxide in alcohol solvents was reported14 to give product and we found that use of a uranium glass filter (λ > 330 nm)
ratios varying from 99:1 at -20
C to 0.6:1 at 196
C was very further improved the cleanness of the reaction.
surprising. That the photoreactions were reported to give rise Overlaid UV-vis spectra (225-500 nm) for the photolysis
exclusively to hydroxide ion photodisplacement products at ∼25
C of 4-nitroanisole (5.4
10-5 M) in argon-purged
was also unexpected. Prototropy would cause such solutions pure water solution with 0.10 M NaOH through the uranium
to contain little hydroxide ion and much alkoxide ion that filter are shown in Figure 1. The isosbestic points at 365 and
262 nm indicate a single-stage, simple reaction, after which
SCHEME 1. Photosubstitution Reactions of Hydroxide Ion the absorptions of the 4-nitrophenoxide ion at 400 nm and
with 4-Nitroanisole the 4-methoxyphenoxide ion at 306 nm are clearly visible.
These absorptions allowed quantitative monitoring of the
two products. The isosbestic point at 365 nm was sharp
under all temperature conditions. The isosbestic point at
262 nm was sharp at 3
C, but slightly ragged at 37
C and at
73
C. When samples were irradiated exhaustively at 3
C,
the UV-vis absorptions of the two products in three runs

FIGURE 1. Electronic spectra for photolysis of 4-nitroanisole (5.4
10-5 M) in aqueous 0.10 M NaOH after irradiation for 0, 2, 4, 8, 16, and
24 min at 25
C.

J. Org. Chem. Vol. 75, No. 22, 2010 7727

JOC Article Wubbels et al.

TABLE 1. Photolyses of 4-Nitroanisole (5.4
10-5 M) in Water Containing 0.020 M NaOH

trial T,
C A¥, 400 nm h, M (
105)
PNP h
% PNP h
mean % PNP h
mean % PMP
1a 3 0.190 1.04 19.1 19.0 81.0
1b 3 0.189 1.03 18.9
2a 37 0.203 1.11 20.4 20.5 79.5
2b 37 0.204 1.12 20.6
3a 73 0.214 1.17 22.1 21.8 78.2
3b 73 0.215 1.18 21.5

accounted for 99.6, 99.4, and 97.2% of the moles of 4- TABLE 2. Arrhenius Theory Calculations for Nitro vs Methoxy Sub-
nitroanisole. This indicates a quantitatively clean reaction giving stitution by Hydroxide Ion in Triplet 4-Nitroanisole with Activation
Energies of 2.17 and 2.58 kcal/mol, Respectively
two products. At the higher temperatures, the two product
absorptions accounted for about 95% of the reactant, owing temperature,
C knitro
10-7 0.5kmethoxy
10-7 % PNP h % PMPh
to some slight thermal or photochemical degradation of the 3 5.74 1.36 19.1 80.9
4-methoxyphenoxide product, as reported previously.17 At 37 8.85 2.27 20.4 79.6
73 12.8 3.51 21.6 78.4
all temperatures, therefore, we used the clearly quantifiable
amount of 4-nitrophenoxide as the measure of methoxide ion
displacement, and the difference from the total molarity of effects, nucleofugality is related to acidities of the conjugate
4-nitroanisole as the quantitative measure of nitrite ion acids,20 which are very similar.21 The actual rate constant for
displacement, giving 4-methoxyphenoxide ion. The results attack at the methoxy-bearing carbon, therefore, should be a
of exhaustive irradiations at three temperatures for the two factor of 2 greater than that inferred from the yield of PNPh.
product yields determined in this way are shown in Table 1. That is, the total rate constant for loss of starting material
A control experiment showed that PNPh, a possible thermal (9.6
107 M-1 s-1) is equal to knitro þ 0.5kmethoxy. We also
hydrolysis product, was not formed detectably by UV-vis know from the observed product yields of 80% and 20% that
monitoring when 4-nitroanisole was heated in the dark in knitro/0.5kmethoxy is equal to 4. The solution of the simulta-
aqueous 0.020 M NaOH at 80
C for a time period equal to neous equations yields the nucleophilic attack rate constants
that of the photochemical reaction. at 25
C of 7.68
107 M-1 s-1 for attack at the nitro-bearing
It is clear that temperature increases cause a modest carbon (knitro), and 3.84
107 M-1 s-1 for attack at the
increase in the yield of the methoxy displacement product, methoxy-bearing carbon (kmethoxy). We assume that the A
PNPh, and a corresponding decrease in the amount of the factor in the Arrhenius equation (ln k = -(Ea/RT) þ ln A) is
nitro displacement product, PMPh. the fastest intermolecular reaction in the medium at 25
C,
If the two reactions represent a simple competition be- which is approximated by the diffusion rate constant. For
tween two pathways from the triplet having different activa- reactants in water with no ionic attraction or repulsion, that
tion energies, it should be possible to reproduce the changes rate constant is 3
109 M-1 s-1.22 On this basis we calculated
in product yields as a function of temperature with Arrhenius the activation energies for the two operative reactions. The
theory. The rate constants were obtained from results we values are 2.17 kcal/mol for attack at the nitro-bearing car-
reported for triplet 4-nitroanisole and hydroxide ion at bon and 2.58 kcal/mol for attack at the methoxy-bearing
approximately 25
C in 33% acetonitrile/water.16 The sum carbon. We then calculated the rate constants for each dis-
of the two reaction rate constants from the triplet state of placement reaction at the various temperatures. The results
4-nitroanisole is 9.6
107 M-1 s-1 for displacement of the and the consequent product ratios are given in Table 2. The
nitro group and displacement of the methoxy group.16 The agreement of the product yields at various temperatures cal-
total rate constant was obtained by Stern-Volmer kinetics, culated by using the Arrhenius equation with those of ex-
which depend on reactant disappearance as the photoprod- periment is excellent. This supports the view that the nucleo-
ucts are formed. We judged16 the intermediate σ-complex phile attacks the triplet at two sites that are differentiated by
for nitro displacement to partition fully to product because slight differences of activation energy.
nitrite ion is far superior to hydroxide ion as a nucleofuge.19 The large temperature effects on photosubstitution ratios
The σ-complex for methoxy displacement is expected to in 4-nitroanisole by hydroxide ion in alcohol solvents were
partition between product and reactant in a ratio of about attributed14 to nitro displacement occurring with a very low
1:1 because the methoxide and hydroxide nucleofuges are activation energy and methoxy displacement involving a
comparable. In such cases in the absence of complicating considerable activation energy. The claimed changes from
a product ratio (nitro:methoxy) of 99:1 at -20
C, to 9:1 at
25
C, to 0.6:1 at 196
C cannot be rationalized, however,
(13) Pinter, B.; De Proft, F.; Veszpremi, T.; Geerlings, P. J. Org. Chem. with an Arrhenius model. With the activation energies
2008, 73, 1243. needed to give a 9:1 ratio at 25
C, as reported,14 the change
(14) Klan, P.; Ruzicka, R.; Heger, D.; Literak, J.; Kulhanek, P.; Loupy,
A. Photochem. Photobiol. Sci. 2002, 1, 1012. to the ratio of 99:1 by Arrhenius theory would require a tem-
(15) M€ uller, P.; Loupy, A.; Klan, P. J. Photochem. Photobiol., A 2005, perature below -200
C, and a temperature of 500
C would
172, 146. predict a product ratio of only 1.3:1. In fact, a temperature
(16) Wubbels, G. G.; Brown, T. R.; Babcock, T. A.; Johnson, K. M.
J. Org. Chem. 2008, 73, 1925. nearing infinity could cause the product ratio only to
(17) Letsinger, R. L.; Ramsay, O. B.; McCain, J. H. J. Am. Chem. Soc.
1965, 87, 2945.
(18) The phenolic products, PMP and PMP, are ionized completely by the (20) Stirling, C. J. M. Acc. Chem. Res. 1979, 12, 198.
alkaline medium to PMP h and PNP h after they are formed. (21) Ballenger, P.; Long, F. A. J. Am. Chem. Soc. 1960, 82, 795.
(19) Broxton, T. J.; Muir, D. M.; Parker, A. J. J. Org. Chem. 1975, 40, (22) (a) Eigen, M. Angew. Chem., Int. Ed. Engl. 1964, 3, 1. (b) Weller, A.
3230. Z. Physik. Chem. 1958, 17, 224.

7728 J. Org. Chem. Vol. 75, No. 22, 2010

Wubbels et al.
JOC Article
SCHEME 2. Photoreaction Species and Sequence for 4-Nitroanisole and Hydroxide Ion

approach 1:1. This suggested that products other than those Scheme 2, and the calculated structures and Gibbs free
claimed were being measured. That the reaction system energies at 298 K are shown in Table 3. The Gibbs energies
could give other products could be inferred from a proto- are calculated from the total energy, after calculation of the
tropic equilibrium effect that was not noted in the report. vibrational frequencies, by correcting for the zero-point
Ethanol has acidity comparable to that of water. With vibrational energies, and the entropy and enthalpy changes
acidity constants of 1.3 and 1.8
10-16 M-1 for ethanol and from zero to 298 K. We also calculated most of the species at
water, respectively,21 the prototropic equilibrium in the higher levels of theory including Hartree-Fock 6-31G*,
reported medium of pure ethanol (or the other primary 6-31þG*, and DFT-B3LYP/6-31G*. These more costly
alcohols used) containing 0.2 M NaOH can be calculated calculations did not produce significantly different or more
quickly to have about 2% of the base in the form of hydrox- reasonable energy increments or geometries. We could not
ide ion, with most of it in the form of alkoxide ion. We apply solvation models to open-shell species, but we could
verified only that the products of photolysis of 4-nitroanisole for triplet transition states. The energy differences of
in 0.2 M NaOH in absolute ethanol were indeed complex. In solvated vs nonsolvated transition states were comparable,
our hands, GC/MS analysis of the photolysis products implying that calculation errors and solvation effects can-
indicated 4-ethoxyanisole (41%), 1-ethoxy-4-nitrobenzene celed each other out for comparable species. The vibrational
(7%), 4-methoxyphenol (38%), and 4-nitrophenol (9%). We frequencies for the transition states included the expected
also detected minor amounts of photoreduction products imaginary frequency for stretching the nucleophile-carbon
such as 4-methoxyaniline and 4,40 -dimethoxyazoxybenzene, bond, with the exception of entry 6. This calculation con-
a process with precedent for other nitroaromatics in alco- verged to an energy maximum saddle point but did not give
holic alkali.23 As in the earlier work,14 we did not dehydrate an imaginary frequency. Of several encounter complexes
our absolute ethanol. Adventitious water may be the cause of found, we have shown as entry 1 only the one of highest
the substantial yields of photosubstitution products of hy- energy.
droxide ion.
Because we were interested in a model for regioselectivity Discussion
with predictive power, we carried out quantum chemical
It has been shown by photosensitization24 and transient
calculations on the reactants, transition states, and intermediates
spectroscopy16 that the excited state of 4-nitroanisole popu-
of the probable mechanism to see if the regiochemical find-
lated rapidly and efficiently by photoexcitation in water is
ings could be discovered by calculation. The Spartan ’08
the triplet (Et ≈ 60 kcal/mol).25 Kinetic17 and quenching26
quantum chemical software at the Hartree-Fock/3-21G(*)
evidence suggested that nucleophiles react directly with
level of theory efficiently found the molecular species
postulated. They are identified in the reaction sequence in
(24) Letsinger, R. L.; Steller, K. E. Tetrahedron Lett. 1969, 1401.
(25) Brinen, J. S.; Singh, B. J. Am. Chem. Soc. 1971, 93, 6623.
(23) Frolov, A. N.; Kuznetsova, N. A.; El’tsov, A. V.; Rtishchev, N. I. Zh. (26) Bonhila, J. B. S.; Tedesco, A. C.; Nogueira, L. C.; Diamantino, M. T.
Organ. Khim. 1973, 9, 963. R. S.; Carreiro, J. C. Tetrahedron 1993, 49, 3053.

J. Org. Chem. Vol. 75, No. 22, 2010 7729

JOC Article Wubbels et al.

TABLE 3. 4-Nitroanisole-Hydroxide Ion Reaction Species Calculated and Kronenberg.27 This rationale lost relevance when it
by Hartree-Fock/3-21G(*) became clear that the nitroaromatic nucleophilic photosub-
stitutions proceeded from the triplet state.24 A reexamina-
tion of the charge criterion using the triplet-state charge
densities, however, concluded that the charge criterion was
still unsatisfactory.9 Application to the photosubstitutions
of 4-nitroanisole was noted as a particular failing of the
approach. That calculated charge at nuclear positions is
unrelated to predominant regioselectivity of substitution
could be inferred also from the absence of regiochemical
effects of charge of nucleophiles. In the case of triplet
4-nitroanisole, for example, the negatively charged nucleo-
phile, hydroxide ion, displaces mainly at the positive charge
favored nitro-bearing carbon, but the neutral nucleo-
philes, ammonia and pyridine, displace exclusively at that
position.7,17
Epiotis and Shaik8 suggested on the basis of frontier
molecular orbital theory (FMO) that the regioselectivity of
nucleophilic aromatic photosubstitution could be predicted
by the ring carbon atom (bearing a displaceable group)
calculated to have the largest orbital coefficient (or electron
density) in the HOMO of the ground state singlet.28 The
model was extended11,12,29 to photoreactions involving elec-
tron transfer from the nucleophile as the initial step
(SN(ET)Ar*),30 wherein the regioselectivity was claimed to
be related to the maximum LUMO coefficient of the ground-
state reactant.
The simple FMO model, or more sophisticated versions
such as those based on spin-polarized Fukui functions,13
predicts the major products of many nucleophilic aromatic
photosubstitutions of nitrophenyl ethers, but it fails in
several cases. It seldom accounts for the ordering of minor
products,16 and it predicts incorrectly for the cases of 4-nitro-
and 2-nitroanisole.13 Allowing for the absence of a nucleo-
fuge at the meta position, it predicts, as observed, that the
triplet nitrophenyl ethers. The halogen element effect evi- favored photodisplacement site for 4-nitroanisole and hy-
dence16 indicated that the initial steps of nucleophilic photo- droxide ion is the nitro-bearing carbon. It does not predict
substitutions proceeded within the triplet manifold through correct regioselectivity for the photoreaction of 4-nitroani-
triplet σ-complexes. That is, reaction of the triplet with the sole with cyanate or cyanide ion.7,16 It should be noted that
nucleophile appeared to be adiabatic, leading rapidly to a σ- these regioselectivity predictions for the nitrophenyl ethers
complex of the same multiplicity. Nonadiabatic reaction was are not risky, and yet they display a high level of error. The
unlikely because there is no electronic triplet state below the simple generalization that SN2Ar* reactions occur meta to
ground state triplet, and intersystem crossing was expected the nitro group and SN(ET)Ar* reactions occur para to the
to be too slow to account for the nucleophilic reaction rates. nitro group does as well as the FMO model or its extensions
The reaction rates approach the diffusion rate, and spin- to predict regioselectivity. It is possible that the HOMO and
orbit coupling effects of halogens on the nitroaromatics LUMO criteria amount only to a cumbersome method of
could not be discerned in the rates of nucleophilic attack.16 identifying the positions meta and para to the nitro group.
The photosubstitutions of triplet nitrophenyl ethers and We question the FMO model for regioselectivity first
many other nitroaromatics with nucleophiles have been the because the relationship of electron density in the ground
subject of many attempts to explain the reactivity and state singlet HOMO or LUMO to reaction from an excited
regioselectivity.6-13 The unusual orientation effect of sub- state triplet should be faint. The orbitals of the ground state
stituents in nucleophilic reactions, (and other reactions) of upon which the predictions rest do not even exist in the
excited aromatic molecules was recognized early by the reacting, excited molecule. Moreover, the bond formation
name, the “meta effect”.6 The effect was rationalized6 by with the nucleophile in SN2Ar3 is electron-paired and prob-
suggesting the occurrence of meta-bridged valence bond ably has nothing to do with the singly occupied, excited state
structures for zwitterionic excited-state reactants. This ra-
tionale, however, was mostly symbolic since it could not (27) Havinga, E.; Kronenberg, M. E. Pure Appl. Chem. 1968, 16, 137.
(28) This was originally stated as the maximum difference of the squares
accommodate the open-shell nature of the excited states and of the HOMO and LUMO coefficients. The authors, however, use the square
the triplet multiplicity. of the HOMO coefficient (HOMO electron density) as a sufficient measure.
The suggestion that charge density in the excited singlet (29) Bunce, N. J.; Cater, S. R.; Scaiano, J. C.; Johnston, L. J. J. Org.
Chem. 1987, 52, 4214.
state could explain regiochemistry in electrophilic and nu- (30) Mutai, K.; Kobayashi, K.; Yokoyama, K. Tetrahedron 1984, 40,
cleophilic photosubstitutions was put forward by Havinga 1755.

7730 J. Org. Chem. Vol. 75, No. 22, 2010

Wubbels et al.
JOC Article
HOMO, or the LUMO, to say nothing of the ground state energy than the favored meta triplet σ-complex. We
HOMO or LUMO. More importantly, it suffers the power- concluded16 that the energy gap interpretation of regioselec-
ful weakness of predicting favored reaction transition states tivity of these reactions was not correct. Indeed, the evidence
solely on the basis of properties of the reactant. This idea has pointed to nucleophilic aromatic photosubstitution of nitro-
an inglorious history in the annals of reactivity and regio- phenyl ethers occurring within the triplet manifold, that is,
selectivity discussions. It is analogous to inferring the regio- adiabatically. Evidence of the element effect on the elemen-
selectivity of electrophilic aromatic substitution reactions tary rate constants and the relative nucleophilicities of
from the resonance structures of reactants, a method that has different attacking reagents suggested, moreover, that the
long been proscribed.31 Standard practice for use of the bond formation process was electron-paired formation of a
resonance model is to consider the relative resonance stabi- σ-bond by the nucleophile with the triplet nitroaromatic
lization of cationic intermediates rather than the delocaliza- molecule.
tion or polarization of reactants to gain insight about the A recent theoretical study13 of the orientation rules em-
relative energies of the preceding transition states. This logic phasized photohydrolysis of nitrophenyl ethers including
rests on the Bell-Evans-Polanyi principle,32 which holds 4-nitroanisole. It modeled the reactions with density func-
that activation energy and enthalpy change are correlated for tional theory by calculating the geometries and energies of all
a set of comparable, elementary reaction steps. the likely encounter complexes, σ-complexes, and transition
Dewar has emphasized33 that there is no theoretical states within the ground state singlet or triplet manifolds. It
justification for reactivity or regioselectivity predictions in found local energy minimum σ-complex intermediates for
alternate or nonalternate π-electron hydrocarbon systems the reactions that had oxygen nucleofugic groups. For triplet
based on reactant properties at nuclear positions such as free 4-nitroveratrol (3,4-dimethoxynitrobenzene) and hydroxide
valence, self-polarization (charge density), and applications ion, the triplet transition state leading to the favored meta
in perturbation theory of HOMO coefficients of frontier σ-complex was found by B3LYP calculation to be 6.1 kcal
orbital theory. The successes that occur owe to the coin- lower in energy than the triplet transition state leading to the
cidence of calculated positional properties and relative tran- para σ-complex. A Møller-Plesset calculation of the same
sition-state energies. The sorting of preferred pathways species, however, reversed the energy difference (to -5.0
occurs on the basis of energy. Energy of a molecular species kcal). Both methods of calculation corroborated at high
can be defined only for the whole and not for particular levels of theory the earlier finding9 that the meta triplet
nuclear positions. Estimating the contribution of certain σ-complex for 4-nitroveratrol and hydroxide ion was lower
positional properties of reactants to prospective competing in energy (by 9.5 kcal) than the para triplet σ-complex. By
transition states is clearly inferior to estimating directly the confining its view to relative energies of successive species
energies of the competing transition states. within spin manifolds, however, it omitted consideration of
Another model for regioselectivity of SN2Ar* reactions whether triplet σ-complexes might undergo intersystem
claimed that the energy gap law for radiationless electronic crossing before completing the substitution reaction. For the
transitions should govern the favored pathways.9 The energy case of 4-nitroanisole, the regiochemical discussion ignored
gap law in electronic spectroscopy states that internal con- the predominant nitro displacement process. The regioselec-
versions between states close in energy are faster than those tivity conclusions of the calculations of this study were
between states far apart in energy. Since singlet meta-to-nitro mixed, but it was the first to use quantum chemical methods
σ-complexes or those for displacement of the nitro group to estimate the relative energies of competing photosubstitu-
have little resonance stabilization, they are much higher in tion transition states of the same multiplicity.
energy than the delocalized ortho or para σ-complexes. Thus Our experimental results for the temperature dependence
the transition from the triplet encounter complex to the less of the product ratio from 4-nitroanisole and those calculated
stable (meta) σ-complexes was thought to be faster than to with a simple Arrhenius model agree very well. This validates
the more stable (ortho or para) σ-complexes.9 the model of competing transition states in the triplet mani-
The energy gap law applies primarily to internal conver- fold, and it provides a sound experimental basis for assessing
sion processes that are fast. The application to photosub- regioselectivity by quantum chemical calculation of the
stitution regioselectivity9 required intersystem crossing relative energies of transition states.
during nucleophilic attack on the triplet nitroaromatic lead- We found several energy minimum encounter complexes
ing to the singlet σ-complex. With rate constants of nucleo- of triplet 4-nitroanisole with hydroxide ion. The one calcu-
philic attack approaching the rate of diffusion, the processes lated to have the highest energy, shown as entry 1 in Table 3,
appeared to be much too fast to permit intersystem cros- placed hydroxide ion near the methoxy-bearing carbon of
sing.16 Moreover, spin-orbit coupling effects of attached triplet 4-nitroanisole. The transition states (entries 2 and 3)
halogens that should have facilitated the intersystem cross- lie 13.3 and 16.5 kcal above the energy of this encounter
ing correlated inversely with the observed rate constants.16 complex, at the Hartree-Fock 3-21G(*) level. The correct
For reaction within the triplet manifold, the energy gap law reference energy of the excited-state reactants appears from
would predict the wrong regioselectivity since the para triplet experiment to be about 2 kcal below the energy of the first
σ-complex was found by calculation9 to be much higher in transition state (entry 2), and we have shown energies
referenced to this value in column 5 of Table 3. Reaction
(31) March, J. Advanced Organic Chemistry: Reactions, Mechanisms, and
species discussed below are referenced to this excited reactant
Structure; McGraw-Hill: New York, 1968; p 387. energy level (-619.824577 au). The difficulty of finding the
(32) Bruckner, R. Advanced Organic Chemistry; Harcourt/Academic correct reference energy of the reactants by calculation is not
Press: San Diego, 2002; p 10.
(33) Dewar, M. J. S. The Molecular Orbital Theory of Organic Chemistry; unexpected because significant calculation errors occur between
McGraw-Hill: New York, 1969; p 362. species having different solvation, charge distributions, and
J. Org. Chem. Vol. 75, No. 22, 2010 7731
JOC Article Wubbels et al.

numbers and types of bonds. For closely comparable species, that the results reported in ref 14 could be caused by an
however, such as two transition states or two σ-complexes, analogous rearrangement mechanism. That suggestion now
the error in the calculated energy difference should be much appears unnecessary because the para substitution on 4-
smaller because of cancellation of calculation errors. Indeed, nitroanisole by hydroxide ion appears to fit a straightfor-
the HF 3-21G(*) energy difference for entry 3 minus entry 2 is ward SN2Ar* model.
3.2 kcal, which may be compared to the difference of 0.4 kcal The calculations of the triplet transition states for expul-
that was found experimentally. The favored transition state sion of nitrite ion or methoxide ion shown as entries 6 and 7,
is the one calculated to have lower energy. At higher levels of respectively, reveal that they lie 14.4 and 18.6 kcal above the
theory, the energy differences (in kcal) were as follows: HF/ respective triplet σ-complexes. These present large activation
3-21G(*) in water (SM8), 6.0; HF/6-31G*, 6.7; HF/6-31G* in energy barriers. They suggest that expulsion of leaving
water (SM8), 11.4; HF/6-31þG* 5.5; HF/6-31þG* in water groups from the triplet σ-complexes would be slow, giving
(SM8), 10.7;34 B3LYP/6-31G*, -1.0; B3LYP/6-31G* in the triplet σ-complexes sufficient lifetime to undergo inter-
water, 7.8. Only one of these methods, B3LYP (vacuum), system crossing. The corresponding ground state singlet
misses the favored transition state (by about 1 kcal). The σ-complex for nitro displacement (entry 8) lies 48.5 kcal
other seven methods are successful at identifying the favored below the triplet σ-complex (entry 4), and that for methoxy
transition state. displacement (entry 9) lies 10.9 kcal below the corresponding
As shown by the results discussed above, we prefer the HF/ triplet σ-complex (entry 5). The former singlet (entry 8),
3-21G(*) calculations for this system because of their lower however, reached energy minimization with an impossibly
cost and adequate accuracy. Calculation of the species in long C-N bond of 3.92 Å. This implies that an energy mini-
Table 3 at the HF/6-31G* level yielded geometries and mum structure was not found with a normal C-N distance
energy differences very similar to those of the HF/3-21G(*) and that the singlet σ-complex is dissociative.36 It implies
level. While the calculations, save one, identify the lower- that nitrite ion loss from the singlet σ-complex would have no
energy transition state, we do not know the reason that the activation energy and would follow intersystem crossing very
calculated energy differences of the competitive transition rapidly. The similarity of the energy gap (67.3 kcal) between
states are typically larger than the experimental values, even entry 8 and the excited reactants, and the spectroscopic
at higher levels of theory that provide large valence sets, triplet energy of 4-nitroanisole (60 kcal)25 suggests that entry
more polarization, diffuse functions for charges, electron 8 represents the ground singlet state of the products, 4-meth-
correlation, and solvation. oxyphenol and nitrite ion. This view was confirmed by direct
The favored regiochemistry could also be identified by calculation of the energy of the singlet hydrogen-bonded
comparing the energies of the triplet σ-complexes. These complex of 4-methoxyphenol and nitrite ion, which was 68.2
(entries 4 and 5) were found to lie 20.8 and 18.3 kcal below kcal below that of the excited reactants. The methoxide ion
the respective transition states (entries 2 and 3). In this case, expulsion is reasonably formulated as an activated reaction
the energy difference at the HF/3-21G(*) level for entry 5 that competes with hydroxide ion expulsion from the singlet
minus entry 4 is 5.7 kcal. These differences (in kcal) at higher σ-complex that lies about 24 kcal below the excited reactants.
levels of theory were: HF/6-31G*, 6.5; HF/6-31þG*, 2.7; We conclude that the required intersystem crossing from
and B3LYP/6-31G*, 5.0. The calculations all identify the triplet reactants to singlet products occurs at the σ-complex
favored pathway, and the differences cluster more closely stage, and that leaving group expulsion occurs from the
than those for the transition states. The lower-energy path- singlet rather than the triplet σ-complex.
way is correctly identified by all methods, and they agree The mechanistic conclusions afforded by the experimental
with results for the transition states. The agreement supports and quantum chemical results of this study agree with those
the view that the mechanism involves electron-paired bond based on element effects16 for nucleophilic reactions of trip-
formation within the triplet manifold, since in that case, these let nitrophenyl ethers. The main features are the following:
transition states and intermediates would be related by an (1) nucleophilic bond formation occurs adiabatically within
elementary reaction step. The correspondence of their rela- the triplet manifold; (2) competitive nucleophilic reactions
tive energies is a manifestation of the Bell-Evans-Polanyi occur through thermally competitive transition states; and
principle. In view of the agreement of the σ-complex energy (3) the elementary reactions produce triplet σ-complexes that
differences, calculation of their relative energies may be a undergo intersystem crossing to singlet σ-complexes, which
more reliable indicator of regioselectivity than calculation of dissociate anionic leaving groups to make the products. The
relative transition-state energies. relative transition-state energy predictor of regioselectivity
Several studies11,12 have suggested that nucleophilic in these reactions appears to have a sound basis. We intend to
photosubstitution para to the nitro group may occur by a test its application to regioselectivity by quantum chemical
mechanism different from SN2Ar*, that being the electron methods for other reactions of the SN2Ar* type that have
transfer-radical coupling (SN(ET)Ar*) mechanism. We re- been reported.7
ported evidence that the para photosubstitutions by amines
on 4-nitroanisole may actually involve bond formation by Experimental Section
the amine at the meta position followed by a fast sigmatropic
Except as noted below, chemicals and solvents were commer-
rearrangement to the para σ-complex.35 We also suggested cial materials of high purity. Ethanol was anhydrous, and
attempts to dehydrate it further were not made. Acetonitrile
(34) The calculation by HF/6-31þG* in water for entry 2 converged only
to twice the normal gradient tolerance, which did not permit calculation of
the vibrational frequencies. The energy difference is that for the total (36) The calculation seeks geometry optimization by stretching the C-N
energies. bond that increasingly produces nitrite ion in the gas phase. As its energy goes
(35) Wubbels, G. G.; Johnson, K. M. Org. Lett. 2006, 8, 1451. up, the energy minimum is realized.

7732 J. Org. Chem. Vol. 75, No. 22, 2010

Wubbels et al.
JOC Article
was chromatographic grade. 1-Ethoxy-4-nitrobenzene and 4- coefficients for the quantitative analyses were: 4-nitroanisole:
ethoxyanisole were made by alkylating the corresponding phe- 317 nm (9700); 4-nitrophenoxide ion: 400 nm (18,300), 306 nm
nol with ethyl iodide in 2-butanone containing K2CO3. These (1050); 4-methoxyphenoxide ion: 306 nm (2920).
substances gave satisfactory 1H NMR spectra and literature The quantum calculations were carried out with Spartan ’08
melting points. software running on a desktop computer with the Windows
UV-vis spectra were obtained with a diode-array spectro- operating system. The structures were found by convergence to
photometer with samples in quartz cuvettes. Gc/ms was carried equilibrium geometry at an energy minimum or a saddle point with
out with a 25 m silicone oil capillary column and an ion trap a gradient tolerance of 4.5
10-4 hartree bohr-1 and a distance
mass spectrometer. tolerance of 1.8
10-3 Å. We calculated the vibrational frequencies
Photolyses for preparative purposes in ethanolic NaOH were for the transition states, and they showed with one exception the
carried out in Pyrex tubes in a Rayonet RPR-208 reactor fitted imaginary frequency for the transition-state vibration.
with eight 300 nm broadband lamps. Workups for chromato-
graphic product analyses were carried out by diluting irradiated Acknowledgment. This paper is dedicated to Professor
samples 5-fold with water, acidifying with H2SO4, extracting
Robert L. Letsinger on the occasion of his 89th birthday.
with CH2Cl2 or toluene, concentrating, and diluting to volume
with CH2Cl2. Products were identified by coinjection with Acknowledgment is made to the donors of the Petroleum
authentic samples as well as by the mass spectra. Research Fund, administered by the American Chemical
Temperature-controlled photolyses were carried out in the Society, for support of this work.
Rayonet reactor with seven 350-nm broadband lamps in quartz
septum-capped cuvettes suspended in water or water/ice at Supporting Information Available: Cartesian coordinates of
controlled temperature in a uranium glass filter sleeve within a the structures reported in Table 3, the total energies, the
vacuum-jacketed quartz well. Reaction solutions were purged imaginary frequencies of transition states, and chromatogram
with argon through syringe needles for 10 min. UV-vis analyses of photoproducts in ethanolic NaOH. This material is available
were done directly in the irradiation cuvettes. The extinction free of charge via the Internet at http://pubs.acs.org.

J. Org. Chem. Vol. 75, No. 22, 2010 7733