Aggregation and alkylation of enolates of 2-phenyl-α-tetralone and 2,6-diphenyl-α-tetralone

Article abstract of DOI:10.1021/ja0010002

The cesium (1-Cs, CsPhPAT) and lithium (1-Li, LiPhPAT) enolates of 2,6-diphenyl-α-tetralone, 1, and the lithium enolate (2-Li, LiPhAT) of 2-phenyl-α-tetralone, 2, are present in dilute THF solution as monomers and dimers with K_1.2 = 1810 (1-Cs,

Full text of DOI:10.1021/ja0010002

10754
J. Am. Chem. Soc. 2000, 122, 10754-10760
Aggregation and Alkylation of Enolates of 2-Phenyl-R-tetralone and
2,6-Diphenyl-R-tetralone1
Daniel Zerong Wang, Yeong-Joon Kim, and Andrew Streitwieser*
Contribution from the Department of Chemistry, UniVersity of California, Berkeley, California 94720-1460
ReceiVed March 20, 2000
Abstract: The cesium (1-Cs, CsPhPAT) and lithium (1-Li, LiPhPAT) enolates of 2,6-diphenyl-R-tetralone,
1, and the lithium enolate (2-Li, LiPhAT) of 2-phenyl-R-tetralone, 2, are present in dilute THF solution as
monomers and dimers with K1,2 ) 1810 (1-Cs, CsPhPAT), 2650 (1-Li, LiPhPAT), and 1930 (2-Li, LiPhAT)
M-1. These values were obtained by singular value decomposition analysis of the UV spectra and by the
dependence of ion pair pK’s with concentration. On the ion pair pK scales previously defined, the monomers
have pK ) 17.80 (1-Cs, CsPhPAT) and 11.14 (1-Li, LiPhPAT). The monomers are much faster than dimers
in alkylation reactions; reaction products from alkyl halides are those of C-alkylation, but 1-Cs (CsPhPAT)
with methyl sulfonates gives large amounts of O-alkylation. Comparison with previous results shows that the
reactivity of cesium enolates parallels their basicity but that lithium enolates show no correlation between ion
pair pK and alkylation reactivity.
Introduction
Lithium enolates have long been known to be frequently
aggregated in ethereal solvents.2-8 We have recently reported
the aggregation equilibrium constants in THF of several lithium
and cesium enolates.9-15 In the present paper these studies are
extended to the lithium (LiPhPAT, 1-Li) and cesium (CsPhPAT,
1-Cs) enolates of 2,6-diphenyl-R-tetralone. The ketone, PhPAT,
1, is related to the p-phenylisobutyrophenone studied previ-
ously,9,14 but the enolates are more conjugated. Deprotonation
gives the conjugated enolates directly without the enolate isomer
problem that complicated the study the enolates of R-phenyl-
(MPCH) and R-p-biphenylylcyclohexanone (MBPCH).7,8,15
Moreover, the tetralone ring system provides a rigid architecture
in which the enolate double bond is constrained to conjugation
with the benzene ring. The lithium enolate of R-tetralone has
been shown to be predominantly a monomer-tetramer equi-
librium in THF by NMR techniques, but with addition of a
2-isopropyl group the enolate is predominantly a dimer.4 It was
therefore important to determine the effect of a 2-phenyl
substituent. Because of the extended conjugation in PhPAT
enolate, the 6-phenyl substituent is not really necessary; it was
included for comparison with a series of alkyl-substituted
compounds, RPAT, that we plan to report on and in which the
6-phenyl substituent is necessary for study by UV spectroscopy.
In this paper, however, we also include a more limited study of
the lithium enolate of the parent system without the 6-phenyl
group, LiPhAT, 2-Li.
(1) Carbon Acidity. 113.
(2) Horner, J. H.; Vera, M.; Grutzner, J. B. J. Org. Chem. 1986, 51,
4212-20.
(3) Jackman, L.; M.; Lange, B. C. Tetrahedron 1977, 33, 2737-2769.
(4) Jackman, L. M.; Bortiatynski, J. AdV. Carbanion Chem. 1992, 1, 45-
87.
(5) Palmer, C. A.; Arnett, E. M. J. Am. Chem. Soc. 1990, 112, 7354-
7360.
(6) Streitwieser, A.; Leung, S. S.-W.; Kim, Y.-J. Org. Lett. 1999, 1, 145-
7.
(7) Streitwieser, A.; Wang, D. Z.-R. J. Am. Chem. Soc. 1999, 121, 6213-
Results and Discussion
9.
(8) Wang, D. Z.-R.; Streitwieser, A. Can. J. Chem. 1999, 77, 654-8.
(9) Abbotto, A.; Streitwieser, A. J. Am. Chem. Soc. 1995, 117, 6358-9.
(10) Abu-Hasanayn, F.; Stratakis, M.; Streitwieser, A. J. Org. Chem.
1995, 60, 4688-9.
UV-Vis Spectra of Enolates. PhPAT, 1, is a known
compound and was prepared in low yield by a slight modifica-
tion of the literature SRN1 reaction.16 Because the SRN1 reaction
proceeds in poor yield with R-tetralones and the product is
difficult to separate from unreacted reactant, PhAT was prepared
by cyclization of 2,4-diphenylbutanoic acid. The cesium enolate
of PhPAT was generated by adding a THF solution of
diphenylmethylcesium (CsDPM) to known amounts of the
(11) Abbotto, A.; Leung, S. S.-W.; Streitwieser, A.; Kilway, K. V. J.
Am. Chem. Soc. 1998, 120, 10807-13.
(12) Bauer, W.; Seebach, D. HelV. Chim. Acta 1984, 67, 1972-88.
(13) Ciula, J. C.; Streitwieser, A. J. Org. Chem. 1992, 57, 431-432;
correction p 6686.
(14) Streitwieser, A.; Krom, J. A.; Kilway, K. A.; Abbotto, A. J. Am.
Chem. Soc. 1998, 120, 10801-6.
(15) Streitwieser, A.; Wang, D. Z.; Stratakis, M. J. Org. Chem. 1999,
64, 4860-4.
(16) Scamehorn, R. G.; Hardacre, J. M.; Lukanich, J. M.; Sharpe, L. R.
J. Org. Chem. 1984, 49, 4881.
10.1021/ja0010002 CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/21/2000

Aggregation and Alkylation of R-Tetralone Enolates
J. Am. Chem. Soc., Vol. 122, No. 44, 2000 10755
ketone with biphenylyldiphenylmethane (BDPM) as an end
point indicator. Known increments of THF were added, and
the spectra were taken as a function of enolate concentration.
The corresponding lithium enolate was generated by adding a
solution of 9,9,10-trimethyl-9,10-dihydroanthracyllithium as
base which also serves as its own end point indicator. Again,
increments of THF were added to the UV cell and the spectra
were taken. The resulting spectra were deconvoluted to re-
move any contribution of absorption from the indicator. The
spectral data are detailed in Tables S1 and S2 (Supporting
Information). For 1-Cs (CsPhPAT) λmax varies from 430.5 to
441.0 nm over the concentration range 1.0 × 10-3 to 1.3 ×
10-5 M (Figure S1, Supporting Information), whereas for the
lithium enolate 1-Li (LiPhPAT) the maximum absorption
wavelength was found in the range of 392.5-415.0 nm over
the concentration range 9.0 ×10-4 to 8.5 × 10-6 M (see Figure
S5, Supporting Information). This behavior has been observed
for other enolates in which different aggregates have different
Figure 1. The spectra of 2-Li (LiPhAT), 1-Li (LiPhPAT), and 1-Cs
(CsPhPAT) monomers and dimers from SVD analysis; λmax are 1-Cs
(CsPhPAT), monomer, 445.0 nm, dimer, 425.0 nm; 1-Li (LiPhPAT),
417.0 nm, dimer, 385.0 nm; 2-Li (LiPhAT), monomer, 381.5 nm, dimer,
361.5 nm.
λmax and for which the extinction coefficients are approximately
the same per enolate unit in the aggregates. The extinction
coefficient at λmax was found by a linear plot of the absor-
bance vs the formal concentration to give ꢀ ) 19366 ( 62
and 19820 ( 49 for CsPhPAT and LiPhPAT, respectively
(Figures S4 and S8, Supporting Information). When these
spectra are normalized to a common concentration, an isosbestic
point appears at 441.0 nm for 1-Cs (CsPhPAT) and 404.0 nm
for 1-Li (LiPhPAT) (Figures S2 and S6, respectively; Supporting
Information). The isosbestic points show that only two con-
centration-dependent species are observable in each solution.
These isosbestic wavelengths also provide better points for
analysis and their extinction coefficients were determined:
1-Cs (CsPhPAT), ꢀ ) 18639 ( 62; 1-Li (LiPhPAT), ꢀ )
19004 ( 24 (Figures S3 and S7, respectively, Supporting
Information).
Similarly, spectral data were obtained for 2-Li (LiPhAT) as
detailed in Table S3 and Figures S9-S11 (Supporting Informa-
tion); λmax varies from 366 to 378 nm over the concentration
range 1.3 × 10-3 to 5.7 × 10-5 M with an isosbestic point at
372 nm and an extinction coefficient of 16992 ( 60. The
reduced conjugation with the absence of the 6-phenyl substituent
results in a significant reduction of both λmax and ꢀ. The lithium
enolate was prepared by treating a solution of the ketone with
a slight excess of LiHMDS and diluting with known amounts
of THF.
SVD Analysis. As in our previous studies, the method of
singular value decomposition (SVD)17 was applied to the
spectral data. Consistent results were obtained only for the
assumption of monomer-dimer mixtures. For 1-Cs (CsPhPAT),
the first three significant coefficients are S1 ) 48.62, S2 ) 1.12,
and S3 ) 0.14, and for 1-Li (LiPhPAT), S1 ) 39.00, S2 ) 1.66,
and S3 ) 0.089. In both cases the small magnitude of the third
significant coefficient indicates that any third component is
negligible, in agreement with the observation of isosbestic
points. From the SVD analysis the spectra of the monomer and
dimer of 1-Cs (CsPhPAT) and 1-Li (LiPhPAT) are shown in
Figure 1; λmax values are 1-Cs (CsPhPAT), monomer, 445.0
nm, dimer, 425.0 nm; and 1-Li (LiPhPAT), 417.0 nm, dimer,
385.0 nm. As in previous cases, the dimer is at shorter
wavelengths than the monomer.7,8,11,14,15
Figure 2. Plot of [dimer] versus [monomer]2 for 1-Li (LiPhPAT). Line
shown through the origin has slope ) 2673 ( 9, R2 ) 0.999.
Information). For the monomer-dimer equilibrium, eq 1, the
corresponding equilibrium constant, K1,2, is given by eq 2. For
2 monomer {K } dimer
(1)
(2)
1,2
[dimer]
K1,2
)
[monomer]2
1-Cs (CsPhPAT), four experiments in 1 mm UV cells give
reproducible K1,2 values, 1766 ( 6 M-1, as shown in Figure
S12 (Supporting Information). Similarly, for 1-Li (LiPhPAT),
four experiments give K1,2 ) 2673 ( 9 M-1, as shown in Figure
2. The linearity of these plots also establishes that the aggrega-
tion equilibrium is between monomer and dimer. The more
limited data for 2-Li (LiPhAT) give a plot of comparable quality
with K1,2 ) 1933 ( 3 M-1, as shown in Figure S13 (Supporting
Information). All three enolates show dimerization constants
of comparable magnitude.
In past work we have learned that the precision of the SVD
results is generally better than the accuracy and that a useful
test for systematic errors is to compare the extrapolated values
of λmax for monomer and dimer from a plot of the experimental
From these derived spectra the amounts of monomer and
dimer were determined for each of the experimental spectra
with results summarized in Tables S1 and S2 (Supporting
λ
max vs mole fraction of monomer with the values derived from
(17) Krom, J. A.; Petty, J. T.; Streitwieser, A. J. Am. Chem. Soc. 1993,
115, 8024-30.
SVD. Such plots are shown in Figures S14-S16 (Supporting

10756 J. Am. Chem. Soc., Vol. 122, No. 44, 2000
Wang et al.
Information); the extrapolated values for 1-Cs (CsPhPAT), M
) 443 nm, D ) 421 nm, for 1-Li (LiPhPAT), M ) 415 nm, D
) 377 nm, and for 2-Li (LiPhAT), M ) 384 nm, D ) 356 nm,
are all in satisfactory agreement with the SVD values.
Proton Transfer Equilibria. Proton transfer equilibria
between enolates and appropriate indicators provide a com-
pletely independent measure of aggregation constants. In such
ion pair equilibria, eq 3, aggregation of the enolate R- M+
makes the observed proton transfer equilibrium constant, Kob,
concentration dependent. In eq 4, Kob is given in terms of the
formal enolate concentration denoted by braces, {R-M+}. This
equilibrium constant is equivalent to the observed ∆pK differ-
ence between ketone and indicator; the observed pK is given
by eq 5 and is also concentration dependent. As shown
previously,17 for a monomer-dimer equilibrium a plot of Kob
vs {R-M+}/Kob gives both Ko, the equilibrium acidity of the
monomer relative to the indicator, and the aggregation equi-
librium constant K1,2 by eq 6.
Figure 3. Observed pK (Cs) for 1 (PhPAT). Small points show the
calculated pK for K1,2 ) 1810 M-1 and pK0 ) 17.80. Squares, diamonds,
and circles are observed pK vs BpFl as indicator (three series); triangles
and pluses are observed pK vs PhFl as indicator (two series).
K0
\
RH + In-M+ y
z R-M+ + InH
(3)
(4)
{R-M+}[In-H]
[RH][In-M+]
Kob
)
pKob(RH) ) pK(InH) - log Kob
(5)
(6)
Kob ) K0 + 2K1,2K0 {R-M+}/Kob
2
In these equations the subscript “ob” emphasizes that these
experimental values are concentration dependent when R-M+
is aggregated, but will often be omitted when the context is
clear.
Suitable indicators must satisfy several criteria: (a) the proton
transfer equilibrium constant should not differ too much from
unity, (b) the spectrum of the deprotonated indicator should
differ significantly from that of the enolate, (c) the extinction
coefficients of deprotonated indicator and enolate should permit
measurement of both, and (d) the deprotonated indicator should
be monomeric in the solution. On the basis of the these criteria,
9-biphenylylfluorene (BpFl, Cs salt: λmax ) 445.0 nm, pK )
17.72, ꢀmax ) 29 400) and 9-phenylfluorene (PhFl, Cs salt: λmax
) 397.0 nm, pK ) 18.15, ꢀmax ) 24 000)18 were chosen as
indicators for 1-Cs (CsPhPAT) and 1,3-diphenylindene (DPI,
Li salt: λmax ) 450.0 nm, pK ) 12.32, ꢀmax ) 32 900)19 was
used as the indicator for 1-Li (LiPhPAT). The indicator pK’s
are relative to assumed standards, the contact ion pair (CIP)
cesium salt and solvent-separated ion pair (SSIP) lithium salt
of fluorene assigned the DMSO value of 23.9 (per hydrogen).20
We note that we are generally careful to refer to these proton
transfer equilibria in THF as “ion pair acidities” and to use the
symbol “pK”; in particular, they are not pKa’s! Many so-called
pKa values have been assigned improperly in nonpolar solvents
such as THF and CH2Cl2. pKa refers to ionic dissociation to
conjugate base and solvated protons; thus, the pK values in
DMSO20 are pKa’s because they refer back to measurements of
[H+] in DMSO by glass electrode.21,22 The ∆pK values from
eq 5 can be converted to ∆pKa values by use of the correspond-
Figure 4. Plot of observed pK(Li) fot 1 (PhPAT) vs log{LiPhPAT}.
Small points show the calculated pK for K1,2 ) 2650 M-1 and pK0 )
11.14. Squares, diamonds, circles, and triangles are four series with
DPI as indicator.
ing ion pair dissociation constants,23,24 but without some known
acid in THF, absolute pKa values cannot be assigned. Only a
few such values have been measured in THF and only for
relatively strong acids.25,26
Several series of experiments were run by mixing known
amounts of indicator and enolate, taking the spectrum and
diluting incrementally with THF. The results are detailed in
Tables S4-S6 (Supporting Information). The lithium equilibria
were corrected for the small amount of dissociation of the LiIn
to free ions in the dilute solutions used.7 As expected, the
observed pK’s vary with concentration (Figures 3 (Cs) and 4
(Li)). The data were plotted according to eq 6 to give the results
summarized in Figures 5 and 6. The two indicators with 1-Cs
(CsPhPAT) give pK0 ) 17.81, K1,2 ) 1875 M-1 and pK0 )
17.79, K1,2 ) 1799 M-1. The results agree well with each other
and with the K1,2 derived above from SVD. We adopt the
average values as pK0 ) 17.80, K1,2 ) 1810 M-1. The calculated
(18) Streitwieser, A.; Ciula, J. C.; Krom, J. A.; Thiele, G. J. Org. Chem.
1991, 56, 1074-6.
(19) Streitwieser, A.; Wang, D. Z.; Stratakis, M.; Facchetti, A.; Gareyev,
R.; Abbotto, A.; Krom, J. A.; Kilway, K. V. Can. J. Chem. 1998, 76, 765-
9.
(20) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456-63.
(21) Kolthoff, I. M.; Reddy, T. B. Inorg. Chem. 1962, 1, 189.
(22) Ritchie, C. D.; Uschold, R. E. J. Am. Chem. Soc. 1967, 89, 1721-
5.
(23) Kaufman, M. J.; Gronert, S.; Streitwieser, A., Jr. J. Am. Chem. Soc
1988, 110, 2829-35.
(24) Antipin, I. S.; Gareyev, R. F.; Vedernikov, A. N.; Konovalov, A. I.
J. Phys. Org. Chem. 1994, 7, 181-91.
(25) Coetzee, J. F.; Deshmukh, B. K.; Liao, C.-C. Chem. ReV. 1990, 90,
827-35.
(26) Deshmukh, B. K.; Siddiqui, S.; Coetzee, J. F. J. Electrochem. Soc.
1991, 138, 124-132.

Aggregation and Alkylation of R-Tetralone Enolates
J. Am. Chem. Soc., Vol. 122, No. 44, 2000 10757
Figure 5. Plots of Kob vs {CsPhPAT (1-Cs)}/Kob for three runs with
BpFl as indicator (line shown is (0.805 ( 0.03) + (2460 ( 109)-
{CsPhPAT}/K0; R2 ) 0.957) and two runs with PhFl as indicator (line
shown is (2.28 ( 0.11) + (1865 ( 100){CsPhPAT}/K0; R2 ) 0.933).
Figure 7. Correlation of pK(Li) with pK(Cs) for the enolate data in
Table 1. The line shown is 0.20 + 0.626 pK(Cs enolate); R2 ) 0.996.
to dimerize, but the trend is clearly affected strongly by other
factors. Indeed, for the first three cases the K1,2 values are
remarkably constant. There is more variation for the lithium
enolates, but the total variation in K1,2 in this series is only 1
power of ten. The greater tendency of the biphenylyl systems
to dimerize compared to phenyl suggests that the p-phenyl
substituent is freer to rotate in the dimer in which the greater
polarization of charge toward the more highly coordinated
oxygen requires less charge delocalization; this phenomenon
shows up for 1-Li (LiPhPAT) and 4-Li (LiBPCH) and is less
important, as expected, for the more weakly coordinated cesium
enolates. We conclude that within a related set of enolates the
aggregation equilibria are similar and affected in a minor way
by factors other than basicity. For larger pK differences, how-
ever, the trend is clear. For the lithium enolate of p-phenyl-
sulfonylisobutyrophenone, pK ) 14.69 and K1,2 ) 5.0 × 104
M-1 10
and the lithium enolate of p-phenylisobutyrophenone
,
(LiPhIBP) with pK ) 15.86 forms a monomer-tetramer
Figure 6. Plot of four runs of Kob vs {LiPhPAT (1-Li)}/Kob with DPI
as indicator. The equation of the line shown is (15.21 ( 1.64) + (1.217
equilibrium.11
The lithium enolates have lower pK values than the corre-
sponding cesium enolates. The lithium enolates also have λmax
at shorter wavelengths than the cesium analogues, indicating
that both are CIP; thus, the shorter O- Li+ bond distance means
a tighter ion pair with a lower ion pair dissociation constant,
Kd. By comparison with Kd’s for SSIP indicators, the pK
difference for MPhPAT of 6.66 units allows an estimate of Kd
for LiPhPAT of about 2 × 10-12 M.23 The point is also shown
by a plot of pK(Li) vs pK(Cs) for the enolate data in Table 1.
The data give a linear correlation (Figure 7) with a slope of
0.63. For the simplest point charge electrostatic model, this slope
would be comparable to the ratio of the O-M+ bond distances.
Reasonable distances are 1.6 Å for O-Li and 2.7 Å for O-Cs
for a ratio of 0.59.
( 0.11) × 106 {LiPhPAT}/Kob and gives K1,2 ) 2637 M-1
Table 1. Comparison of Properties of Related Enolates
.
cesium
lithium
enolate
pK0
K1,2 M-1
pK0
K1,2 M-1
1-M (MPhPAT)
2-M (MPhAT)
17.80
1810
11.14
2650
1930
4300
2800
420
4-M (MBPCH)a
3-M (MPCH)b
19.30
19.82
18.07
1900
1800
3500
595
12.31
12.69
11.62
PhCHdC(OM)CH2Phc
BiPhCHdC(OM)CH2BiPhd 17.10
MPhIBPe
25.08
15.86
a References 7 and 15. b Reference 8. c Reference 39. d Reference
13. e Enolate of p-phenylisobutyrophenone; refs 11 and 14.
Kinetic Study. Kinetic measurements were made by addi-
tion of a constant excess amount of alkylating agent (pseudo-
first-order conditions) to varying known amounts of enolate and
then following the initial rate of reaction of the enolate (10-
20%). Kinetics experiments were run with 1-Cs (CsPhPAT)
using n-hexyl bromide (HexBr), n-hexyl iodide (HexI), methyl
tosylate, and methyl brosylate and with 1-Li (LiPhPAT) using
benzyl bromide (BnBr) and o-methyl- (o-MeBnBr), o-chloro-
(o-ClBnBr), and m-chlorobenzyl bromides (m-ClBnBr). These
compounds were chosen for their low volatility in glovebox
handling, HexI was included to test for reaction by SET (single
electron transfer), and the lithium enolate required the more
reactive benzyl bromides for convenient reaction times.
pK as a function of {CsPhPAT} is shown as the locus of points
in Figure 3. Similarly the data for 1-Li (LiPhPAT) vs DPI are
plotted in Figure 6; the results from four separate runs give
pK0 ) 11.14 ( 0.05 and K1,2 ) 2637 ( 237 M-1. This value
for K1,2 is in good agreement with that derived from SVD. We
adopt the average value as K1,2 ) 2650 M-1. The calculated
pK as a function of {LiPhPAT} is shown as the locus of points
in Figure 4.
The results are compared in Table 1 with those determined
previously for the related conjugated enolates 3-M (MPCH) and
4-M (MBPCH). Among the cesium enolates there is a rough
trend that more stable enolates (lower pK) have a lower tendency

10758 J. Am. Chem. Soc., Vol. 122, No. 44, 2000
Wang et al.
Figure 8. Plots of rate versus [M][RX] for the reaction of 1-Cs
(CsPhPAT) with alkylating reagents. Slopes of lines shown are triangles,
HexBr, 0.0098 ( 0.0002; squares, HexI, 0.139 ( 0.001; diamonds,
MeOTs, 0.109 ( 0.002; circles, MeOBs, 0.738 ( 0.009.
Figure 9. Plots of rate versus [M][RX] for the reactions of 1-Li
(LiPhPAT) with benzyl bromides. Slopes of lines shown are triangles,
BnBr, 0.0343 ( 0.0003; squares, o-MeBnBr, 0.0365 ( 0.0006;
diamonds, o-ClBnBr, 0.0150 ( 0.0002; circles, m-ClBnBr, 0.0723 (
0.0007.
In previous studies we showed how the total reaction in eq
7 can be dissected into contributions by monomer and dimer.10,27
The total rate equation, eq 8, in which M and D refer to
monomer and dimer, respectively, can be rearranged to eq 9.
Kinetics data plotted as eq 9 would give linear plots in which
the slope gives kM and the intercept is kD. Several previous
examples of such plots gave intercepts indistinguishable from
zero, indicating reaction under these conditions solely with the
monomer.7,11,15 This result is also true in the present cases.
Figures S17-S19 (Supporting Information) show intercepts
indistinguishable from zero.
Figure 10. Rate vs [M][RX] for reaction of 2-Li (LiPhAT) with benzyl
bromide. Slope of line shown is 0.036 ( 0.002.
Table 2. Second-Order Rate Constants for Reaction of Enolate
Monomers with Alkylating Agents in THF at 25 °C
C-/O-alkylation
Alternatively, since reaction is primarily with monomer, a
plot of rate vs [RX][M] gives directly the second-order rate
constant kM (eq 10).
enolate
RX
k2, M-1 s-1
ratio
1-Cs (CsPhPAT) HexBr
0.0098 ( 0.0002d
0.139 ( 0.001d
0.109 ( 0.002d
0.738 ( 0.009
100% C
100% C
1/2
1/3
100% C
HexI
MeOTs
MeOBs
-d{MPhPAT}/dt ) kM[RX][M]
(10)
1-Li (LiPhPAT)
2-Li (LiPhAT)
BnBr
0.0343 ( 0.0003
o-MeBnBr 0.0365 ( 0.0006
o-ClBnBr 0.0150 ( 0.0002
m-ClBnBr 0.0723 ( 0.0007
The resulting plots are shown in Figures 8 (CsPhPAT), 9
(LiPhPAT), and 10 (LiPhAT), and the rate constants are
summarized in Table 2.
100% C
100% C
BnBr
0.036 ( 0.002
The results lead to some interesting conclusions. The reactiv-
ity of 2-Li (LiPhAT) monomer and 1-Li (LiPhPAT) monomer
toward benzyl bromide is the same within experimental error.
Little difference would be expected for the effect of a p-phenyl
group, and the result adds confidence to the overall approach.
The reaction of n-hexyl iodide with 1-Cs (CsPhPAT) is 14 times
that of the bromide and only slightly more reactive than methyl
tosylate. These reactivities are not out of line with typical SN2
reactions28 and indicate that the alkyl iodide reaction is not single
electron transfer (SET). Reactions with methyl tosylate are now
available for three cesium enolate monomers. These reactivities
are summarized in Table 3. Comparison of log k with the
corresponding pK values gives a linear correlation with a
Brønsted slope of 0.28 (Figure S20, Supporting Information);
that is, the basicity of the cesium enolates is a valid measure of
ion pair nucleophilicity. The situation is entirely different for
lithium enolates. As summarized in Table 3 data are available
for the reactivities of four lithium enolate monomers with
m-chlorobenzyl bromide, and these show no correlation at all
with pK. For the tighter lithium enolate ion pairs, increasing
nucleophilicity accompanying greater basicity is balanced
(27) Abu-Hasanayn, F.; Streitwieser, A. J. Am. Chem. Soc. 1996, 118,
8136-7.
(28) Streitwieser, A. Chem. ReV. 1956, 56, 571.

Aggregation and Alkylation of R-Tetralone Enolates
J. Am. Chem. Soc., Vol. 122, No. 44, 2000 10759
Table 3. Second-Order Rate Constants of Alkylating Agents with
Different Enolate Monomers in THF at 25 °C
2. All of the alkyl halides give complete C-alkylation, in
agreement with previous results.7,11,14,15 Only in the case of the
most basic enolate, CsPhIBP, does benzyl chloride give a small
amount (3%) of O-alkylation.14 Both LiPhIBP and CsPhIBP
give comparable amounts of C- and O-alkylation with methyl
sulfonates.11,14 With either CsBPCH or LiBPCH, methyl sul-
fonates give only C-alkylation,7,15 in contrast to the present case
of 1-Cs (CsPhPAT) where mostly O-alkylation was observed.
The difference might mean that the enolate carbon in 1 (PhPAT)
is more sterically hindered, thus directing more reaction toward
oxygen. These generalizations can be added to those summarized
by le Noble three decades ago.29
k2 with MeOTs,
k2 with m-ClBnBr,
enolate
M-1 s-1
M-1 s-1
CsPhIBPa
14.5
0.46
0.109
4-Cs (CsBPCH)b
1-Cs (CsPhPAT)
LiPhIBPc
0.255
1.34
1.47
3-Li (LiPCH)d
4-Li (LiBPCH)e
1-Li (LiPhPAT)
0.0723
a Cesium enolate of p-phenylisobutyrophenone, ref 14. b Reference
15. c Lithium enolate of p-phenylisobutyrophenone, ref 11. d Reference
8. e Reference 7.
Conclusion
Scheme 1
The cesium and lithium enolates of 1, 2,6-diphenyl-R-tetra-
lone, and the lithium enolate of 2, 2-phenyl-R-tetralone, show
monomer-dimer equilibria in dilute THF solution at 25 °C with
K1,2 ) 103 M-1, the same magnitude found previously for the
enolates of another conjugated ketone, 4, R-biphenylylcyclo-
hexanone. At synthesis concentrations of >0.1 M, these enolates
are >90% dimer. As in all of our enolate studies thus far, the
dimers are much less reactive in alkylation reactions than the
monomers.30 Monomeric 1-Cs (CsPhPAT) is less reactive in
such alkylations than more basic cesium enolates, but for lithium
enolates there appears to be no simple relationship between ion
pair basicity and alkylation reactivity. Methyl sulfonates give
mostly O-alkylation with 1-Cs (CsPhPAT), but both enolates
give only C-alkylation with alkyl halides. The alkylation with
hexyl iodide appears to be a normal ion pair SN2 reaction and
not SET.
Experimental Section
All UV measurements were carried out in a glovebox under an argon
atmosphere at a constant temperature of 25.0 ( 0.1 °C, maintained by
a cooling bath. The sample compartment located in the floor of the
glovebox was connected to a Shimadzu 3801 spectrometer with fiber
optic cables. THF was purified as described previously.31 The alkylating
agents and indicators were purified by vacuum sublimation or distil-
lation.
2,6-Diphenyl-1-tetralone, 1. 6-Phenyltetralin32 was oxidized with
chromium trioxide in acetic acid by following the procedure of Allinger
and Jones33 in 57% yield. NMR showed the product to be a mixture of
95% 6-phenyl-R-tetralone and 5% 7-phenyl-R-tetralone (5.3%). Pure
6-phenyl-R-tetralone was obtained by recrystallization twice and
sublimation three times, mp 114-115 °C (lit. 105-7 °C,34 106-8 °C,35
112.5-113.5 °C36).
against the greater difficulty in increasing the oxygen-lithium
bond distance in going to the transition state and more subtle
steric effects at the reacting carbon. This aspect is also brought
out by the effect of ortho-substitution with different lithium
enolates; for example, the relative rates for the series BnBr,
o-ClBnBr, o-MeBnBr vary by a factor of 2 between reaction
with 1-Li (LiPhPAT) and 4-Li (LiBPCH),7 even though both
enolates appear to have similar steric environments around the
reacting carbon.
Finally, reaction products for several of the reactions were
determined by GC-MS. For the reactions for 1-Cs (CsPhPAT)
with hexyl bromide and iodide, only one product was observed;
it was readily identified as the C-alkylation product because
the base MS peak at m/z ) 298 (M - C6H12) is the expected
McLafferty rearrangement product (Scheme 1a). The reactions
of 1-Cs (CsPhPAT) with methyl tosylate and brosylate give
two products. That coming from the GC first is identified as
the O-alkylation product because the base peak is also the parent,
m/z ) 312. The only important fragment peak is m/z ) 221 (M
- PhCH2) corresponding to deep-seated rearrangement. The
second product is identified as the C-alkylation product. The
base peak at m/z ) 194 (M - PhC3H5) is rationalized in Scheme
1b. The reactions of 2-Li (LiPhAT) and 1-Li (LiPhPAT) with
benzyl bromide also give single products identified as those of
C-alkylation; the base peaks at m/z ) 193 and 269, respectively,
are rationalized in Scheme 1c. A preparative scale reaction was
run with 1-Li (LiPhPAT) and o-chlorobenzyl bromide. The
product was identified as the C-alkylation product by NMR; in
particular, a signal for the -O-CH2- group is missing. These
results for the C-/O-alkylation ratio are summarized in Table
2,6-Diphenyl-R-tetralone, 1, was prepared by reaction with iodo-
benzene and potassium tert-butoxide in DMSO by following a literature
procedure16 except for the use of argon in place of nitrogen. The product
was laboriously separated from unreacted 6-phenyltetralone by dif-
ferential sublimation under high vacuum to give a 3% yield: mp 149-
1
150 °C; H NMR (300 MHz, CDCl3) δ 8.18 (d, J ) 8.16 Hz, 1H),
7.65 (d-t, J1 ) 6.86 Hz, J2 ) 1.53 Hz, 2H), 7.58 (d-d, J1 ) 8.18 Hz,
J2 ) 1.74 Hz, 1H), 7.51-7.39 (multi, 5H), 7.37-7.34 (multi, 1H),
7.30 (d-t, J1 ) 7.12 Hz, J2 ) 1.46 Hz, 1H), 7.27-7.17 (multi, 2H),
3.84 (t, J ) 7.94 Hz, 1H), 2.52-2.44 (multi, 2H), 3.24-3.00 (multi,
(29) le Noble, W. Synthesis 1970, 1-6.
(30) This conclusion contrasts with some others based on product studies
of methylation in ethereal solvents: Jackman, L. M.; Lange, B. C. J. Am.
Chem. Soc. 1981, 103, 4494-9.
(31) Gronert, S.; Streitwieser, A., Jr. J. Am. Chem. Soc. 1986, 108, 7016-
22.
(32) Hey, D. H.; Wilkinson, R. J. Chem. Soc. 1940, 1030.
(33) Allinger, N. L.; Jones, E. S. J. Org. Chem. 1962, 27, 70.
(34) Itoh, K.; Miyake, A.; Tada, N.; Hirata, M.; Oka, Y. Chem. Pharm.
Bull. 1984, 32, 130.
(35) El-Zohry, M. F.; El-Khawaga, A. M. J. Org. Chem. 1990, 55, 4036.
(36) Lyle, T. A.; Daub, G. H. J. Org. Chem. 1979, 44, 4933.

10760 J. Am. Chem. Soc., Vol. 122, No. 44, 2000
Wang et al.
2H); 13C NMR (400 MHz, CDCl3) δ 197.9, 144.5, 140.0, 139.7, 128.9,
128.5, 128.4, 128.4, 128.2, 127.3, 127.2, 126.9, 125.6, 54.3, 31.2, 28.9;
MS (EI, m/z, relative intensity), 300 (M+ + 2, 2.7), 299 (M+ + 1,
21.3), 298 (M+, 86.4), 207 (20.6), 194 (100.0), 166 (20.1), 165 (42.8);
HRMS C22H18O calcd 298.1358, found 298.1358. Anal. Calcd for
C22H18O: C, 88.56; H, 6.08. Found: C, 88.66; H, 6.22.
(3) 1-Cs (CsPhPAT) + HexBr or HexI. The solution was taken
out of box and carried out on GC-MS directly. Both reactions gave
only one product: 384 (M + 2, 3.28), 383 (M + 1, 21.60), 382 (M,
70.17), 367 (0.05), 354 (0.06), 353 (0.11), 311 (0.46), 305 (0.09), 299
(24.38), 298 (100.0), 297 (20.95), 278 (5.01), 269 (16.94), 221 (6.40),
207 (73.18).
2-Phenyl-1-tetralone, 2. A solution of n-BuLi (10 mL, 2.5 M in
hexane) was added to 3 mL of diisopropylamine in THF (20 mL) at
-78 C followed by 1.4 g of phenylacetic acid and then 1.6 mL of
â-phenylethyl bromide. The mixture was stirred at -78 C for 30 min
and was gradually allowed to warm to room temperature. The solution
was stirred for an additional 10 h. After pumping off the solvent, 100
mL of water was added to the residual yellow oil. After 2 weeks, yellow
crystals formed and the solid (0.6 g) was dried and cyclized by
following the procedure of Newman. After recrystallization from ethanol
and sublimation, 0.4 g of white solid was obtained: mp 73-74 °C
(4) 1-Li (LiPhPAT) + BnBr. Only one product was found on GC-
MS: 389 (M + 1, 22.0), 388 (M, 89.3), 310 (5.7), 298 (14.7), 297
(68.4), 269 (100.0), 194 (38.0).
(5) 1-Li (LiPhPAT) + 2-ClBnBr. The reaction was carried out on
a preparative scale. A vial containing 5.295 mg of LDA and 5.40 g of
THF was shaken and 14.7 mg of PhPAT was added. The solution was
left in the glovebox for 2 days to complete the formation of LiPhPAT.
Then 21.0 µL of 2-ClBnBr was added and the solution was mixed.
After 1 week in the glovebox the solution was quenched with 1 drop
of water. GC-MS showed only one product identified as that of
C-alkylation. Solvent was removed, and the residue was purified on
preparative TLC to give 21.0 mg of product; MS (m/z, relative
intensity), 424 (M + 2, 0.65), 423 (M + 1, 0.52), 422 (M, 1.80), 389
(5.44), 388 (32.30), 387 (100.0), 386 (3.42), 345 (0.62), 310 (0.56),
309 (0.72), 298 (8.45), 297 (32.73), 296 (6.73), 270 (11.99), 269 (52.19),
194 (22.80); HRMS C29H2335ClO calcd 422.1437, found 422.1445;
1
(lit.37,38 76-77 °C); H NMR δ (300 MHz) 8.1 (1 H, d), 7.5 (1 H),
7.4-7.2 (7 H), 3.8 (1 H), 3.1 (2 H), 2.45 (2 H); m/z 222.
Kinetic Studies. The enolate solutions were prepared as in the
spectral studies, and known amounts of the alkyl halide or sulfonate
were added. Excess alkylating agent was used to give pseudo-first-
order conditions. The resulting kinetic solutions generally contained
0.0002-0.001 M enolate and 0.006-0.04 M alkylating agent. The
enolate absorption was followed for 10-20% of the reaction, and the
resulting linear relation with time was used as the initial rate of reaction.
The kinetic results are shown graphically in the Supporting Information,
and the rate constants are summarized in Tables 2 and 3.
Product Analyses. The reaction mixtures were allowed to run to
completion in the glovebox and analyzed by GC-MS (MS given as
m/z, relative intensity).
(1) 1-Cs (CsPhPAT) + MeOTs: both C- and O-products, C/O )
1.0/2.0. 2-MePhPAT (C-alkylation), 314 (M + 2, 0.9), 313 (M + 1,
6.3), 312 (M, 25.2), 207 (10.4), 195 (15.3), 194 (100.0), 165 (53.2).
O-MePhPAT (O-alkylation), 314 (M + 2, 3.3), 313 (M + 1, 26.3),
312 (M, 100.0), 310 (2.4), 297 (3.7), 296 (4.7), 281 (8.5), 269 (11.8),
235 (5.7), 222 (8.2), 221 (45.9).
1
C29H2337ClO calcd 424.1408, found 424.1421; H NMR (400 MHz,
CDCl3) δ (ppm) 8.26 (d, J ) 8.22 Hz, 1H), 7.51 (t-d, J1 ) 6.98 Hz,
J2 ) 1.45 Hz, 3H), 7.41 (t-d, J1 ) 7.78 Hz, J2 ) 1.95 Hz, 2H), 7.36-
7.30 (multi, 2H), 7.28-7.22 (multi, 5H), 7.10 (t-d, J1 ) 7.41 Hz, J2
) 1.67 Hz, 1H), 7.02 (t-d, J1 ) 7.51 Hz, J2 ) 1.27 Hz, 1H), 6.88
(d-d, J1 ) 7.68 Hz, J2 ) 1.66 Hz, 1H), 3.69 (d, J ) 13.78 Hz, 1H),
3.44 (d, J ) 13.78 Hz, 1H), 2.88 (t-d, J1 ) 17.02 Hz, J2 ) 4.12 Hz,
1H), 2.81-2.75 (multi, 2H), 2.29 (t-d, J1 ) 13.06 Hz, J2 ) 4.89 Hz,
1H); 13C NMR (400 MHz, CDCl3) δ (ppm) 199.1, 145.8, 143.8, 139.9,
138.7, 135.8, 135.7, 133.0, 131.6, 129.3, 128.8, 128.8, 128.5, 128.1,
127.6, 127.4, 127.2, 127.1, 127.0, 126.2, 125.4, 55.9, 41.5, 30.2, 25.8.
Acknowledgment. This work was supported in part by NIH
Grant GM-30369 and NSF Grant 9980367.
(2) 1-Cs (CsPhPAT) + MeOBs: both C- and O-products, C/O )
1.0/3.2).
Supporting Information Available: Additional tables and
figures. This material is available free of charge via the Internet
at http://pubs.acs.org.
(37) Newman, M. S. J. Am. Chem. Soc. 1938, 60, 2847.
(38) Newman, M. S. J. Am. Chem. Soc. 1940, 62, 870.
(39) Gareyev, R.; Ciula, J. C.; Streitwieser, A. J. Org. Chem. 1996, 61,
4589-93.
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