Reactions of molecules with two equivalent functional groups. 5. Anomalous reactivity of 1,10-cyclooctadecanedione. Crystal and molecular structures of cis,cis-1,10-Diphenyl-1,10-cyclooctadiene and the stereoisomers of 1,10-diphenyl-1,10-cyclooctadecanediol

Article abstract of DOI:10.1021/jo930376d

The reaction of the title diketone (3) with phenyl Grignard produces (with rate constant k₁) the conjugate base (6-M) of 10-hydroxy-10-phenylcyclooctadecanone (6), which is subsequently converted (with rate constant k₂) to the conjugate base of the title diol, as a mixture of the cis (7, 55%) and trans (8, 45%) isomers. The ratio k₂/k₁, 2.2 ± 0.4, indicates that the carbonyl group in 6-M is 4.4 times as reactive as each carbonyl in 3. Competition experiments further demonstrate that the relative rates (per carbonyl) for addition of phenylmagnesium bromide to 3, 10-methylenecyclooctadecanone (11), and cyclopentadecanone (12) are 1.0:0.60:1.92. Possible reasons for this order of reactivity are discussed. Diols 7 and 8 undergo facile double dehydration to form the title diene 13, which is predicted by molecular mechanics calculations to be the most stable of the four possible symmetrical diene isomers. The structures of 7, 8, and 13 were secured by single-crystal X-ray studies.

Full text of DOI:10.1021/jo930376d

J . Org. Chem. 1996, 61, 727-734
727
Rea ction s of Molecu les w ith Tw o Equ iva len t F u n ction a l Gr ou p s.
5. An om a lou s Rea ctivity of 1,10-Cycloocta d eca n ed ion e. Cr ysta l
a n d Molecu la r Str u ctu r es of
cis,cis-1,10-Dip h en yl-1,10-cycloocta d ien e a n d th e Ster eoisom er s of
1,10-Dip h en yl-1,10-cycloocta d eca n ed iol1
Roger S. Macomber,* Ioannis Constantinides, J eanette Krause Bauer, Gregory Smith,
Angela Button, and David O. Lindstrom
Department of Chemistry, University of Cincinnati, Cincinnati, Ohio 45221-0172
Received March 9, 1993X
The reaction of the title diketone (3) with phenyl Grignard produces (with rate constant k1) the
conjugate base (6-M) of 10-hydroxy-10-phenylcyclooctadecanone (6), which is subsequently converted
(with rate constant k2) to the conjugate base of the title diol, as a mixture of the cis (7, 55%) and
trans (8, 45%) isomers. The ratio k2/k1, 2.2 ( 0.4, indicates that the carbonyl group in 6-M is 4.4
times as reactive as each carbonyl in 3. Competition experiments further demonstrate that the
relative rates (per carbonyl) for addition of phenylmagnesium bromide to 3, 10-methylenecyclooc-
tadecanone (11), and cyclopentadecanone (12) are 1.0:0.60:1.92. Possible reasons for this order of
reactivity are discussed. Diols 7 and 8 undergo facile double dehydration to form the title diene
13, which is predicted by molecular mechanics calculations to be the most stable of the four possible
symmetrical diene isomers. The structures of 7, 8, and 13 were secured by single-crystal X-ray
studies.
In 1980 we described a mathematical model2a for
testing the degree of independent reactivity of two
separate but equivalent functional groups in the same
bifunctional molecule X2. The sequence below depicts the
reaction of X2 with reagent R which converts functional
group X to derivative functionality P. The reaction occurs
In the oxidation of the isomers of 1 with solid γ-MnO2,
the κ values ranged from 0.08 and 0.12 for the ortho and
meta isomers (k1 . k2) to 1.5 for the para isomer.1
Clearly, κ values substantially less than 0.5 indicate
the ability of a given reaction to produce useful amounts
of monoadduct. But even more importantly, the actual
k1 and k2 values, when compared to rate constants of
appropriate monofunctional model compounds, also pro-
vide quantitative measures of the interactions between
the functional groups.
During separate studies directed toward the synthesis
of novel tricyclic alkyne 2,4a it was observed that attempts
to add nucleophiles to just one of the carbonyl groups of
1,10-cyclooctadecanedione (3) gave predominately the
diadduct (and unreacted 3),even when the mole ratio of
in two discrete steps, first producing “monoadduct” XP
which is subsequently converted to “diadduct” P 2. If the
functional groups (X and X or P and X) act independently,
and the reactions are irreversible, the ratio of rate
constants k2/k1 (≡κ) should equal 0.50.2a
In the past we reported detailed kinetic studies which
test this “independent functional groups” (IFG) model.
For example, while the hydroxyl groups of para and meta
bis(hydroxymethyl)benzene (1) underwent acetylation
independently (κ ) 0.55 and 0.52, respectively), the ortho
isomer deviated from IFG behavior to a modest extent
(κ ) 0.61).2b Interestingly, acetylation of the much more
flexible 1,6-hexanediol conformed closely to IFG behavior
(κ ) 0.48).3 By contrast, nucleophilic substitution reac-
tions of a homologous series of R,ω-dibromoalkanes
exhibited increasing deviation from IFG behavior as the
alkane chain length decreased from five carbons (κ )
0.61) to four (κ ) 0.77) to three (κ ) 1.15).2c These effects
can be even more pronounced in heterogeneous reactions.
reagent to 3 was less than 1:1.4b,c For example, attempts
to prepare the mono ethylene ketal of 3 led instead to
the diketal and unreacted 3.4a,b Similarly, reaction with
1 equiv of typical Wittig reagents (vide infra) gave
predominantly the dialkene, minor amounts of ketoalk-
ene, and unreacted 3.4a,b Most important vis a´ vis the
synthesis of 2, addition of a limiting amount of lithium
(or dilithium) acetylide to 3 gave diadduct 5 (and unre-
X Abstract published in Advance ACS Abstracts, J anuary 1, 1996.
(1) For paper 4 in the series, see: Constantinides, I.; Macomber, R.
S. J . Org. Chem. 1992, 57, 6063.
(2) (a) Macomber, R. S.; Bopp, T. T. Synth. Commun. 1980, 10, 767.
(b) Constantinides, I.; Lourdes-Guerra, M.; Macomber, R. S. J . Phys.
Org. Chem. 1990, 3, 789. (c) Constantinides, I.; Macomber, R. S. J .
Phys. Org. Chem. 1992, 5, 327.
(3) Constantinides, I. Ph.D. Dissertation, University of Cincinnati,
1992.
(4) (a) Macomber, R. S.; Hemling, T. C. J . Am. Chem. Soc. 1986,
108, 343. (b) Hemling, T. C. Ph.D. Dissertation, University of
Cincinnati, 1985. (c) Kersman, D. A.; Hemling, T. C.; Ho, D. M.;
Macomber, R. S. J . Chem. Res., Synop. 1989, 270; J . Chem. Res.,
Miniprint 1989, 2001.
0022-3263/96/1961-0727$12.00/0 © 1996 American Chemical Society

728 J . Org. Chem., Vol. 61, No. 2, 1996
Macomber et al.
prepared by published procedures.5 Interestingly, highly
purified 3 exhibits two well-defined maxima in its UV
spectrum: 286 (ꢀ 45) and 208 nm (ꢀ 33). The former band
can be assigned to the n f π* transition of the carbonyl
group. The latter band, however, may be evidence for a
weak transannular electronic interaction between the
carbonyls.
Sch em e 1
Reaction of 3 with 1 molar equiv of phenyl Grignard
provided a product mixture from which pure diols 7 and
8 could be isolated by fractional crystallization. The
structures of 7 and 8 were determined by single-crystal
X-ray analysis (Figures 1 and 2) to be the cis and trans
diols, respectively. [Interestingly, both 7 and 8 crystallize
with four independent molecules (each with a slightly
different conformation) per unit cell.] Monoadduct 6
could be isolated in small amounts by HPLC.
The rate of reaction between a Grignard reagent and
a ketone to give the metal alkoxide is quite fast even at
very low temperature, making the direct measurement
of rate constant using classical techniques (mixing the
reactants and analyzing the mixture as a function of
time) very difficult. However, for the consecutive-com-
petitive reactions in Scheme 2 a different approach can
be adopted to find κ. Specifically, the ratio of rate
constants κ ) (k2 + k2′)/k1 can be readily obtained from
experiments where the Grignard reagent is added in
measured incremental portions to a solution of diketone
3 with known initial concentration. A small hydrolyzed
aliquot of the reaction mixture is analyzed after each
addition, giving the experimentally observed concentra-
tions of 3, 6, 7, and 8 as functions of the amount of
reagent consumed. Two independent methods are then
used to calculate the best fit value of κ. In the first
method, the entire concentration data set is compared
to values calculated by an “incremental” kinetics simula-
tion program,6 where κ is varied to give the best least-
squares fit between observed and calculated concentra-
tions of the reaction mixture components. Alternatively,
the value of κ can be determined iteratively for each
aliquot using an equation derived form the appropriate
integrated rate equations2b,7 (see Experimental Section).
Both methods give comparable values of κ.
Table 1 summarizes the results of three reactions
where phenyl Grignard was added incrementally to a
solution of 3. The value of κ for each run was determined
by the former method. The average value of κ for the
three runs is 2.2 ( 0.4; i.e., the second addition is more
than twice as fast as the first, indicating that the
reactivity of the carbonyl group in 6-M is 4.4 times that
of either carbonyl in 3. The detailed concentration data
for run 1 are shown in Table 2, along with the aliquot-
by-aliquot κ values generated by the second method. The
average κ value by the latter method, 2.7 ( 1.3, agrees
with the former value, though there is greater experi-
mental uncertainty, owing to the lower precision in the
measurement of the small amount of 3 remaining late
in the reaction. There is a modest 55/45 preference for
formation of the cis diol 7 over the trans isomer 8,
indicating that k2/k2′ ) 1.22. Figure 3 illustrates the
agreement between the observed concentrations and
acted 3); no monoadduct 4 could be detected by NMR
(Scheme 1).4b,c These observations suggested that in the
reactions of 3 the ratio k2/k1 must be significantly greater
than 0.5, either because monoadduct formation (k1) is
retarded or diadduct formation (k2) is accelerated, relative
to the reactivity of “normal” ketones.
Interestingly, diol 5 could be crystallized, and the
crystalline material was demonstrated by an X-ray study
to possess the trans configurations.4c Because no other
signals were seen in the 1H and 13C NMR spectra of
chromatographically homogeneous crude 5, it was pre-
sumed that this trans isomer was the predominant or
perhaps exclusive product. We have now secured evi-
dence (see Experimental Section) for the formation of a
minor amount of cis-5.
Because neither 4 (if formed) nor the isomers of 5 could
be readily quantitated by any of the common analytical
techniques, we have undertaken a detailed study of the
reaction between 3 and phenyl Grignard. It was antici-
pated that the four potential components of this reaction
mixture (3, 6, 7, and 8, Scheme 2) could be readily
separated by HPLC with UV detection, leading to a
determination of κ and, thereby, an assessment of the
nature of transannular interactions between the func-
tional groups in 3 and its derivatives. The results of this
study are described below.
(5) (a) Blomquist, A. T.; Prager, J .; Wolensky, J . J . Am. Chem. Soc.
1955, 77, 1804. (b) Ruzicka, L.; Stall, M.; Huyser, H. W.; Bookenoogen,
H. A. Helv. Chim. Acta 1930, 13, 1152.
(6) Macomber, R. S.; Constantinides, I. J . Chem. Educ. 1991, 68,
985.
(7) (a) Wideqvist, S. Acta Chem. Scand. 1962, 16, 1119. (b)
Wideqvist, S. Arkiv Kemi 1955, 8, 545. (c) McMillan, W. G. J . Am.
Chem. Soc. 1957, 79, 4838.
Resu lts a n d Discu ssion
In order to quantify the amounts of 3, 6, 7, and 8 by
UV it was first necessary to determine the chromato-
graphic retention characteristics and relative UV re-
sponse factors (ꢀ ratios) for 6-8 vs 3. Diketone 3 was

Reactions of Molecules with Equivalent Functional Groups
Sch em e 2
J . Org. Chem., Vol. 61, No. 2, 1996 729
those calculated from the best fit value of κ (2.36) for run
number 1, Table 1.
It is informative to consider certain other anomalous
physical properties of 3 in addition to its weak UV band
at 208 mm (vide supra). The molecule crystallizes in a
It is clear from the observed κ value for 3 of 2.2 that
either (a) the rate constant (k1) for addition of phenyl
Grignard to a carbonyl group of 3 is slower than expected
(b) the rate constant (k2) for addition to the carbonyl of
6-M is accelerated, or (c) some combination of both effects
is occurring.
It would be straightforward to account for 6-M having
reduced reactivity toward carbonyl additions by invoking,
for example, formation of “ketal” 9 to protect the remain-
ing carbonyl. But for 6-M to be more reactive than 3, the
C
2h conformation with the two carbonyl dipoles trans, and
zero net dipole moment.9 Essentially the same confor-
mation was found by Allinger using MM2 calculations9
to be the lowest energy one accessible to “free” 3.
Surprisingly, in solution 3 exhibits a dipole moment of
2.78 D, compared to 2.47 D for cyclooctadecanone itself.9
This suggests that in solution 3 adopts a set of easily
accessible conformations where the carbonyl dipoles do
not cancel one another. It can be estimated from a simple
trigonometric calculation that the observed dipole mo-
ment is consistent with a time-averaged angle between
coplanar carbonyls of 111°. This factor may also be
associated with the 208 nm UV band.
One interpretation of the above facts is that in solution
3 spends a substantial fraction of its time in folded
(8) One reviewer has suggested that the preferential formation of
diadduct is a result of the Grignard reagent being dimeric under these
conditions. Such a possibility has been demonstrated by concentration-
dependence studies in the lithiation of 3,3′-dibromostilbene (Beak, P.;
Liu, C. Tetrahedron 1994, 50, 5999). We feel this is unlikely for two
reasons. First, the same preference is observed in a variety of different
types of reactions, most of which involve reagents that are undeniably
monomeric. Moreover, during our experiments the Grignard is diluted
to <0.01 M during addition, well below the concentrations where
dimers are believed to form: March, J . Advanced Organic Chemistry,
4th ed.; Wiley-Interscience: New York, 1992; p 183ff.
alkoxide functionality in 6-M would somehow have to
activate the second addition.8 Moreover, the fact that a
variety of nucleophiles4b,c give qualitatively the same
result as phenyl Grignard indicates that the increase in
κ is not due to some unique property of the PhMgBr
reagent.8
(9) Allinger, N. L.; Gorden, B. J .; Newton, M. G.; Norskov-Lauritsen,
L.; Profeta, S. Tetrahedron 1982, 38, 2905.

730 J . Org. Chem., Vol. 61, No. 2, 1996
Macomber et al.
F igu r e 1. PLUTO structural diagram from X-ray analysis of
7 (cis isomer). There are four independent molecules per unit
cell.
F igu r e 2. PLUTO structural diagram from X-ray analysis of
8 (trans isomer). There are four independent molecules per
unit cell.
conformations such as 10, where two of the four carbonyl
faces are blocked from nucleophilic attack. But once
attack does take place, the resulting 6-M adopts a
different conformation so that subsequent nucleophilic
attack occurs at a faster than normal rate.
Ta ble 1. Kin etic Da ta for th e Rea ction of 3 w ith
P h MgBr a in THF a t 0 °C
run
[3]0, M
κb
deviationc
1
2
3
0.0204
0.0254
0.0209
average
2.36
2.57
0.0031
0.0040
0.0015
1.73
2.2 ( 0.4d
a
b
A 1.0 M solution of PhMgBr in THF was used. κ ) (k2 + k2′)/
k1, calculated with the method described in ref 6. c Square root of
sum of squared deviations of experimental concentrations from
d
theoretically calculated6 concentrations. ( standard deviation.
Ta ble 2. Com p lete Con cen tr a tion Da ta for Ru n 1 of
Ta ble 1
PhMgBr
consumed, [3],
[6],
mM
[7], [8],
mM mM
κa,b
The folded conformation of 3 could be attributed either
to a dipole-dipole interaction between the carbonyls (as
in 10) or simply to a conformational consequence of the
two sp2-hybridized carbons in an 18-membered ring. In
order to differentiate between these factors, as well as
establish the relative reactivity of 3 vs a “normal” ketone,
equiv
mM
[7]/[8]
0.0
20.4
17.9
11.0
9.1
4.1
1.6
0.0
2.0
3.6
3.6
3.7
0.0 0.0
0.2 0.2
3.3 2.5
4.1 3.6
6.9 5.7
8.0 7.1
0.16
0.74
0.94
1.42
1.67
50/50
57/43
53/47
55/45
53/47
4.3
3.3
3.0
1.8
1.1
3.7
averagesc
54 ( 3/46 ( 3 2.7 ( 1.3
a
From the equation7c
κ-1
[3]
[6]
) 0
[3]
1
1 -
-
(
)
[
]
κ - 1
[3]0
The incremental model6 gave κ ) 2.36. c ( standard deviation.
b
diketone 3 has been allowed to compete (in separate
experiments) with 10-methylenecyclooctadecanone (11)4a,b
and cyclopentadecanone (12) for a limiting amount of

Reactions of Molecules with Equivalent Functional Groups
J . Org. Chem., Vol. 61, No. 2, 1996 731
F igu r e 3. Plot of observed concentrations of 3, 6, and 7 + 8 (symbols) and calculated concentrations (lines, using κ ) 2.36) vs
molar equivalents of PhMgBr consumed.
phenyl Grignard. If the reagent were to react preferen-
tially (per carbonyl) with 11 and 12, the lower reactivity
of 3 must be due to reasons other than the sp2-hybridiza-
tion of two ring carbons. On the other hand, comparable
reactivity (per CdO) of 3 with 11 or 12 would be evidence
that there is no significant carbonyl dipole interaction
in 3.
When 3 and enone 11 were allowed to compete for a
limiting amount of phenyl Grignard, the rate constant
ratio k(11)/k1(3) was 0.30, indicating that enone 11 is only
60% as reactive as 3 on a per carbonyl basis. Interest-
ingly, a UV spectrum of 11 exhibits a maximum at 225
nm (ꢀ 121) with a shoulder of 278 nm (ꢀ 53.4). It is
tempting to attribute the former band to a weak tran-
sannular interaction between the CdO and CdC bonds,
as has been seen in some related compounds.10
In a similar competition experiment between 3 and
ketone 12 the ratio [3]/[12] decreased only 5% through
68% consumption of total carbonyls. Computer simula-
tion6 of the competitive consumption of PhMgBr by 3,
6-M, and 12 indicated that the rate constant ratio k(12)/
k1(3) is 0.96. Thus, on a per carbonyl basis, 3 is only half
as reactive as 12.
Thus, the relative per carbonyl reactivity of the four
compounds of interest are 11, 0.60; 3, 1.0; 12, 1.9; and
6-M, 4.4. Assuming the reactivity of monoketone 12 can
be taken as “normal”, it is clear that the anomalous
behavior of 3 must be attributed to a combination of a
nearly 50% retardation of the first addition and a >100%
enhancement of the rate of the second addition. Fur-
thermore, whatever factors cause the retardation of the
first addition to 3 apparently causes an even larger (70%)
retardation in the addition to 11.
trans, has two exo and two endo faces. Interestingly,
enone 11, with the most “open” CdO angle, appears to
present two reasonably accessible faces. Clearly, intui-
tive estimates of steric accessibility do not seem to
correlate with the observed patterns of reactivity.
In an attempt to identify factors that might be respon-
sible for the rate retardations and enhancements, we
have carried out molecular mechanics calculations on the
four carbonyl substrates.11 In addition to the expected
conformation of 3 with the carbonyls trans (18.5 kcal/
mol), we also located a minimum at 17.4 kcal/mol with
essentially Cs symmetry that has the carbonyls cis.
Similarly, in monoadduct 6-M there are two minima. The
more stable (19.1 kcal/mol) has the CsO and CdO bonds
cis (and the oxygens 5.3 Å apart), while the trans
conformation has an energy of 22.5 kcal/mol. The lowest
energy conformation of 11 also has the H2CdC bond cis
to the CdO bond.
The first generalization that can be made is that all
four structures yield minimum energy conformations
with the CdO bond(s) more or less perpendicular to the
mean plane of the ring. The OdC- - -C angles (where the
latter C represents the ring carbon most nearly opposite
the carbonyl carbon) were found to be 11, 132°; trans-3,
116.6°/103.0°; cis-3, 92.3°/92.1; 12, 98.2°; cis-6-M, 57.6°,
where the larger the angle the more the CdO bond is
flattened toward the outside of the ring (Figure 4). On
the basis of a comparison of the angle trends with the
relative rates, it seems that the more the carbonyl is bent
back toward the center of the ring, the faster it reacts.
During the isolation of diols 7 and 8 it was observed
that when the HCI used for workup was not efficiently
neutralized, recrystallization of the crude 55/45 mixture
of 7 and 8 resulted in deposition of a new crystalline solid
with molecular formula C30H40 (i.e., double dehydration
of 7 and 8). Spectroscopic analysts suggested a highly
symmetrical diene structure. The material was ulti-
mately identified by X-ray diffraction (Figure 5) as cis,cis-
A CdO group bent at an angle to the mean ring plane
presents a more accessible exo face, and a less accessible
endo face. Ketone 12 and monoadduct 6-M thus both
appear to have only one accessible face in their respective
most stable conformation. Diketone 3, whether cis or
(10) A similar pair of bands is exhibited by 3-methylenecyclobu-
tanone. Silverstein, R. M.; Bassler, G. C.; Morrill, T. C. Spectrometric
Identification of Organic Compounds, 5th ed.; J ohn Wiley & Sons: New
York, 1991; p 304.
(11) Molecular mechanics calculations were performed with the
MM+ force fields of Hyper-Chem (Release 3 for Windows), AUTODESK
(1992).

732 J . Org. Chem., Vol. 61, No. 2, 1996
Macomber et al.
F igu r e 4. Space-filling models of the most stable conformations of 11, trans-3, 12, and cis-6-M.
Ta ble 3. Molecu la r Mech a n ics Ca lcu la tion s on th e F ou r
Sym m etr ica l Isom er s of 1,10-Dip h en ylcycloocta d eca d ien e
(13)11
rel energy,
isomer
kcal/mol
trans,trans-1,10-diphenyl-1,9-cyclooctadecadiene
cis,cis-1,10-diphenyl-1,9-cyclooctadecadiene
trans,trans-1,10-diphenyl-1,10-cyclooctadecadiene
cis,cis-1,10-diphenyl-1,10-cyclooctadecadiene (13)
34.86
29.26
39.15
23.56
In an attempt to explain the regio- and stereoselective
formation of 13 by acid-catalyzed dehydration of 7 and
8, molecular mechanics calculations11 were also per-
formed for the four possible isomeric 1,10-diphenylcy-
clooctadienes that possess the Cs or C2 symmetry ob-
served in the NMR spectra of 13. From the results of
these calculations (Table 3), 13 is predicted to be the
thermodynamically favored product. This correlation
adds confidence that the results of calculations on 3, 6-M,
11, and 12 (vida supra) are similarly reliable. The fact
that 13 constitutes 90% of the initially formed diene
mixture, and only 70% at equilibrium, suggests that there
is a kinetic as well as thermodynamic preference for its
formation.
F igu r e 5. PLUTO structural diagram from X-ray analysis of
13.
1,10-diphenyl-1,10-cyclooctadecadiene (13). Analysis of
The regiospecificity noted for the dehydration of 7 and
8 is more pronounced than that observed for dehydration
of the isomers of 3,7-diphenylbicyclo[3,3,0]octane-3,7-diol
(14) and related compounds,12 where transannular com-
the mother liquor by 1H NMR revealed that 13 was
formed almost exclusively (∼90%), accompanied by two
other minor diene isomers; no 7 or 8 remained. When
13 was heated (50 °C) for several days with excess
trifluoroacetic acid, equilibration of these diene isomers
was observed, with 13 still constituting 70% of the
equilibrium mixture. Thus, 13 is both the kinetically and
thermodynamically preferred product.
munication between the functional groups is less likely
owing to the rigidity of the molecule. It is interesting to
note that nucleophilic attack by phenyl organometallic

Reactions of Molecules with Equivalent Functional Groups
J . Org. Chem., Vol. 61, No. 2, 1996 733
The ratio of rate constants κ ) (k2 + k2′)/k1 for each aliquot
reagents on the precursor bicyclo[3.3.0]octadienones is
modestly stereoselective, with the nucleophile preferring
to approach from the less sterically hindered “exo” face.12
Such factors are not present in 3.
(data point) was determined iteratively from the equation2b,7
κ-1
[3]
[6]
[3]
1
1 -
-
) 0
(
)
[
]
κ - 1
[3]0
Exp er im en ta l Section
The κ value for a given run was taken as the mean of point-
by-point κ values. The κ value for the entire run was
independently determined by varying κ to locate the best least-
squares fit of the experimental concentrations of the entire
run to the concentration predicted by an “incremental method”
computer program.6
Gen er a l. The following instruments were used: Rigaku
AFC5R four-circle diffractometer and a Siemens R3m/v diffrac-
tometer (X-ray crystal structures); Bruker AC 250 (1H and 13C
NMR, using CDCl3/TMS); Hewlett-Packard Model 5995 (GC/
MS); Perkin-Elmer 1600 FT-IR (IR); Spectra-Physics SP 8800
HPLC with Spectra 100 variable wavelength UV detector and
Hewlett-Packard 3394 integrator (HPLC). The HPLC analy-
ses were performed with a 235 × 4.70 (i.d.) mm Whatman P/5
ODS 3 reversed-phase column.
For the reaction of 3 with phenyl Grignard, the response
factor for each alcohol product (P) relative to the starting
diketone (S) was determined by HPLC analysis of standard
solutions and application of the equation
Isola tion of 6, 7, a n d 8. A 100 mL round bottomed flask
containing 280 mg (1.0 mmol) of 3 in 50 mL of dry THF under
nitrogen gas was inserted in an ice bath, and 0.5 mL of a
solution of PhMgBr (ca. 2.0 M) in THF was added at once via
syringe. The reaction was left to warm to room temperature
and stirred for 10 h. (HPLC analysis of a hydrolyzed aliquot,
after response factors were determined, was found to have the
following constitution: [3] ) 6.0 mM, [6] ) 3.2 mM, [7] ) 5.9
mM, [8] ) 4.9 mM.) The mixture was poured into 20 mL of
20% HCI. The organic layer was separated, and the aqueous
layer was extracted twice with 30 mL of ether. The combined
ether layers were washed with NaHCO3 (1.0 M), water, and
brine and dried over MgSO4. Evaporation of the solvent left
300 mg of a pale yellow solid. Fractional crystallization with
ethyl acetate/methanol (1/1 v/v) first deposited 60 mg of the
less soluble trans isomer 8 (pure by HPLC); after concentration
of the mother liquor a second crystallization afforded 30 mg
of pure cis isomer 7, both compounds occurring as colorless
crystals. Analytical data for 8: mp 169-171 °C; 1H NMR δ
1.36 (m, 24 H), 1.60 (s, 2 H), 1.85 (m, 8 H) 7.2-7.6 (m, 10 H);
13C NMR δ14 22.44, 27.13, 28.18, 39.66, 125.27, 126.61, 128.05,
147.75. Analytical data for 7: mp 158-161 °C; the 1H NMR
spectrum of this material was virtually superimposable on that
of 8. Single crystals of both 7 and 8 were submitted for X-ray
diffraction analysis to confirm their structure and determine
their stereochemistry.15 Diols 7 and 8 exhibited virtually
identical mass spectra: no molecular ion was observed, only
fragments resembling the mass spectrum of 13 (vide infra).
HPLC separation of the crude reaction mixture provided a
moles of P signal area of S
moles of S signal area of P
RFP
)
(
)(
)
Standard solutions were prepared from pure materials or, in
the case of 6, a mixture with 3 quantitatively analyzed by
integration of 13C-NMR carbonyl signals (δ6 ) 212.22 ppm, δ3
) 211.93 ppm). The response factors at 264 nm are given
below: 6, 0.192; 7, 0.110; 8, 0.115. Gradient elution with water/
acetonitrile was used (45/55 for the first 2 min, then changing
linearly to 35/65 over 60 min). The relative retention times
were 3 < 6 < 8 < 7.
For the competition reactions between 3 and 11 the follow-
ing gradient elution was utilized:
time (min)
% CH3OH
% H2O
0
90
91
55
85
100
45
15
0
All solvent changes were linear from each time point given.
The retention times were 32 min for 3 and 78 min for 11.
For the competition reaction between 3 and 12, the following
gradient elution was utilized:
1
small amount (ca. 1 mg) of 6: H NMR δ 1.1-1.4 (m, 20 H),
1.63 (m, 4 H), 1.81 (m, 4 H), 2.42 (m, 4 H), 7.1-7.4 (m, 5 H);
13C (partial) δ 212.22; MS m/ z 341 (M - OH), 340 (M - H2O,
base), 323, 322, 145, 144, 143, 142, 141, 131, 130, 129, 128,
119, 118, 117, 115, 105, 104, 91, 81, 77, 69, 67, 55, 43, 41.
Isola tion of 13. When 71.5 mg (0.255 mmol) of 3 was
treated with 2 mmol (excess) of PhMgBr, and the crude product
was recrystallized with ethyl acetate/ethanol containing one
drop of concd HCI, 68 mg (67%) of 13 precipitated as colorless
time (min)
% CH3OH
% H2O
0
60
54
60
46
40
Elution Times: 3, 40 min; 12, 70 min.
Ma ter ia ls. The Grignard reagent was prepared by pub-
lished methods13 and diluted with dry THF to give a concen-
tration of 1.0 M. Bromobenzene used for the preparation of
the phenyl Grignard was distilled prior to use. THF was
freshly distilled over potassium. All glassware was oven-dried.
Diketone 3 was prepared as previously described, except THF
was used as solvent, rather than benzene.5
Kin etic Meth od . A 100 mL round bottomed flask contain-
ing 280 mg (1.00 mmol) of 3 in 50 mL of dry THF under
nitrogen was inserted in an ice bath, and every 10-15 min a
measured volume (0.2-0.5 mL) of 1.0 M PhMgBr in THF was
added via syringe. Immediately before the addition of the
following portion of the Grignard an aliquot (1 mL) of the
reaction mixture was withdrawn, mixed with 1.0 mL of an
aqueous solution of acetic acid (0.2 M) and a few drops of
ethanol (if not homogeneous), and analyzed by HPLC. The
concentrations of 3, 6, 7, and 8 in each aliquot were determined
from peak integrations (corrected for response factors) and the
known initial concentration of 3.
(14) The signal for the OH-bearing carbons (ca. δ 65 ( 5) could not
be located with confidence.
(15) The authors have deposited atomic coordinates for the struc-
tures of 7, 8, and 13 with the Cambridge Crystallographic Data Centre.
The coordinates can be obtained, on request, from the Director,
Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge,
CB2 1EZ, U.K. Crystal data for 7: C30H44O2, M ) 436.7, monoclinic
space group P21/n, a ) 11.813(2) Å, b ) 47.652(7) Å, c ) 19.269(3) Å,
â ) 93.53(1)°, Z ) 16, U ) 10,825(3) Å3, T ) 21 °C, Fcalcd ) 1.073 g
cm-3, µ ) 0.464 mm-1, Cu KR radiation using a Rigaku AFC5R rotating
anode diffractometer. Anisotropic refinement of the four crystal-
lographic-independent molecules stands at Rf ) 7.64%, Rwf ) 12.25%
for 5706 reflections (1172 variable parameters) with F g 3σ(F). Large
thermal motion is observed for the phenyl groups. Conformational
disorder associated with carbons 4-6 of molecule C has been partially
sorted out. Crystal data for 8: C30H44O2, M ) 436.7, triclinic space
group P-1, a ) 10.825(2) Å, b ) 11.238(2) Å, c ) 22.851(4) Å, R ) 77.01-
(1)°, â ) 85.28(2)°, γ ) 86.65(2)°, Z ) 4, U ) 2697.1 Å3, T ) 20 °C, Fcalc
) 1.075 g cm-3, µ ) 0.061 mm-1, Mo KR radiation using a Siemens
R3m/v diffractometer. Final Rf ) 8.95%, Rwf ) 6.65% for 5404
reflections 578 variable parameters) with F g 3σ(F). Large thermal
motion is observed for some of the phenyl groups; however, disorder
could not be sorted out. Crystal data for 13: C30H40, M ) 400.6,
orthorhombic space group Pbca, a ) 10.943(2) Å, b ) 7.531(2) Å, c )
30.002(5) Å, Z ) 4, U ) 2472.5 Å3, T ) 21 °C, Fcalc ) 1.076 g cm-3, µ
) 0.413 mm-1, Cu KR radiation using a Rigaku AFC5R rotating anode
diffractometer. Final Rf ) 4.76%, Rwf ) 8.49% for 1579 reflections (137
variable parameters) with F g 4σ(F).
(12) Quast, H.; Carlsen, J .; Herbert, T.; J aniak, R.; Roschert, H.;
Peters, E. M.; Peters, K.; von Schnering, H. G. Liebigs Ann. Chem.
1992, 495.
(13) Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis (Vol.
1); J ohn Wiley and Sons, Inc.: New York, 1967; pp 415-417.

734 J . Org. Chem., Vol. 61, No. 2, 1996
Macomber et al.
1
crystals, mp 133-135 °C: H NMR δ 1.2-1.6 (m, 20 H), 2.19
15% EtOAc/ligroin to elute 3. Fractions containing 11 were
combined and rotary evaporated to give 0.1524 g (0.548 mmol,
42.6%) of a yellow oil: 1H NMR (CDCl3) δ 4.55 (s, 2H), 2.24 (t,
J ) 6.9, 4H), 1.46 (qnt, J ) 6.9, 4H), 1.27 (qnt, J ) 6.9, 4H),
1.13 (brs, 16H); UV λ 225 nm (ꢀmax ) 121.3), shoulder at 278
nm (ꢀ ) 53.4).
Gr ign a r d Com p etition Rea ction betw een 3 a n d 11 (or
12). A solution of 3 (55.1 mg 0.197 mmol) and 11 (108.7 mg
0.391 mmol) in 4 mL of dry THF was placed in a 5 mL 2-neck
flask equipped with a stirbar and a static Ar bubbler. A 0.10
mL aliquot was removed from the solution, and 1 drop of 0.1
M HCl was added. Small amounts of THF and/or ethanol were
added to make the aliquot homogeneous. This initial aliquot
was then analyzed by HPLC.
A 0.08 mL portion of a 1.0 M phenyl Grignard solution
(equal to 10.2% of the total number of carbonyls in the reaction
solution) was added. The solution was allowed to stir for 1 h
at 0 °C; then another 0.10 mL aliquot was removed. The
workup and analysis was as previously described. Additional
measured portions of the Grignard reagent were added, and
aliquots were analyzed, until either 3 or 11 was fully consumed
(HPLC).
The integrated peak areas for each aliquot, together with
the known initial ratio of 3 to 11, were used to determine the
ratios of 3 to 11 as a function of reagent added. Multiple
analyses of each aliquot were performed until the ratios of 3
to 11 had a relative standard deviation of 10% or less.
(q,16 4 H), 2.52 (t, J ) 7, 4 H), 5.63 (t, J ) 8, 2 H), 7.2-7.4 (m,
8 H); 13C NMR δ17 28.39, 28.64, 28.86, 29.15, 29.32, 29.58,
126.44, 128.14, 129.91, 140.12, 143.45. MS m/ z 401, 400 (Mt),
143, 141, 131, 130, 129, 128, 118, 117, 116, 115, 105, 104, 103,
92, 91 (base), 79, 77, 67, 55, 41, 36; IR (CCl4) 3084, 3062, 3022,
2926, 2854, 1597, 1493, 1461, 1446, 1260, 1075, 1031 cm-1
.
The structure of 13 was confirmed by single-crystal X-ray
analysis.15
Evid en ce for th e F or m a tion of cis-5. The mother liquor
from CHCl3 recrystallization of trans-5 (mp 138-140 °C)4c was
evaporated and the residue recrystallized twice from CCl4. The
resulting broad melting solid (mp 96-102 °C), which could not
be further purified by recrystallization, exhibited a TLC Rf
value (0.55) differentiable from the trans-5 (0.64, neutral
alumina, 1:1 ethyl acetate/ligroin, I2 visualization) present as
an inseparable minor (5-10%) impurity. However, the 13C
NMR spectrum of the broad melting impure cis isomer was
superimposable on that of trans-5.
Syn th esis of 11.4a ,b To a suspension of 0.6169 g of Zn (9.43
mmol) and 0.0265 g (0.095 mmol) of PbCl2 in 10 mL of dry
THF was added 0.24 mL of CHI3 (3.85 mmol). This suspension
was placed under argon and in an ice bath, and 2.2 mL of a
1.0 M TiCl4 solution in CH2Cl2 was added.18 After 15 min of
stirring, 0.5679 g of 3 (2.03 mmol) in 4 mL of THF was added
dropwise. After stirring at room temperature for 24 h, the
mixture was filtered through Florisil (5 cm × 8 cm), and the
filtrate was rotary evaporated. The product mixture was
purified by column chromatography through 20 g of 230-400
mesh silica using ligroin to elute 1,10-dimethylenecycloocta-
decane (0.1064 g, 19.1%), 1% EtOAc/ligroin to elute 11, and
Ack n ow led gm en t is made to the donors of the
Petroleum Research Fund administered by the Ameri-
can Chemical Society for support of this work. The
authors also thank Dr. Fred Wireko (Procter and
Gamble, Miami Valley Laboratories) for the data col-
lection on 7 and 13. The authors also appreciate the
thoughtful input of Professor Allan Pinhas and Dr. J eff
Nauss of this department.
(16) A degenerate doublet of triplets with both J values equal.
(17) The signal at δ 29.15 is much more intense than those of the
other five alkyl carbons, suggesting that it comprises two carbons. Also,
we were not able to locate the vinyl CH carbon signal, expected in the
region δ 115 ( 5.
(18) Takai, K.; Hotta, Y.; Oshima, K.; Nozaki, H. Tetrahedron Lett.
1978, 27, 2417.
J O930376D