phenol and the oxidation potential of its conjugate base as
in eq 2.11 Using our measured values,12 the differences in
the O-H BDEs (∆BDEs) were estimated for 1-3 relative
to phenol. The values are shown alongside the other relevant
data collected in Table 1.
Table 2. Calculateda Solution- and Gas-Phase Properties of the
Three Constitutional Isomers of Imidazole-Phenol
Solution Phaseb
c
pKa
E° d
∆BDEe
E° f
∆BDE (kcal/mol) ) 23.06∆E° + 1.363∆pKa
(2)
1
2
3
4
12.9 (-1.8)
13.0 (-1.7)
13.4 (-1.3)
14.7 (0.0)
0.406 (+0.003)
0.578 (+0.175)
0.398 (-0.005)
0.403 (0.000)
-2.4
+1.7
-1.9
0.0
1.82 (-0.10)
1.91 (-0.01)
1.65 (-0.27)
1.92 (0.00)
The results indicate that the o- and p-Im-substituted
phenoxyl radicals are modestly stabilized relative to phen-
oxyl, and the meta isomer is more significantly destabilized.
This is consistent with what would be expected of a π-ED
substituent, which stabilizes phenoxyl radicals when substi-
tuted in the ortho or para positions due to both delocalization
of the unpaired electron spin and stabilization of the electron-
poor phenoxyl ring by π-donation through resonance.13 Thus,
while Im appears to stabilize the electron-rich phenoxides
by inductively withdrawing electron density, it also appears
to stabilize the electron-poor phenoxyl radicals by donating
electron density. The π-ED effect would be expected to be
even more dramatic on the direct oxidation of the phenol to
the phenolic radical cation. Indeed, when the oxidation of
the phenols was examined in organic solution (acetonitrile)
by cyclic voltammetry, the anodic peak potentials for the
para and meta isomers14 displayed large shifts to lower
potentials relative to phenol (see the Supporting Information).
Given that the O-H BDEs and potentials for the phenoxyl/
phenoxide and phenoxyl radical cation/phenol couples are
estimates based on irreversible peak potentials and the results
appear somewhat contradictory in the sense that they reveal
both significant ED and EW properties of Im as a substituent,
we sought to corroborate the foregoing with the results of
theoretical calculations.
It has been demonstrated that B3LYP15 density functional
model calculations are generally in excellent agreement with
experimental O-H BDEs13,16 and ionization potentials17 in
substituted phenols, and thus, we performed these and other
calculations18 to help better understand the somewhat puz-
zling trends observed in our experimental results. The data
are presented in Table 2.
It is important to note that the calculated minimum energy
conformation of the ortho isomer is in good agreement with
the X-ray crystallographic structure of o-Im-p-cresol,22
especially the critical angle between the planes of the Im
and PhOH rings.23 The calculated pKa’s are higher than the
experimental values by ca. 4 log units. This was not
unexpected given the well-documented problems of con-
tinuum models in reproducing accurate solvation energies
Gas Phase
PAg
EAh
O-H BDEi
IPj
1
2
3
325.8 (-14.9) 63.7 (+10.9) 83.6 (-3.7) 186.8 (-8.4)
328.9 (-11.8) 65.8 (+13.0) 89.0 (+1.7) 189.5 (-5.7)
328.8 (-11.9) 62.4 (+9.6)
52.8 (0.0)
85.3 (-2.0) 184.2 (-11.0)
87.3 (0.0) 195.2 (0.0)
4k 340.7 (0.0)
a (U)B3LYP/6-311+G(2d,2p)//(U)B3LYP/6-31G(d) unless otherwise
indicated. b Solvation energies calculated using the COSMO polarized
continuum model19 for water (ꢀ ) 78.39) unless otherwise indicated.
c Calculated from PAs of the phenoxide anions corrected for solvation
energies. d In volts vs NHE; calculated from EAs of the phenoxyl radicals
corrected for solvation energies. e In kcal/mol; derived from pKa and E° as
in eq 2. f In volts vs NHE in acetonitrile (ꢀ ) 36.64); calculated from IPs
corrected for solvation energies. g Proton affinities (∆G°) of the phenoxide
anions. h Electron affinities (∆G°) of the phenoxyl radicals. i Absolute bond
dissociation enthalpies (∆H°) of the phenols, calculated using the HLM as
in ref 16. j Ionization potentials (∆E0) of the phenols, calculated as in ref
17. k Experimental values: 342.3 ( 2.0 kcal/mol,20 52.0 ( 0.1 kcal/mol,20
86.7 ( 0.7 kcal/mol,21 196.2 ( 0.1 kcal/mol.20
for many anions.24 Regardless and most importantly, the trend
of increasing acidity along the series PhOH < 3 < 2 < 1 is
(18) All calculations were performed with the Gaussian 03 suite of
programs. Gaussian 03, Revision B.02: Frisch, M. J.; Trucks, G. W.;
Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.;
Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J.
M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.;
Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara,
M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda,
Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.;
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.;
Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.;
Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.;
Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J.
V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.;
Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D.
J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe,
M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.;
and Pople, J. A.; Gaussian, Inc., Wallingford CT, 2004.
(19) Barone, V.; Cossi, M. J. Phys. Chem. A 1998, 102, 1995.
(20) Lias, S. G. Ionization Energy EValuation. In NIST Chemistry
WebBook; NIST Standard Reference Database Number 69; Linstrom, P.
J., Mallard, W. G., Eds.; National Institute of Standards and Technology:
Gaithersburg, MD, March 2003.
(21) Mulder, P.; Korth, H.-G.; Pratt, D. A.; DiLabio, G. A.; Valgimigli,
L.; Pedulli, G. F.; Ingold, K. U. J. Phys. Chem. A 2005, 109, 2647.
(22) Naruta, Y.; Tachi, Y.; Chishiro, T.; Shimazaki, Y.; Tani, F. Acta
Crystallogr. E 2001 57, 500.
(23) The calculated angle between the phenol and imidazole ring planes
in o-ImPhOH and o-Im-p-cresol is 42.5°, essentially identical to the
crystallographic value of 42.2° for the latter.22 For comparison, this angle
is 44° in bovine heart cytochrome c oxidase.2a Incidentally, the intra-
molecularly H-bonded o-isomer is the lowest energy conformer (by ca. 1
kcal/mol) in the gas phase. In contrast with previous theoretical studies,5
we have chosen to present the data for only the non-intramolecularly
H-bonded conformer since it should be the only relevant conformer in the
condensed phase due to stronger intermolecular H-bonding. This is also
the only conformer present in crystal structures of cross-linked models where
the hydrogen atoms are resolved; see, e.g., ref 22. The computed angles
for m-ImPhOH and p-ImPhOH were 37.0° and 43.1°, respectively.
(11) Bordwell, F. G.; Bausch, M. J. J. Am. Chem. Soc. 1986, 108, 1979.
(12) The calculation of reliable absolute O-H BDEs requires reversible,
or quasi-reversible, redox processes. These conditions are not met by the
phenoxyl/phenoxide couples studied here.
(13) Pratt, D. A.; DiLabio, G. A.; Mulder, P.; Ingold, K. U. Acc. Chem.
Res. 2004, 37, 334 and references therein.
(14) The ortho isomer has limited solubility in aprotic organic solvents.
(15) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648. (b) Lee, C.; Yang,
W.; Parr, R. G. Phys. ReV. B 1988, 37, 785.
(16) DiLabio, G. A.; Pratt, D. A.; Lofaro, A. D.; Wright, J. S. J. Phys.
Chem. A 1999, 103, 1653.
(17) DiLabio, G. A.; Pratt, D. A.; Wright, J. S. J. Org. Chem. 2000, 65,
2195.
Org. Lett., Vol. 7, No. 13, 2005
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