Synthesis and characterization of novel quinone methides: Reference electrophiles for the construction of nucleophilicity scales

Article abstract of DOI:10.1002/ejoc.200900299

Novel synthetic routes to the aryl-substituted quinone methides 3a-f have been developed, and a previously reported Mannich approach has been used for the syntheses of the acceptor substituted quinone methides 2e-g. The secondorder rate constants for the

Full text of DOI:10.1002/ejoc.200900299

FULL PAPER
DOI: 10.1002/ejoc.200900299
Synthesis and Characterization of Novel Quinone Methides:
Reference Electrophiles for the Construction of Nucleophilicity Scales
Dorothea Richter,[a] Nathalie Hampel,[a] Thomas Singer,[a] Armin R. Ofial,[a] and
Herbert Mayr*[a]
Dedicated to Professor Armin de Meijere on the occasion of his 70th birthday
Keywords: Electrophilicity / Nucleophilicity / Kinetics / Linear free-energy relationships / Quinone methides
Novel synthetic routes to the aryl-substituted quinone
methides 3a–f have been developed, and a previously re-
ported Mannich approach has been used for the syntheses of
the acceptor substituted quinone methides 2e–g. The second-
it was possible to calculate the electrophilicity parameters E
for these quinone methides. With E parameters between –12
and –17, these readily accessible quinone methides are re-
commended as reference electrophiles for the construction of
order rate constants for the reactions of 3c–f and 2e–g with nucleophilicity scales.
the carbanions 9a–h were determined photometrically in
DMSO. With Equation (1), logk2 = s(N + E), and the known
nucleophilicity parameters N and s for the carbanions 9a–h,
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
As the second-order rate constants for the hydration of
simple QM model compounds were found to be 104–105
times smaller than those of their reactions with amines and
thiols, the kinetic data provided important information
about the efficiencies of QMs as alkylation agents under
physiological conditions.[8] Variation of substituents in or-
tho-quinone methides revealed further insights into the re-
versibility of the QM adduct formation with deoxynucleo-
tides.[9]
In recent years, we have established benzhydrylium ions
1 and structually related, aryl-substituted para-quinone me-
thides 2 as reference electrophiles for the construction of
the most comprehensive nucleophilicity scale presently
available.[10,11]
Introduction
Quinone methides (QM) are formally obtained when one
oxygen atom of a quinone is replaced by a methylene group.
They are reactive intermediates in organic synthesis[1] and
biosynthesis.[2] Recently they were reported to be efficient
cross-linking and target-promoted alkylation reagents for
DNA.[3] As QMs are capable of forming covalent bonds to
amino acids and peptides, they serve as mechanism-based
inhibitors of enzymes and as both promotors of tumor
growth and anticancer drugs. Hence, the reactions of simple
ortho- and para-QMs have been subject of a variety of ki-
netic studies by the groups of Wan,[4] Kresge,[5] and Rich-
ard.[6] Freccero used laser flash photolytic techniques for
the generation of the parent quinone methides o-QM and
p-QM and systematically quantified the reactivities of these
highly reactive electrophiles towards O-, N-, and S-nucleo-
philes in aqueous solutions.[3,7]
From the second-order rate constants of their reactions
with various classes of nucleophiles it was possible to calcu-
late their electrophilicity parameters E as well as the N and
s parameters of π-, σ-, and n-nucleophiles (e.g., carban-
ions,[11,12] alkenes,[10a,10b] amines and amino acids[13] or hy-
dride donors[10a,14]) as defined by Equation (1).[15]
[a] Department Chemie und Biochemie, Ludwig-Maximilians-
Universität München,
Butenandtstrasse 5–13 (Haus F), 81377 München, Germany
Fax: +49-89-2180-77717
E-mail: Herbert.Mayr@cup.uni-muenchen.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900299.
logk2(20 °C) = s(N + E)
(1)
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k2: second-order rate constant (in Lmol–1 s–1)
E: electrophilicity parameter
N: nucleophilicity parameter
s: nucleophile-specific slope parameter
By employing different substituents X and Y in p- and
m-position, the electrophilicities of 1 and 2 have been varied
by almost 30 orders of magnitude while the steric situation
around the center of electrophilicity was kept almost con-
stant.
The least electrophilic benzhydrylium ion 1a and the
most reactive tert-butyl-substituted quinone methide so far
characterized (2d) differ by almost six orders of magnitude
in electrophilicity (Scheme 1).
Scheme 2. Synthesis of the tert-butyl-substituted quinone methides
2e–g.
The analogous Mannich synthesis did not work for other
types of quinone methides. For their syntheses, the 4-hy-
droxy-substituted benzhydrols 5 were used as key-interme-
diates. According to Unangst et al., 4-hydroxy-3,5-diphenyl-
benzaldehyde 4a is efficiently synthesized by treating the
commercially available 2,6-diphenylphenol with urotropin
in acetic acid (Duff reaction, Scheme 3).[18]
Scheme 3. Synthesis of 4-hydroxy-3,5-diphenylbenzaldehyde 4a by
Duff reaction.
Treatment of 4a or of the commercially available hy-
droxybenzaldehydes 4b and 4c with 2.4 equiv. of arylmagne-
sium bromide in THF gave the hydroxybenzhydrols 5a–f
(Scheme 4).
Scheme 1. Reactivities of the quinone methides 2a–d in comparison
with the least reactive benzhydrylium ion 1a.
This large gap has been bridged by the 2,6-diphenyl-sub-
stituted quinone methides 3a and 3b for which the electro-
philicity parameters E(3a) = –12.18 and E(3b) = –13.39 had
been determined.[11]
The practical application of 3a and 3b was limited, how-
ever, by the very cumbersome syntheses of these com-
pounds.[16] We now report on more efficient syntheses of 3a
and 3b as well as on a straightforward access to other qui-
none methides of similar structure and the determination
of their electrophilicities.
Scheme 4. Grignard reaction for the synthesis of the hydroxy-
benzhydrols 5a–f.
Alcohols 5a,c,d, i.e., compounds with Ar = 4-MeO-C6H4
or C6H5 have been converted into the benzhydryl chlorides
6a,c,d by treatment with thionyl chloride. The reactions of
6a,c,d with triethylamine gave the quinone methides 3a,c,d
(Scheme 5), in analogy to the method reported by Pospi-
sek.[19]
Results and Discussion
Syntheses
The method previously reported[17] for the syntheses of
Addition of ethereal HBF4 to a solution of the dimeth-
2a–d and 2g was adjusted to the syntheses of the fluorine ylamino-substituted 4-hydroxybenzhydrols 5e,f in dichloro-
substituted quinone methides 2e–f (Scheme 2). methane at 0 °C led to the formation of the dark-violet
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Reference Electrophiles for Nucleophilicity Scales
Scheme 8.
The dimethylamino-substituted compounds 3b,e,f are in-
tensively red, while all the other quinone methides are yel-
low. Their UV/Vis absorption maxima between 350 and
533 nm are shown in Figure 1.
Scheme 5. Synthesis of 3a,c,d via the benzhydryl chlorides 6a,c,d.
benzhydrylium tetrafluoroborates 7e,f which yielded the
quinone methides 3e,f after treatment with triethylamine
(Scheme 6).
Scheme 6. Synthesis of 3e,f via the intermediate benzhydryl cations
7e,f.
Figure 1. UV/Vis spectra of the quinone methides 2e–g and 3a–f in
DMSO, λmax [nm] in parentheses. Molar decadic absorption coeffi-
cient ε for 2e: 31600, 2f: 25400, 2g: 30100, 3a: 32200, 3b: 39000, 3c:
30800, 3d: 31100, 3e: 41700, 3f: 43800 Lmol–1 cm–1.
Both methods described in Schemes 5 and 6 failed for
the synthesis of 3b. Following a procedure described by Jer-
keman and Koutek,[20] 5b was converted into the sulfone 8
by refluxing with PhSO2Na in aqueous acetic acid. Agita-
tion of a dichloromethane solution of 8 with concentrated
aqueous sodium hydroxide gave rise to the formation of 3b
(Scheme 7). This method has previously been employed for
the synthesis of other quinone methides by Koutek.[21]
Kinetic Measurements
The reactions of the quinone methides 2e–g and 3c–f
with the carbanions 9a–h (Table 1) were followed photo-
metrically in DMSO at 20 °C. To obtain pseudo-first-order
conditions, solutions of the quinone methides were mixed
with an excess (10–100 equiv.) of the nucleophiles 9a–h.
Each reaction was studied with at least four different nu-
cleophile concentrations (for details, see the Supporting In-
formation). The decays of the absorptions of the electro-
philes were followed by stopped-flow or conventional UV/
Vis spectroscopy, depending on the rates of the reactions.
From the fit of the absorbance At to the exponential func-
tion At = A0 exp(–kobst) + C, we were able to derive the
first-order rate constants kobs. Plots of the first-order rate
constants kobs (s–1) vs. the nucleophile concentrations were
linear with slopes k2 (Lmol–1 s–1) and negligible intercepts
(Figure 2). The second-order rate constants k2 for the reac-
tions derived by this method are listed in Table 1.
Scheme 7. Synthesis for 3b via the sulfone 8.
In the case of the dimethylamino-substituted quinone
methides 2b, 3b, 3e, and 3f the zwitterionic resonance struc-
ture drawn in Scheme 8 is gaining importance. Rotation
around the exocyclic double bond of the quinone methide
>ring, therefore, occurs which results in a coalescence of
the NMR signals of the substituents R. The coalescence
phenomena were poorly reproducible, however, possibly be-
Correlation Analysis
The E parameters for 2e–g and 3c–f were calculated from
cause the rotation of the cyclohexadiene ring requires (acid) the second-order rate constants k2 of their reactions with
catalysis, and we have abstained from determining the cor- the carbanions 9a–h and the previously reported N and s
responding rotational barriers.
parameters for 9a–h (Table 1). For this purpose, the squares
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Table 1. Second-order rate constants k2 (Lmol–1 s–1) for the reactions of the quinone methides 2e–g and 3c–f with the carbanions 9a–h[a]
in DMSO at 20 °C.
[a] For all kinetic measurements, the salts 9-K+ were used. For N and s parameters (in DMSO) of 9a see ref.[22], for 9b–h see ref.[11]. [b]
CAUTION: Because of explosion hazards,[23] the isolation of 9a-K+ should be avoided! [c] Calculated from Equation (1); see section
“Correlation Analysis”.
Figure 2. Determination of the second-order rate constant k2
(Lmol–1 s–1) for the reaction of 3d with 9a in DMSO at 20 °C.
of the deviations between calculated and experimental rate
constants [∆2 = Σ(logk2 – s(N + E))2] were minimized using
a nonlinear solver software.[24] The resulting E parameters
for the quinone methides 2e–g and 3c–f are listed in the last
column of Table 1.
Figure 3. Plot of logk2 for the reactions of the quinone methides
2e–g and 3c–f with the carbanions 9a–h in DMSO vs. the electro-
philicity parameters E of 2e–g and 3c–f (Table 1). The depicted
correlation lines are those derived in refs[11, 22] from the reactions
of the carbanions 9a–h with the so far established reference electro-
philes. The electrophilicity parameters for 2e–g and 3c–f result from
a best fit of the second-order rate constants in Table 1 to the fixed
correlation lines of the carbanions 9a–h (see text).
Figure 3 illustrates that the second-order rate constants
for the reactions of the quinone methides 2e–g and 3c–f
with the carbanions 9a–h match satisfactorily the previously
reported logk2 vs. E correlation lines for the reactions of
these carbanions with benzhydrylium ions and other qui-
none methides.
In order to compare the reactivities of these quinone me-
thides with those of the parent compounds o-QM and p- better correlation for the para-substituted quinone methide
QM, we used the rate constants determined by Freccero[3] (Figure 4). The E parameters for o-QM (E = –3.1) and p-
and Kresge[5b,5d] (in water at 25 °C) for the reactions of QM (E = –5.2) were subsequently calculated by the same
these quinone methides with a series of different n-nucleo- error minimization method[24] described above for 2e–g and
philes with known N and s parameters (water, chloride, bro- 3c–f. The electrophilicity parameters for o-QM and p-QM
mide, primary and secondary amines, and amino acids).[3] thus determined are considered preliminary because the nu-
As required by Equation (1), a linear plot of (logk)/s vs. N cleophiles investigated do not belong to the set of reference
was obtained for both o-QM and p-QM, with a slightly nucleophiles[10a,10b] and the temperature has not been cor-
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Reference Electrophiles for Nucleophilicity Scales
rected to 20 °C. Please note that application of Equation
(1) enforces a slope of 1.0 for the correlation lines in Fig-
ure 4. A better fit would be obtained if an additional elec-
trophile-specific slope parameter would be introduced as
previously shown for SN2 reactions.[13b] It turned out that
the rate constants were reproduced by Equation (1) within
an error limit of a factor of 4, even though the reaction of
o-QM with Cys2– (k2 = 1.3 ϫ 108 Lmol–1 s–1) may already
be attenuated by its vicinity to the diffusion limit.
Figure 5. Comparison of the electrophilicities E of the new quinone
methides 2e–g and 3c–f with those of the previously reported ana-
logues 2a–d and 3a,b. For “jul”-substituent see 2a in Scheme 1.
Figure 4. Preliminary determination of the electrophilicity param-
eters E according to Equation (1) for o-QM and p-QM from the
kinetics of their reactions with water, chloride, bromide, primary
and secondary amines, and amino acids in aqueous solution (at
25 °C, for amines and Gly– at pH 12.0, for Cys2– at pH 12.2; see
the Supporting Information for the employed rate constants k from
refs.[3,5b,5d] as well as reactivity parameters N and s from ref[10h]).
Figure 5 summarizes the electrophilicities E of all qui-
none methides so far characterized by Equation (1). The
electrophilic reactivities of the parent quinone methides o-
QM and p-QM are comparable to those of stabilized carbo-
cations (tropylium ion, E = –3.7),[10b] i.e., they are more
electrophilic than Terrier’s superelectrophiles which have so
far been considered the strongest neutral nucleophiles.[25] In
Scheme 9. Electrophilicity parameters E of 4-(dimethylamino)-
phenyl-substituted quinone methides.
The much weaker electron-donating ability of phenyl
contrast, the substituted para-quinone methides 2 and 3 are compared to alkyl or alkoxy groups is reflected in an in-
much less reactive (–18.0 Ͻ E Ͻ –11.5) comparable to other crease of the electrophilicity of 3b by a factor of 104 com-
Michael acceptors[22,26] or electron-deficient arenes.[12g,25,27] pared to the reactivity of 2b, 3e or 3f.
The influence of different 2,6-substituents R on the elec-
With the characterization of the electrophilicity E for
trophilicity of aryl-substituted quinone methides can be il- compounds 2e–g, reactivity parameters for seven di-tert-bu-
lustrated by comparing the 4-(dimethylamino)phenyl-sub- tyl-substituted quinone methides are available, in which the
stituted compounds 2b, 3e, 3f, and 3b (Scheme 9).
substituent X at the phenyl ring varies from strongly elec-
Replacement of the tert-butyl groups in 2b by methyl (Ǟ tron-donating (X = 4-NR2) to strongly electron-accepting
3f), causes an increase of electrophilicity by one order of (X = 4-NO2).
magnitude. Though alkoxy groups commonly have a much
Figure 6 shows a linear correlation with Hammett’s σ+
stronger +M-effect than alkyl groups, the methoxy substi- parameters. The slope of 1.20 corresponds to a reaction
tuted quinone methides 3d and 3e show similar reactivities constant ρ = 1.20 for the reaction with a nucleophile of s =
as the corresponding tert-butyl-substituted compounds (2c 1 and to ρ = 0.84 for the reaction with a nucleophile of s =
and 2b).
0.7.
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2,6-Di-tert-butyl-4-(3,5-difluorobenzylidene)cyclohexa-2,5-dienone
(2f): From 2,6-di-tert-butylphenol (5.16 g, 25.0 mmol), 3,5-di-
fluorobenzaldehyde (3.55 g, 25.0 mmol), piperidine (4.94 mL,
4.26 g, 50.0 mmol) and acetic anhydride (2.55 g, 50.0 mmol): 3.91 g
(47%); yellow crystals; m.p. 111–113 °C (from n-hexane). 1H NMR
(CDCl3, 600 MHz): δ = 1.30 [s, 9 H, C(CH3)3], 1.33 [s, 9 H,
3
4
C(CH3)3], 6.84 (tt, JHF = 8.7, JHH = 2.2 Hz, 1 H), 6.94–6.97 (m,
2 H), 6.97 (d, J = 2.1 Hz, 1 H), 7.03 (s, 1 H), 7.40 (d, J = 2.1 Hz,
1 H) ppm. 13C NMR (CDCl3, 151 MHz): δ = 29.47, 29.49 [2q,
C(CH3)3], 35.1, 35.5 [2s, C(CH3)3], 104.2 (td, 2JCF = 25.4 Hz), 112.8
2
4
(ddd, JCF = 20.4, JCF = 5.4 Hz), 126.7 (d), 133.5 (s), 134.4 (d),
138.6 (td, 4JCF = 2.8 Hz), 138.8 (ts, 3JCF = 9.6 Hz), 148.7 (s), 150.3
(s), 163.0 (dds, 1JCF = 249.7, 3JCF = 13.0 Hz), 186.5 (s, C=O) ppm.
MS (EI): m/z (%) = 331 (18), 330 (40) [M+], 316 (21), 315 (77), 301
(18), 287 (29), 275 (29), 274 (25), 273 (100), 127 (16), 57 (19), 44
(33). HRMS (EI): calcd. for C21H24F2O 330.1795; found 330.1790.
C21H24F2O (330.42): calcd. C 76.34, H 7.32; found C 76.03, H 7.43.
Figure 6. Correlation of the electrophilicity parameter E of the qui-
none methides 2a–g with Hammett’s Σσ+ parameters. σ+ for 2b–g:
ref.[28], σ+ for 2a: ref.[10a]
.
2,6-Di-tert-butyl-4-(4-nitrobenzylidene)cyclohexa-2,5-dienone (2g):
From 2,6-di-tert-butylphenol (5.16 g, 25.0 mmol), 4-nitrobenzalde-
Conclusions
The newly developed syntheses of compounds 3a and 3b hyde (3.78 g, 25.0 mmol), piperidine (4.94 mL, 4.26 g, 50.0 mmol)
and acetic anhydride (2.55 g, 50.0 mmol): 5.74 g (68%); yellow so-
lid; m.p. 163–164 °C (from n-hexane). 1H NMR (CDCl3,
300 MHz): δ = 1.30 [s, 9 H, C(CH3)3], 1.34 [s, 9 H, C(CH3)3], 7.02
(d, J = 2.5 Hz, 1 H), 7.16 (s, 1 H), 7.38 (d, J = 2.5 Hz, 1 H), 7.60
(d, J = 9.0 Hz, 2 H), 8.31 (d, J = 8.8 Hz, 2 H) ppm. 13C NMR
(CDCl3, 75.5 MHz): δ = 29.46, 29.48 [2q, C(CH3)3], 35.1, 35.6 [2s,
C(CH3)3], 123.9 (d), 126.6 (d), 130.8 (d), 134.35 (d), 134.40 (s),
138.3 (d), 142.3 (s), 147.4 (s), 149.1 (s), 150.7 (s), 186.4 (s, C=O)
ppm. MS (EI): m/z (%) = 340 (14), 339 (38) [M+], 325 (14), 324
(60), 310 (15), 297 (15), 296 (27), 284 (23), 283 (24), 282 (100), 278
(11), 165 (10). C21H25NO3 (339.43): calcd. C 74.31, H 7.42, N 4.13;
found C 74.14, H 7.52, N 4.08.
reported in this article provide a straightforward access to
these compounds whose electrophilicities are in between
those of 1a and 2d (Scheme 1). These compounds and sev-
eral other novel quinone methides described in this article
represent a group of colored electrophiles which are struc-
turally related to benzhydrylium ions and, therefore, are
valuable reference compounds for the characterization of
nucleophiles.
Experimental Section
Hydroxybenzhydrols 5a–f. General Procedure: To magnesium turn-
ings (2.6 equiv.) in dry THF (5 mL), a solution of the appropriate
para-substituted bromobenzene (2.4 equiv.) in dry THF (20 mL)
was added dropwise under nitrogen. After refluxing for 75 min, the
mixture was cooled to room temperature and a solution of the
adequate 4-hydroxybenzaldehyde 4a–c (1 equiv.) in dry THF
(20 mL) was added dropwise. After stirring for 12 h, the reaction
mixture was hydrolyzed with saturated aqueous NH4Cl solution
(25 mL). The aqueous phase was washed with diethyl ether (2 ϫ).
Then the combined organic layers were dried with MgSO4 and the
solvent was evaporated under reduced pressure. Crude products
with low solubility in diethyl ether were suspended in diethyl ether
(100 mL). After 1 h of stirring the purified product was isolated by
filtration. Crude products with high solubility in Et2O were crys-
tallized from diethyl ether/n-pentane.
2,6-Di-tert-butyl-Substituted Quinone Methides 2e–g: The quinone
methides 2e–g were prepared following a procedure described by
Evans et al.:[17] In a Dean–Stark apparatus, a solution of 2,6-di-
tert-butylphenol and the corresponding benzaldehyde in toluene
was heated to reflux. Piperidine was added within 1 h and heating
was continued for another 3 h. After cooling just below the boiling
point of the reaction mixture, acetic anhydride was added and stir-
ring was continued for 15 min. Then the reaction mixture was
poured on ice-water (500 mL) and extracted with CH2Cl2
(4ϫ200 mL). The combined organic phases were dried (MgSO4),
and the solvent was removed under reduced pressure. The crude
products were purified by column chromatography (3:2, CH2Cl2/n-
hexane) and recrystallized from n-hexane.
2,6-Di-tert-butyl-4-(3-fluorobenzylidene)cyclohexa-2,5-dienone (2e):
From 2,6-di-tert-butylphenol (5.16 g, 25.0 mmol), 3-fluorobenzal-
dehyde (3.10 g, 25.0 mmol), piperidine (4.94 mL, 4.26 g,
50.0 mmol) and acetic anhydride (2.55 g, 50.0 mmol): 4.58 g (59%);
(4-Hydroxy-3,5-diphenylphenyl)(4-methoxyphenyl)methanol
(5a):
From 4-bromoanisole (2.41 mL, 3.59 g, 19.2 mmol) and 4-hydroxy-
3,5-diphenylbenzaldehyde 4a (2.19 g, 8.00 mmol): 2.54 g (83%);
1
yellow crystals; m.p. 86–88 °C (from n-hexane). H NMR (CDCl3,
1
colorless solid; m.p. 117–118 °C (from Et2O/n-pentane). H NMR
300 MHz): δ = 1.30 [s, 9 H, C(CH3)3], 1.33 [s, 9 H, C(CH3)3], 6.99
(d, J = 2.4 Hz, 1 H), 7.04–7.18 (m, 3 H), 7.18–7.25 (m, 1 H), 7.37–
7.45 (m, 1 H), 7.46 (d, J = 2.5 Hz, 1 H) ppm. 13C NMR (CDCl3,
75.5 MHz): δ = 29.48, 29.51 [2q, C(CH3)3], 35.0, 35.5 [2s,
(CDCl3, 600 MHz): δ = 2.18 (s, 1 H, CHOH), 3.78 (s, 3 H, OMe),
5.40 (s, 1 H, OHarom.), 5.81 (s, 1 H), 6.87 (d, J = 8.6 Hz, 2 H),
7.21–7.57 (m, 14 H, Harom.) ppm. 13C NMR (CDCl3, 151 MHz): δ
= 55.3 (q, OMe), 75.5 (d), 113.9 (d), 127.68 (d), 127.73 (d), 128.10
(d), 128.7 (s), 128.8 (d), 129.3 (d), 136.2 (s), 136.4 (s), 137.5 (s),
148.7 (s), 159.0 (s) ppm.
2
2
C(CH3)3], 115.9 (dd, JCF = 21.3 Hz), 116.8 (dd, JCF = 22.1 Hz),
4
3
126.0 (dd, JCF = 3.0 Hz), 127.2 (d), 130.3 (dd, JCF = 8.4 Hz),
132.8 (s), 134.8 (d), 138.0 (ds, JCF = 8.4 Hz), 140.3 (dd, JCF
3
4
=
1
2.5 Hz), 148.3 (s), 149.8 (s), 162.8 (ds, JCF = 247.2 Hz), 186.5 (s,
C=O) ppm. MS (EI): m/z (%) = 313 (12), 312 (36) [M+], 298 (17),
297 (81), 283 (17), 270 (12), 269 (36), 257 (19), 256 (27), 255 (100).
HRMS (EI): calcd. for C21H25FO 312.1889; found 312.1887.
C21H25FO (312.43): calcd. C 80.73, H 8.07; found C 80.37, H 8.22.
(4-Hydroxy-3,5-diphenylphenyl)[4-(dimethylamino)phenyl]methanol
(5b): From 4-bromo-N,N-dimethylaniline (2.69 g, 13.4 mmol) and
4-hydroxy-3,5-diphenylbenzaldehyde 4a (1.54 g, 5.60 mmol): 1.74 g
(79%); pink solid; m.p. 63–65 °C (from Et2O/n-pentane). 1H NMR
(CDCl3, 300 MHz): δ = 2.09 (s, 1 H, CHOH), 2.92 (s, 6 H, NMe2),
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Reference Electrophiles for Nucleophilicity Scales
5.36 (s, 1 H, OHarom.), 5.79 (s, 1 H), 6.70 (d, J = 8.8 Hz, 2 H), 60.8 mg, 0.51 mmol): 1H NMR (CDCl3, 300 MHz): δ = 5.44 (br. s,
7.24–7.56 (m, 14 H, Harom.) ppm. 13C NMR (CDCl3, 75.5 MHz): 1 H, OH), 6.16 (s, 1 H), 7.23–7.55 (m, 17 H, Harom.) ppm. 13C
δ = 40.6 (q, NMe2), 75.7 (d), 112.5 (d), 127.5 (d), 127.6 (d), 128.0 NMR (CDCl3, 75.5 MHz): δ = 64.2 (d), 127.6 (d), 127.9 (d), 128.0
(d), 128.5 (s), 128.8 (d), 129.3 (d), 132.0 (s), 136.6 (s), 137.6 (s), (d), 128.6 (d), 128.8 (s), 128.9 (d), 129.29 (d), 129.34 (d), 133.5 (s),
148.4 (s), 150.1 (s) ppm.
137.1 (s), 141.0 (s), 149.1 (s) ppm.
(4-Hydroxy-3,5-diphenylphenyl)(phenyl)methanol (5c): From bro-
mobenzene (2.02 mL, 3.01 g, 19.2 mmol) and 4-hydroxy-3,5-di-
phenylbenzaldehyde 4a (2.19 g, 8.00 mmol): 2.06 g (73%); colorless
solid; m.p. 147–149 °C (from Et2O/n-pentane). H NMR (CDCl3,
300 MHz): δ = 2.28 (d, J = 3.1 Hz, 1 H, CHOH), 5.41 (s, 1 H,
(4-Hydroxy-3,5-dimethoxyphenyl)(4-methoxyphenyl)methyl Chlo-
ride (6d): From 5d (1.00 g, 3.46 mmol) in CH2Cl2 (40 mL) and
SOCl2 (303 µL, 493 mg, 4.15 mmol): 1H NMR (CDCl3, 300 MHz):
δ = 3.81 (s, 3 H, OMe), 3.86 (s, 6 H, 2ϫOMe), 5.53 (br. s, 1 H,
OH), 6.08 (s, 1 H), 6.64 (s, 2 H), 6.87 (d, J = 8.7 Hz, 2 H), 7.32 (d,
J = 8.7 Hz, 2 H) ppm. 13C NMR (CDCl3, 75.5 MHz): δ = 55.3 (q,
OMe), 56.4 (q, 2ϫOMe), 64.8 (d), 104.8 (d), 113.8 (d), 129.0 (d),
132.3 (s), 133.4 (s), 134.5 (s), 146.8 (s), 159.3 (s) ppm.
1
OHarom.), 5.80 (d, J = 2.8 Hz, 1 H), 7.20–7.54 (m, 17 H, Harom.
)
ppm. 13C NMR (CDCl3, 75.5 MHz): δ = 75.9 (d), 126.4 (d), 127.5
(d), 127.7 (d), 128.2 (d), 128.5 (d), 128.7 (s), 128.8 (d), 129.3 (d),
136.2 (s), 137.4 (s), 143.8 (s), 148.8 (s) ppm.
Quinone Methides 3a,c,d: Under an atmosphere of dry N2, the
benzhydryl chloride 6 was dissolved in dry CH2Cl2 and 1.2–
1.3 equiv. of NEt3 were added. After stirring for 2 h, diethyl ether
or n-pentane was added. The resulting precipitate was filtered off
and dried under reduced pressure.
(4-Hydroxy-3,5-dimethoxyphenyl)(4-methoxyphenyl)methanol (5d):
From 4-bromoanisole (2.41 mL, 3.59 g, 19.2 mmol) and 4-hydroxy-
3,5-dimethoxybenzaldehyde 4b (1.46 g, 8.00 mmol): 1.92 g (83%);
colorless solid. 1H NMR (CDCl3, 300 MHz): δ = 2.14 (d, 3J =
3.5 Hz, 1 H, CHOH), 3.82 (s, 3 H, OMe), 3.88 (s, 6 H, 2ϫOMe),
5.48 (s, 1 H, OHarom.), 5.76 (d, 3J = 3.3 Hz, 1 H), 6.62 (s, 2 H),
6.89 (d, J = 9 Hz, 2 H), 7.30 (d, J = 9 Hz, 2 H) ppm. 13C NMR
(CDCl3, 75.5 MHz): δ = 55.3 (q, OMe), 56.3 (q, 2 OMe), 75.9 (d),
103.3 (d), 113.8 (d), 127.8 (d), 134.0 (s), 135.2 (s), 136.1 (s), 147.0
(s), 159.1 (s) ppm.
2,6-Diphenyl-4-(4-methoxybenzylidene)cyclohexa-2,5-dienone (3a):
From 6a (313 mg, 780 µmol) in CH2Cl2 (10 mL) and NEt3 (141 µL,
103 mg, 1.01 mmol): 199 mg (70%); yellow solid; m.p. 125–126 °C
(from Et2O). 1H NMR (CD2Cl2, 400 MHz): δ = 3.87 (s, 3 H, OMe),
7.02 (d, J = 8.8 Hz, 2 H), 7.35–7.47 (m, 8 H, Harom.), 7.55–7.63 (m,
6 H, Harom.), 7.93 (dd, J = 2.6, J = 0.6 Hz, 1 H) ppm. 13C NMR
(CD2Cl2, 101 MHz): δ = 55.6 (q, OMe), 114.7 (d), 127.8 (d), 127.9
(d), 128.01 (d), 128.02 (d), 128.3 (s), 129.3 (d), 129.4 (d), 130.1 (s),
132.5 (d), 133.0 (d), 137.1 (s), 137.5 (s), 138.3 (s), 140.2 (d), 146.6
(d), 161.7 (s), 183.5 (s, C=O) ppm. MS (EI): m/z (%) = 366 (16),
365 (18), 364 (64) [M+], 363 (100). HRMS (EI): calcd. for C26H20O2
364.1463; found 364.1465.
(4-Hydroxy-3,5-dimethoxyphenyl)[4-(dimethylamino)phenyl]meth-
anol (5e): From 4-bromo-N,N-dimethylaniline (4.80 g, 24.0 mmol)
and 4-hydroxy-3,5-dimethoxybenzaldehyde 4b (1.82 g, 10.0 mmol):
1
1.29 g (43%); light purple solid. H NMR (CDCl3, 300 MHz): δ =
3
2.07 (d, J = 3.5 Hz, 1 H, CHOH), 2.94 (s, 6 H, NMe2), 3.86 (s, 6
H, 2ϫOMe), 5.45 (s, 1 H, OHarom.), 5.70 (d, 3J = 3.4 Hz, 1 H),
6.63 (s, 2 H), 6.70 (d, J = 8.8 Hz, 2 H), 7.21 (d, J = 8.8 Hz, 2 H)
ppm. 13C NMR (CDCl3, 75.5 MHz): δ = 40.6 (q, NMe2), 56.3 (q,
OMe), 76.0 (d), 103.2 (d), 112.4 (d), 127.7 (d), 131.9 (s), 133.8 (s),
135.5 (s), 146.9 (s), 150.2 (s) ppm.
2,6-Diphenyl-4-benzylidenecyclohexa-2,5-dienone (3c): From 6c
(530 mg, 1.58 mmol) in CH2Cl2 (8 mL) and NEt3 (286 µL, 210 mg,
2.06 mmol): 386 mg (71%); yellow crystals; m.p. 170–172 °C (from
CH2Cl2/n-pentane). 1H NMR (CDCl3, 300 MHz): δ = 7.35–7.61
(m, 17 H, Harom.), 7.86 (dd, J = 2.6, J = 0.6 Hz, 1 H) ppm. 13C
NMR (CDCl3, 75.5 MHz): δ = 127.97 (d), 128.02 (d), 128.04 (d),
128.07 (d), 129.0 (d), 129.2 (d), 129.3 (d), 129.9 (d), 130.7 (d), 131.8
(s), 132.5 (d), 135.4 (s), 136.3 (s), 136.7 (s), 138.9 (s), 139.7 (d),
140.6 (s), 146.0 (d), 183.8 (s, C=O) ppm. MS (EI): m/z (%) = 335
(22), 334 (100) [M+], 333 (70), 256 (22). HRMS (EI): calcd. for
C25H18O 334.1358; found 334.1355.
(4-Hydroxy-3,5-dimethylphenyl)[4-(dimethylamino)phenyl]methanol
(5f): From 4-bromo-N,N-dimethylaniline (4.80 g, 24.0 mmol) and
4-hydroxy-3,5-dimethylbenzaldehyde 4c (1.50 g, 10.0 mmol): 1.88 g
(69%); light purple solid. 1H NMR ([D6]DMSO, 400 MHz): δ =
2.12 (s, 6 H, 2ϫMe), 2.83 (s, 6 H, NMe2), 5.33 (d, J = 4.0 Hz, 1
H), 5.42 (d, J = 4.0 Hz, 1 H), 6.64 (d, J = 8.8 Hz, 1 H), 6.84 (s, 2
H), 7.11 (d, J = 8.8 Hz, 1 H), 7.98 (s, 1 H, OHarom.) ppm. 13C
NMR ([D6]DMSO, 101 MHz): δ = 16.7 (q, Me), 40.3 (q, NMe2),
73.8 (d), 112.1 (d), 123.4 (s), 126.1 (d), 126.9 (d), 134.2 (s), 136.9
(s), 149.3 (s), 151.6 (s) ppm.
2,6-Dimethoxy-4-(4-methoxybenzylidene)cyclohexa-2,5-dienone
(3d): From 6d (1.07 g, 3.46 mmol) in CH2Cl2 (25 mL) and NEt3
(576 µL, 420 mg, 4.15 mmol): 584 mg (62%); yellow crystals; m.p.
178–180 °C (from CH2Cl2/n-pentane). 1H NMR (CD2Cl2,
400 MHz): δ = 3.78 (s, 3 H, OMe), 3.80 (s, 3 H, OMe), 3.86 (s, 3
H, OMe), 6.43 (s, 1 H), 6.91 (s, 1 H), 7.00 (d, J = 8.8 Hz, 2 H),
7.12 (s, 1 H), 7.48 (d, J = 8.6 Hz, 2 H) ppm. 13C NMR (CD2Cl2,
101 MHz): δ = 55.5 (q, OMe), 55.56, 55.57 (2q, 2 OMe), 105.7 (d),
113.1 (d), 114.5 (d), 128.7 (s), 129.0 (s), 132.0 (d), 140.7 (d), 152.1
(s), 153.7 (s), 160.6 (s), 174.8 (s, C=O) ppm. MS (EI): m/z (%) =
273 (20), 272 (100) [M+], 271 (19), 254 (17), 243 (41), 242 (30), 241
(16), 226 (28), 211 (22), 196 (15), 171 (16), 169 (18), 143 (22), 128
(20), 115 (53). HRMS (EI): calcd. for C16H16O4 272.1049; found
272.1052. C16H16O4 (272.30): calcd. C 70.57, H 5.92; found C
70.35, H 5.86.
Benzhydryl Chlorides 6a,c,d: Under an atmosphere of dry N2,
SOCl2 (1.2 equiv.) in dry CH2Cl2 (≈ 5 mL) was added dropwise to
a solution of the 4-hydroxybenzhydrol (1 equiv.) in dry CH2Cl2 at
0 °C. After stirring at this temperature for 2 h, the solvent was re-
moved under reduced pressure. Because the products were formed
nearly quantitatively, they were used for the following step without
further purification.
(4-Hydroxy-3,5-diphenylphenyl)(4-methoxyphenyl)methyl Chloride
(6a): From 5a (500 mg, 1.31 mmol) in CH2Cl2 (18 mL) and SOCl2
(115 µL, 187 mg, 1.57 mmol): 1H NMR (CDCl3, 300 MHz): δ =
3.80 (s, 3 H, OMe), 5.44 (s, 1 H, OH), 6.16 (s, 1 H), 6.87 (d, J =
8.8 Hz, 2 H), 7.32–7.57 (m, 14 H, Harom.) ppm. 13C NMR (CDCl3,
75.5 MHz): δ = 55.3 (q, OMe), 64.2 (d), 113.9 (d), 127.9 (d), 128.8
(d), 128.9 (d), 129.0 (d), 129.3 (d), 129.8 (s), 133.4 (s), 133.7 (s),
137.1 (s), 149.1 (s), 159.3 (s) ppm.
Quinone Methides 3e,f: Under an atmosphere of dry N2, the 4-
hydroxybenzhydrol (1 equiv.) was dissolved in dry CH2Cl2 and
cooled to 0 °C. Then ethereal HBF4 solution (1.1 equiv.) was added
at 0 °C. After 5 min, NEt3 (1.3 equiv.) was added. Stirring at room
temperature was continued for 3 h before the mixture was extracted
(4-Hydroxy-3,5-diphenylphenyl)(phenyl)methyl Chloride (6c): From
5c (150 mg, 0.43 mmol) in CH2Cl2 (6 mL) and SOCl2 (37 µL,
Eur. J. Org. Chem. 2009, 3203–3211
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3209

D. Richter, N. Hampel, T. Singer, A. R. Ofial, H. Mayr
FULL PAPER
with water (3ϫ). The organic layer was dried with MgSO4 and the
solvent was removed under reduced pressure.
under pseudo-first-order conditions. First-order rate constants kobs
(s–1) were obtained by fitting the single exponential At = A0 exp-
(–kobst) + C to the observed time-dependent absorbance (averaged
from at least 4 kinetic runs for each nucleophile concentration in
the case of stopped-flow experiments). Second-order rate constants
k2 (Lmol–1 s–1) listed in Table 1 were obtained from the slopes of
the plots of kobs vs. the nucleophile concentrations which gave lin-
ear correlations with negligible intercepts.
2,6-Dimethoxy-4-[4-(dimethylamino)benzylidene]cyclohexa-2,5-dien-
one (3e): From 5e (500 mg, 1.65 mmol) in CH2Cl2 (40 mL), ethereal
HBF4 (250 µL, 1.81 mmol) and NEt3 (297 µL, 217 mg, 2.15 mmol):
395 mg (84 %); red crystals (from CH2Cl2/n-pentane); m.p. 163–
165 °C. 1H NMR (CDCl3, 600 MHz): δ = 3.07 (s, 6 H, NMe2), 3.83
(s, 6 H, 2ϫOMe), 6.43 (br. s, 1 H), 6.75 (d, J = 8.9 Hz, 2 H), 7.02
(br. s, 1 H), 7.08 (s, 1 H), 7.45 (d, J = 8.9 Hz, 2 H) ppm. 13C NMR
(CDCl3, 151 MHz): δ = 40.8 (q, NMe2), 55.5 (q, OMe), 106.3 (d),
112.1 (d), 113.7 (d), 124.1 (s), 126.4 (s), 132.5 (d), 142.8 (d), 150.9
(s), 174.6 (s, C=O) ppm. HRMS (EI): calcd. for C17H19NO3
285.1365; found 285.1366.
Concentrations and rate constants for the individual kinetic experi-
ments for the reactions of quinone methides with carbanions are
given in the Supporting Information.
Supporting Information (see also the footnote on the first page of
this article): Details about the kinetic measurements and copies of
the NMR spectra are given in the Supporting Information.
2,6-Dimethyl-4-[4-(dimethylamino)benzylidene]cyclohexa-2,5-dien-
one (3f): From 5f (200 mg, 737 µmol) in CH2Cl2 (60 mL), ethereal
HBF4 (110 µL, 811 µmol) and NEt3 (133 µL, 100 mg, 958 µmol):
149 mg (80%); red needles; m.p. 127–128 °C (from acetonitrile). 1H
NMR (CD2Cl2, 400 MHz): δ = 2.01 (d, J = 1.1 Hz, 3 H, Me), 2.06
(d, J = 1.2 Hz, 3 H, Me), 3.06 (s, 6 H, NMe2), 6.75 (d, J = 8.6 Hz,
2 H), 7.05 (br. s, 1 H), 7.07 (s, 1 H), 7.50 (d, J = 8.7 Hz, 2 H), 7.71
(br. s, 1 H) ppm. 13C NMR (CD2Cl2, 101 MHz): δ = 16.1, 16.8 (2q,
2 Me), 39.9 (q, NMe2), 112.0 (d), 123.6 (s), 127.9 (s), 131.5 (d),
133.1 (d), 133.8 (s), 136.2 (s), 139.6 (d), 144.7 (d), 151.6 (s), 186.4
(s, C=O) ppm. MS (EI): m/z (%) = 254 (17), 253 (100) [M+], 252
(11). HRMS (EI): calcd. for C17H19NO 253.1467; found 253.1461.
Acknowledgments
We thank Dr. Florian Seeliger for studying the kinetics of the reac-
tion of 2g + 9g. Financial support of this work by the Deutsche
Forschungsgemeinschaft (DFG) (SFB 749) and the Fonds der
Chemischen Industrie is acknowledged.
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(4-Hydroxy-3,5-diphenylphenyl)[4-(dimethylamino)phenyl]methyl-
benzenesulfone (8): The alcohol 5b (200 mg, 506 µmol) and
PhSO2Na (133 mg, 809 µmol, 2 equiv.) were dissolved in 40 mL of
a 1:1 mixture of water and acetic acid. Concd. H2SO4 (22 µL,
40 mg, 0.40 mmol) was added. After heating to 100 °C for 7 h, the
mixture was cooled down and was diluted with water. The precipi-
tate was collected and dried in vacuo; 125 mg (48%); colorless so-
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1 H), 5.42 (s, 1 H, OH), 6.64 (d, J = 8.9 Hz, 2 H), 7.29–7.64 (m,
21 H, Harom.), 7.68 (d, J = 7.1 Hz, 2 H, Harom.) ppm.
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2,6-Diphenyl-4-[4-(dimethylamino)benzylidene]cyclohexa-2,5-dien-
one (3b): The sulfone 8 (50 mg, 96 µmol) was dissolved in CH2Cl2
(20 mL) and shaken with conc. aqueous NaOH (500 µL) for 2 min.
To the organic layer, n-pentane (80 mL) was added and the re-
sulting precipitate was separated by filtration. The volatile compo-
nents of the filtrate were removed under reduced pressure: 23.4 mg
(65%); dark violet solid; m.p. 189–191 °C. 1H NMR (CDCl3,
300 MHz): δ = 3.07 (s, 6 H, NMe2), 6.72 (d, J = 8.9 Hz, 2 H), 7.32–
7.65 (m, 14 H, Harom.), 8.00 (d, J = 2.5 Hz, 1 H) ppm. 13C NMR
(CDCl3, 75.5 MHz): δ = 40.0 (q, NMe2), 112.1 (d), 123.5 (s), 127.4
(d), 127.56 (d), 127.62 (d), 127.9 (d), 129.2 (d), 129.4 (d), 132.8 (d),
133.7 (d), 137.3 (s), 137.8 (s), 139.4 (s), 140.7 (d), 148.1 (d), 151.8
(s), 182.9 (s, C=O) ppm. MS (EI): m/z (%) = 379 (19), 378 (28),
377 (88) [M+], 376 (100). HRMS (EI): calcd. for C27H23NO
377.1780; found 377.1794.
Kinetics: All kinetics were studied UV/Vis photometrically. The
rates of the slow reactions (τ1/2 Ͼ 10 s) were determined by using
a J&M TIDAS diode array spectrophotometer controlled by Lab-
control Spectacle software and connected to a Hellma 661.502-QX
quartz Suprasil immersion probe (5 mm light path) via fibre optic
cables and standard SMA connectors. For the evaluation of fast
kinetics (τ1/2 Ͻ 10 s) commercial stopped-flow spectrophotometer
systems (Hi-Tech SF-61DX2 or Applied Photophysics SX.18MV-
R) were used. The temperature of the solutions was kept constant
(20.0Ϯ0.1 °C) by using circulating bath thermostats.
Solutions of the quinone methides were mixed with an excess (10–
100 equiv.) of the nucleophiles 9a–h in order to achieve kinetics
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3210
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 3203–3211

Reference Electrophiles for Nucleophilicity Scales
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Received: March 20, 2009
Published Online: May 14, 2009
Eur. J. Org. Chem. 2009, 3203–3211
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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