Studies on pinacol chemistry
by Dan R Bruss
A thesis submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in
Chemistry
Montana State University
© Copyright by Dan R Bruss (1985)
Abstract:
Synthetic methodology employing pinacol chemistry is explored. An investigation of the
stereochemical consequences of pinacol formation as related to the method of coupling is presented.
Aluminum and titanium-mediated pinacol coupling of alkyl substituted cyclohexanones are shown to
exhibit distinct stereoselectivity. It is found that the aluminum procedure produces primarily axial
orientation of the alkyl groups, while the titanium coupling prefers equatorial orientation. A rapid
method of separation and identification of the resulting diastereomers is discussed. A pronounced alkyl
substituent effect on the course of the pinacol rearrangement of
cyclohexyl-3-methylcyclohexane-l,l'-diol is noted. While the exact nature of the effect is unknown,
MNDO studies indicate that it does not appear to be electronic in nature. Baeyer-Villiger oxidation of
spiroketones and acid catalyzed rearrangement of spiroalcohols are presented. Rearrangement of
spiro-[4,5]-6-methyldecan-6-ol to 9-methyl-Δ4,10-octalin demonstrated the potential utility of this
reaction as an entry into decalin based terpenes. STUDIES ON PINACOL CHEMISTRY
by
Dan R. Bruss
A thesis submitted in partial fulfillment
of the requirements for the degree
of
Doctor of Philosophy
in
Chemistry
MONTANA STATE UNIVERSITY
Bozeman, Montana
August 1985
ii
APPROVAL
of a thesis submitted by
Dan R. Bruss
This thesis has been read by each member of the thesis
committee and has been found to be satisfactory regarding
content, English usage, format, citations, bibliographic style,
and consistency, and is ready for submission to the College of
Graduate Studies.
Approved for the Major Department
Head, Major Department
Approved for the College of Graduate Studies
Date
Graduate Dean
iii
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reproduce and distribute by abstract in any format.”
Date
J ' /^ S S '
I
iv
Organic chemistry just now is enough to drive one mad. It gives
me the impression of a primeval tropical forest, full of the
most remarkable things? a monstrous and boundless thicket, with
no way of escape, into which one may well dread to enter.
— Friedrick Wdhler
If I have seen further than other men, it is because I stood on
the shoulders of giants.
— Isaac Newton
V
ACKNOWLEDGEMENTS
Sincere appreciation and gratitude are extended to those
who have influenced my life and contributed to my education.
Special thanks are extended to Joe Sears for his patience and
assistance with the mass spectral analyses; to the staff of the
x-ray facility for providing structures; to John Cardellina for
taking an interest in my professional development, to Ron Warnet
for his encouragement as an educator, chemist, and trail guide;
to my advisor Dr. Bradford P. Mundy for his patience and
infectious love of chemistry; to my parents for their influence
love and encouragement; and to my wife Kathy for her love,
companionship, and for not grumbling when I did.
vi
TABLE OF CONTENTS
Page
LIST OF TABLES... ........................................
viii
LIST OF FIGURES...........................................
x
ABSTRACT.... ................................................
1.
INTRODUCTION..........................................
!
2.
RESULTS AND DISCUSSION....................
Pinacol Coupling...................................
Pinacol Rearrangement........................... .
Secondary Rearrangements...........................
12
12
44
64
3.
EXPERIMENTAL. ..........................................
General Preparation of Pinacols....................
Preparation of Isomeric (+)-3-Methylcyclohexyl-3Methylcyclohexane-I,I '-Diols.....................
Preparation of Isomeric 4-MethyIeyelohexyl-4Methylcyelohexane-1,1 1-Diols......................
Preparation of Isomeric Cyclohexyl-3-Methylcyclohexanone-1 f1 1-Diols..........................
Preparation of Spiro-[5,5]-6-Oxadecan-7-one,78.......
Preparation of Isomeric Cyclohexyl-4-Methylcyclohexane-1,1 '-Diols............................
Preparation of Cyclopentylcyclopentane-I,I '-Diol, 48.
Preparation of Spiro-[4,5]-Decan-6-one, 49..........
Preparation of Spiro-[4,5]-6-Methyldecan-6-ol, 66__
Rearrangement of Spiro- [4,5] -6-Methyldecan-6-ol, 6j5..
Preparation of Spiro-[4,5]-I-Methyldecan-l-o1, 75__
Rearrangement of Spiro-[4-5]-I-Methyldecan-1-ol, 75..
Product Ratio Study on the Coupling of R - (+)-Methyleye Iohexanone, I ........................
Preparation of Cyclopentylcyclohexane-I,I-'Diol, _4...
Preparation of Isomeric Spiroundecanones _5 and ....
Attempted Photopinacolization of R - (+)-3-MethylcycIohexanone, I..........
Solvent Effect Test on Aluminum Coupling of R - (+)-3Methylcyclohexanone, ]_.............
Charge Exchange Mass Spectral Analyses of 1,1'Bicycloalkyl Diols................................
Reductive Coupling of Racemic 3-MethyI-CycIohexanone.
73
74
75
77
79
81
82
83
84
84
85
86
87
88
89
89
90
91
91
91
vii
TABLE OF CONTENTS— Continued
Page
Semiemperical (MNDO) Studies on Model CarbonylAluminum Complexes................................
92
Comparison of Radical Anion and Dianion Geometries of
the 3-Pentanone-Al Complex Model (46).............
93
94
Analysis of Carbocation 56 by MNDO..77..............
Analysis of Carbocation 57 by MNDO..................
95
Preparation of Isomeric Spiro-[5,6]-Methyldocecan7-ones............................................
96
X-ray Diffractometry on Diol 341.....................
98
X-ray D i f f r a c t o m e t r y on Diol 3_7...............
98
99
MNDO Analysis of Carbocations _58 and 59^............
Lanthanide Induced Shift Study on Spiroketone D ..... 101
SUMMARY....................................................
102
REFERENCES CITED...........................................
104
APPENDIX...................................................
109
viii
LIST OF TABLES
Page
Table
1.
Distribution of coupling products...............
4
Table
2.
Product distribution in the methylcyclohexanone
studies................................. .......
5
^C-NMR spectra of (+ )-3-methy!cyclohexanone
self-coupling products..........................
16
Physical and spectroscopic data for isomeric
3-methylcyclohexy1-3-methyIeyeIohexane-I ,I 'diols...........................................
17
Table
Table
Table
Table
Table
Table
Table
3»
4.
5. ^ C - N M R spectra of 4-methyl cyclohexanone
self-coupling products................
6.
I.
8.
9.
21
x -NMR spectra of axial isomer from mixed
coupling products of cyclohexanone with (+)-3methy Ieye Iohexanone.............................
29
70 eV electron impact spectra of isomeric
4-me thy Ieye Iohexy I- 4-me thy Icyc Iohexane-1 ,1 'diols..............
30
Major fragmentations for charge exchange spectra
of isomeric 4-methylcyclohexyl-4-methylcyc Iohexane-1 ,1 1-diols....... ..................
34
Brief summary of pinacolrearrangement of
47
CAD spectra of symmetrical diols ^8 and 20. and
spiroketones _49 and ElO..........................
501
70 eV electron impact spectra of spiroketones 5^
and 6^........
51
Table 12.
CAD spectra of spiroketone5^ and
6i..... ........
52
Table 13.
CAD spectrum of unsymmetricaldiol jl.............
53
Table 14.
Slopes from the plot of change in shift versus
[Eu (fod) 3/D]....................................
62
Table 10.
Table 11.
ix
LIST OF TABLES— continued
Page
Table 15.
MNDO summary of 45..............................
92
Table 16.
MNDO parameters of 45............................
93
Table 17.
MNDO summary of _46........................
93
Table 18.
MNDO parameters of 4j5...........................
94
Table 19.
MNDO summary and parameters of_46 anion..........
94
Table 20.
MNDO summary and parameters of 5_6................
95
Table 21.
MNDO summary and parameters of 31_...............
96
Table 22.
X-ray data for 34...............................
98
Table 23.
X-ray data for 6_................................
99
Table 24.
MNDO summary and parameters of 5j3...............
100
Table 25.
MNDO summary and parameters of 59...............
101
X
LIST OF FIGURES
Page
Figure
Figure
I.
2.
Generalized scheme for pinacol chemistry of
cyclic ketones...............................
2
Reported stereospecificity in (R) -( + )-3-methylcyclohexanone self-coupling...................
3
Figure
3.
Typical naturally occurring spirocompounds....
5
Figure
4.
Cyclopentyl and cyclohexyl diols..............
6
Figure
5.
Ring size effects on the pinacol rearrangement.
7
Figure
6.
Cyclohexyl and tetrahydropyranyl tosylates....
8
Figure
7.
Pinacol rearrangement of 21............. ......
8
Figure
8.
Synthesis of karahanaenone.'...................
9
Figure
9.
Synthesis of grahamimycin A1 ..................
10
Figure 10.
Potential diastereomers from 3-methylcyclohexanone self-coupling....................
13
Figure 11.
Tetrahydroxyadipic acid.................... .
13
Figure 12-.
Product ratios for the coupling of
(+ )- 3-me thy !cyclohexanone.................. .
17
Figure 13.
I^c-NMR spectrum of diequatorial isomer 2 .....
19
Figure 14.
11
Figure 15.
Figure 16.
C-NMR spectrum of diequatorial fraction
derived from racemic coupling.................
20
The reductive coupling of 4-methylcyclohexanone,
40..................................... .......
22
Crystal structure of diaxial isomer of
.3-methylcyclohexyl-3-methylcyclohexane-l,1 1diol, 34........................ ..............
23
xi
LIST OF FIGURES-continued
,
Figure 17.
Crystal structure of diaxial isomer of
4-me thy Ieye Iohexy I- 4-me thy Ieye Iohexane-1,1 1diol, 37......................................
Page
24
Figure 18. Stereo drawings of 3-methyl diaxial, J34........
26
Figure 19.
Stereo drawings of 4-methyl diaxial, 37.........
27
Figure 20.
Mixed reductive coupling of 3-methylcyclohexanone, I, with cyclohexanone, 19......
28
Proposed major cleavage for I,I1-bicycloalkyl
diols.........................................
28
Comparison of cis and trans isomers to promote
1,4-H20 elimination...........................
32
Figure 23.
General mechanism for reductive coupling......
36
- Figure 24.
,Proposed mechanism by McMurry to form olefins
by reductive coupling.........................
37
Titanium mediated coupling to form diequatorial
isomer........................................
38
Mechanistic rationalization to account for
axial-equatorial product formation............
39
Photochemical reaction of R - (+)-3-methylcyc Iohexanone.................................
40
Figure 28.
Proposed dianion induced coupling.............
41
Figure 29.
Optimized aluminum-formaldehyde complex by MNDO
42
Figure 30.
Initial 3-pentanone-aIuminum model............
43
Figure 31.
Optimized 3-pentanone-aIuminum complex........
43
Figure 32.
Schematic diagram of a tandem mass spectrometer
with forward geometry (S = source, E = electron
sector, C = collisional chamber, B = magnetic
sector, D = d e t e c t o r ) .....................
46
Effect of product distribution as a function of
sulfuric acid concentration...................
48
Figure 21.
Figure 22.
Figure 25.
Figure 26.
Figure 27.
Figure 33.
xi i
LIST OF FIGURES-continued
Page
Figure 34.
Possible mechanism of the secondary rearrange­
ment of spiranone _5..........................
49
Figure 35.
Possible products from the rearrangement of 41
55
Figure 36.
Model carbocations to determine methyl group
influence..................................
55
Carbocations used to explore stabilizing
effect of methyl group..'...................
56
Figure 38.
Nonequivalence of alpha protons in 52........
58
Figure 39.
Structure of Eu (fod) 3 ........................
59
Figure 40.
Structural parameters involved in the
McConnel!-Robertson equation.................
60
Figure 41.
Numbering scheme of unsubstituted spironone 50
63
Figure 42.
Rearrangement of 60_..........................
65
Figure 43.
Robinson annulation of 2—methy!cyclohexanone,
63, with MVK, 64.............................
66
Figure 44.
Entry to decalin system via spiroketone 49___
67
Figure 45.
Rationalization of cationic rearrangement of
66 •••.........................................
67
Possible use of 69^ to prepare terpene'
intermediates................................
69
Figure 47.
Proposed rearrangement of 75.................
70
Figure 48.
Attempted rearrangement of spiroalcohol 75....
70
Figure 49.
Mechanism for the Baeyer-Villiger
rearrangement.............
70
Figure 50.
Baeyer-Villiger rearrangement of 7£..........
71
Figure 51.
Possible macrolide entry via spiroketone 6...''.
72
Figure 37.
Figure 46.
xiii
ABSTRACT
Synthetic methodology employing pinacol chemistry is
explored. An investigation of the stereochemical consequences
of pinacol formation as related to the method of coupling is
presented. Aluminum and titanium—mediated pinacol coupling of
alkyl substituted cyclohexanones are shown to exhibit distinct
stereoselectivity. It is found that the aluminum procedure
produces primarily axial orientation of the alkyl groups, while
the titanium coupling prefers equatorial orientation. A rapid
method of separation and identification of the resulting
diastereomers is discussed. A pronounced alkyl substituent
effect on the course of the pinacol rearrangement of cyclohexyl3-methylcyclohexane-l,l'-diol is noted. While the exact nature
of the effect is unknown, MNDO studies indicate that it does not
appear to be electronic in nature. Baeyer-Villiger oxidation of
spiroketones and acid catalyzed rearrangement of spiroalcohols
are presented. Rearrangement of spiro-[4,5]-6-methyldecan-6-ol
to 9-methyl-A4,10-octalin demonstrated the potential utility of
this reaction as an entry into decalin based terpenes.
I
CHAPTER I
INTRODUCTION
A fundamental tenant of organic synthetic methodology is
the ability to generate stereoselective formation of carboncarbon bonds which readily allow further transformation.
While
few processes can approach the general applicability of a
paradigm such as the Diels-Alder reaction, any process which
generates more complex organic structures in a predictable way
is highly desirable.
As an outgrowth of the work previously
carried out in our laboratory on several aspects of pinacol
chemistry, it became evident that this chemistry possessed a
number of attributes that could potentially expand its
generality.
Since the first reported rearrangement of pinacol to
pinacolone in the mid-nineteenth century,this reaction has
been studied extensively.
At the same time, a host of methods
have been developed to generate the requisite 1,2-diols.
Our
principal interest focused on the meta!-mediated reductive
coupling of cyclic ketones, followed by mineral acid
rearrangement.
Figure I summarizes this approach.
The rationale was straightforward.
Coupling of the ketones
afforded conversion from sp^ hybridization to functionalized sp^
centers.
Rearrangement of the 1,2-diols would then provide
2
entry into functionalized quaternary centers, often a difficult
synthetic task.
Once formed, these spiroketones could further
be modified or fully transformed.
Figure I.
Generalized scheme for pinacol chemistry of cyclic
ketones.
Several methods exist for effecting the reductive coupling
of carbonyl compounds by zero or low valent state metals.
Traditionally, aluminum amalgam2'3'4 has been employed to
generate the 1,2-diols.
More recently, McMurry^ has found that
TiCl3/K is an effective reducing agent which yields not diols,
but alkenes.
Shortly after this report, Corey and co-workers6
found that high yields of 1,2-glycols were formed by reacting
aldehydes and ketones with a low valent titanium source
generated in situ from titanium tetrachloride and magnesium
amalgam.
3
Additional reagents have since been examined.
Porta and
Clerici7 have successfully used the mild reaction conditions of
aqueous TiClg to produce diols directly instead of the
aforementioned alkenes.
Low valent cerium has been shown by
Imamota8 to carry out effective coupling, while Cotton et al9
have successfully characterized a tungsten-aIkoxide complex.
Two of these procedures, when applied to the same ketone,
appeared to have distinctive stereochemical consequences.
In
1978, Munoz-Madrid and Pasqual4 reported the formation of a
single product, 2_, from the aluminum mediated coupling of
(R)-( +)-3-methylcyclohexanone.
On the other hand, Kim10
characterized 2 as the sole product when the Corey method was
employed to couple the same ketone.
These results are
summarized in Figure 2.
HO OH
Figure 2.
Reported stereospecificity in (R)-( +)-3-methyl­
cyclohexanone self-coupling.
4
These- results were certainly intriguing.
Controlled
stereochemical discrimination is a powerful asset in synthesis.
This laid the groundwork for a portion of the present study.
While earlier works suggested a statistical distribution of
products from a mixed reductive coupling, Mundy and co-workers10
demonstrated this not to be the case for various cycloalkanone
coupling reactions.
These results are summarized in Tables I
and 2.
Distribution of coupling products.
CycIoalkanones
C6-C6
C5-C5 C5-C6 C6-C6
14.1
■ 1.6
4.1
0.6
11.4
0.3
42.0
2.4
18.2
3.8
C5-C5
C5-C7
C7-C7
C5-C5
C5-C7
C7-C7
8.0
■■ +3.7
4.2
2.9
27.8
4.3
33.9
1.6
10.8
3.7
C 7-C7
8.7
6. 4
C6-C7
C 7-C7
0
1
n
cn
16.7
4.7.
(Ti
C6 + C7
Pinacols
10.2
+ 0.4
0
Ol
1
O
C5 + C7
c5-c5
U
1
LD
O
C5 + c6
Alkenes
C6-C7
1.8
+1.0
7.2
5.5
4.8
5.9
28.7
6.5
48.8
3.6
(Tl
Table I.
As mentioned earlier, acid-catalyzed rearrangement of these
diols provides direct entry into the spirane skeletons.
A
growing number of naturally occurring spiro-compounds, several
of which are illustrated in Figure 3, has prompted vigorous
research in this area.11
5
Table 2.
Product distribution in the methy!cyclohexanone
studies.
AA
Olefina
AB
BB
AA
Pinacola
AB
BB
2-Me-Bc + Ab
8.82
+0.16
0.83
0.16
11.82
0.29
59.13
4.36
20.39
1.27
8.01
2.15
3-Me-B + A
2.05
jK) .90
4.74
1.18
1.75
0.76
26.21
2.33
49.61
2.12
15.62
5.54
39.10
+7.51
51.97
11.88
8.93
5.85
4-Me-B + A
aIn percent
bA = Cyclohexanone
cB = Methylcyclohexanone
spirolaurenonel^
spirovetivane1^
Chamigrene1^
Acoradiene
Figure 3.
Typical naturally occurring spirocompounds.
6
Considerable effort has been expended on understanding the
pinacol rearrangement in general. Factors such as migratory
aptitude of the substituents, diol stereochemistry, reaction
media, product and intermediate stability, and ring effects have
been studied extensively.
Much of this early work has been
cogently discussed.
The effects of ring size on the course of the pinacol
rearrangement have been approached from several points of view.
Meerwein17 examined the rearrangement of cyclopentyl and
cyclohexyl diols (Figure 4), concluding that ring expansion
occurred more readily for the cyclopentyl precursors.
HO OH
Figure 4.
HO OH
Cyclopentyl and cyclohexyl diols.
Botteron and Wood1 and more recently Mundy and Srinivasa11
examined the ring size effect on the rearrangement of the mixed
diol, 4.
Srinivasa found the reaction to be highly dependent
on temperature and acid concentration.
A summary of this and
additional mixed diols is shown in Figure 5.
Mundy and
Srinivasa concluded that the formation of the initial
carbocation directed the course of rearrangement.
The
variability of the product ratio for _4 was thought to be a
matter of thermodynamic vs. kinetic control.
7
HO OH
HO OH
HO OH
Figure 5.
Ring size effects on the pinacol rearrangement.
Kiml^ explored a heteroatom effect on the pinacol
rearrangement in diol 21.
Solvolysis studies on the tosylates
16 and JL7 (Figure 6) showed a rate retardation of the
tetrahydropyranyl system relative to the carbocyclic
counterpart.
This was attributed to the dipole produced by the
oxygen atom which would destabilize the formation of the remote
carbocation.
Kim expected to see a similar destabilization for
only one carbocation.
This would have yielded spiroketone 23.
Instead, only _22 was formed by rearrangement (Figure 7).
Although this illustrates a very definite dipole effect, the
source of this specificity has not been resolved.
Recently the combination of diol formation by reductive
coupling followed by rearrangement has been employed
8
Figure 6.
Cyclohexyl and tetrahydropyranyl tosylates.
HO OH
+
HO OH
Figure 7.
Pinacol rearrangement of 21.
synthetically.
Chandrasekaran20 prepared the unsymmetrical
diol, 2j>, in good yield.
The key intermediate was then
rearranged via boron trifluoride to yield two ring enlarged
ketones which upon hydrogenation gave karahanaenone,
constituent of Japanese hop and cypress oil (Figure 8).
, a
It is
9
interesting to note that the crucial step of this synthesis
focused on the pinacol rearrangement.
The success of this step
hinged on a judicious choice of catalyst.
Figure 8.
Synthesis of karahanaenone.
Similarly, GhiringhelIi2^ opted to utilize the titanium
mediated reductive coupling reaction to carry out the critical
carbon-carbon bond formation to produce the macrolide antibiotic
(+)-grahamimycin A^, 33.
This provided a novel and effective
method to generate intermediate size rings (Figure 9).
10
Figure 9.
Synthesis of grahamimycin A1 , 33.
These syntheses illustrate the potential stereochemical
ramifications of the reductive coupling and pinacol
rearrangement when they are employed.
Formation of the diol
during the macrolide synthesis yielded four diastereomers in a
1:8:8:1 ratio.
Since the glycol was converted to the diketone,
this mixture did not present a problem.
It can be readily seen,
however, that selective formation and separation could play a
significant role in other natural product syntheses.
While the
formation of the two eyeloheptenone isomers in the karahanaenone
synthesis were also converted to the same intermediate, here too
an understanding of the influence of substituents on the course
of the rearrangement might prove vital for approaches to other
11
targets.
For these reactions to be useful synthetically with
the bicycloalkyl diols, control of the stereochemistry in both
diol formation and rearrangement would be pre-eminent.
The purpose of this work was to examine the feasibility of
moving from paper chemistry to the real world with a view to
synthetic applicability.
Aspects of each of the three phases
illustrated in Figure I were investigated.
Our principal
concern was to explore the stereochemical consequences of alkyl
substituents, and at the same time, examine possible methods to
separate and characterize the subtle isomeric mixtures produced
by these reactions.
Finally, in an attempt to propel this
chemistry into a broader perspective, several reactions were
explored that might enable radical transformation of the spiro
systems. .
12
CHAPTER 2
RESULTS AND DISCUSSION
Pinacol Coupling
The differences in stereospecificity of pinacol formation
as related to the method of coupling of R- (+)-3-methylcyclohexanone, as reported by Munoz-Madrid^ and Kim-*-®, forced us
to re-examine these coupling reactions.
The 3-methyleyeIohexyI-
3-methylcyclohexane-l,l'-diol system presents an intriguing
stereochemical problem.
Upon initial inspection, one would
expect eight possible diastereomers involved in the reductive
coupling since there are four stereo centers in the molecule.
f. However, the potential symmetry of the system reduces this
number to five, as illustrated in Figure 10.
not without precedent in the literature.
This situation is
Eliel^ points out
that careful examination of the 2,3,4,5-tetrahydroxyadipic acids
(Figure 11) reveals an analogous reduction in the number of
stereoisomers.
Here too, four stereocenters yield only five
diastereomers.
By utilizing optically pure (R)-(+)-3-methylcyclohexanone,
the meso compounds are eliminated as possibilities, thereby
leaving only three diastereomers that could potentially be
formed.
13
We repeated the coupling by the classical aluminum amalgam
procedure and indeed found what appeared as a single product.
Analysis by packed-column GLC revealed only one peak which, when
collected and inspected by proton-NMR, showed two distinct
doublets (J = 7 Hz) located at 0.85 and 1.10 ppm.
Integration
of each doublet confirmed them as two methyl resonances.
These
data supported the assignment of 3 as the sole product from this
reaction.
HO OH
HO OH
HO OH
Figure 10.
Potential diastereomers from 3-methy!cyclohexanone
self-coupling.
H0H0H0 HO
HO2C
Figure 11.
Tetrahydroxyadipic acid.
CO2H
14
To further convince ourselves that the product was indeed
homogeneous and not a mixture, a portion of the crude product
was purified by flash chromatography.
Utilizing a system
employing silica gel as adsorbent and a.50:50 petroleum ether:
diethyl ether mixture as solvent, fractions of the eluting diol were collected and analyzed by proton-NMR.
To our surprise (and
satisfaction), we found three isomeric diols.
Although flash
chromatography provided us with a new compound, j34, the question
of whether or not 3- was indeed a unique compound or simply a
mixture of 2 and 34 still needed to be addressed.
Separation of the mixture was unambiguousIy achieved with
analysis by capillary GC-MS. Utilization of a 30 m Durobond I
column, rapid scanning and short inter-scan delays afforded
clean separation of three peaks exhibiting characteristic mass
,spectra of the diols.
Co-injection with pure sample obtained
from flash chromatography identified the isomers in their order
of elution.
While proton-NMR and GC-MS provided us with valuable
information, -^C-NMR turned out to be the most illuminating.
Since the routine carbon-NMR spectrum exhibits a chemical shift
range which is about twenty times that of proton-NMR, much more
subtle differences in chemical shift can be readily observed.
Although the aliphatic regions of the carbon spectra were very
similar and provided nothing more than a count of carbons, the
isolated downfield region involving the carbons bearing the
hydroxyl groups (~75-80 ppm) showed some very important
15
differences, confirming that J3 was indeed not a mixture of 2 and
34.
These data are summarized in Table 3.
With this information in hand we re-examined the titanium
mediated coupling of R-(+)-3-methylcyclohexanone.
Injection of
a sample of the "pure" diol, 2, onto the GC-MS-systemr revealed
two isomers.
Co-injection with authentic samples and NMR
analysis of the flash chromatography purified samples showed the
major product as _2 and the minor product as 3.
Figure 12
summarizes the results of the two procedures while Table 4
presents the physical and proton-NMR data.
To ascertain the ratio of isomers present by the two
different coupling methods, each procedure was carried out in
triplicate and mass spectral analysis of each sample was
performed in triplicate.
Results of this study demonstrated
,that the product ratios for both coupling reactions are
consistent.
Clearly the two coupling processes yielded
distinctly different stereoselectivity in a predictable manner.
The margin of error encountered by this study is included with
the data presented in Figure 12.
As mentioned earlier, the reductive coupling of racemic
3-methylcyclohexanone could yield two additional diastereomers.
To probe this, self-coupling was carried out by both procedures
and the crude product mixtures were analyzed by GC-MS.
Both
samples yielded data that corresponded in the number of peaks
and areas to the results found with (+)-3-methylcyclohexanone.
After separation by flash chromatography, a fraction presumed
Table 3
CH3
13
C-NMR spectra of (+ )-3-methy!cyclohexanone self-coupling products
HO OH
CH3
CH3
HO OH
HO OH
^'CH3
TCH3
CH3
34
3
3aa
3 ae
3 ee
IOO-IOl0C
77-78°
70-71'
77.20
37.09
76.83
76.54
76.38
39.88
39.68
36.97
34.60
31.38
27.57
2
34.66
31.49
30.55
30.32
27.98
27.97
27.60
22.78
22.77
21.74
21.66
21.18
21.22
17.42
17.56
17
[Al-Hg]
16.4 + 1.6
52.7 + 3.6
[Ti]
82.7 + 1.9
17.3 + 1.9
Figure 12.
Table 4.
30.9 + 2.0
Product ratios for the coupling of (+)-3-methylcyclohexanone .
Physical and spectroscopic data for isomeric 3-methyleyeIohexy1-3-methylcyclohexane-I7I 1-Diols.
Diol
M.P. (0C)
IwH-NMR (Methyl)
1
76-77
0.85 ppm
2
70-71
1.10 ppm
-0.85 ppm
100
"1.10 ppm
to be pure single diequatorial isomer was analyzed by carbonNMR.
Although the carbon bearing the hydroxyl group had a
resonance frequency identical to the spectrum obtained from the
optically active counterpart, two additional carbon resonances
appeared.
The differences in frequency from carbons that
appeared in the optically pure spectrum were both 5.5 Hz.
Since
this was a broad-band decoupled spectrum, these could not be
construed as carbon-hydrogen couplings.
It appeared that a
mixture of the two diequatorial isomers was present.
This
mixture was not separable by the procedures employed for the
18
other mixtures.
Figures 13 and 14 show the subtle differences
of the two spectra.
We next turned our attention to the coupling of 4-methylcyclohexanone, 40.
Since our main concern involved exploration
of methodology, it was important that other cycloalkanone
systems be examined to see if the coupling processes provided us
with predictable product differences.
As with the R-(+)-3-
m ethylcyclohexanone coupling, Warnet2^ found the aluminummediated reaction yielded predominantly the axially oriented
products, while the low valent titanium coupling principally
generated the equatorialIy oriented compounds.
This is sum­
marized in Figure 15, with the I3C-NMR data tabulated in Table 5.
The exclusive presence of axially oriented methyl groups in
compounds _34 and 37. posed an interesting structural question.
Were these groups truly axial or were the rings deformed?
Certainly x-ray structure determination would be the most direct
probe of this question; and with the recent acquisition of an xray diffractometer such a study was quite feasible.
Purified sampl-e-s-of 34 -and 37 were each -dissolved—Tn-Trot---hexane.
The solutions were allowed to cool and the hexane
evaporated slowly until crystals of each of the compounds were
formed.
This process allowed formation and selection of single
crystals of each to be utilized for the x-ray diffractometer.
The crystal of the diaxial isomer of 3-methyIcyclohexy1-3methyIcyclohexane-1,1'-dioI at first appeared to belong to the
centrosymmetric triclinic space group.
Since the molecule was
Figure 13.
C-NMR spectrum of diequatorial isomer 2.
Figure 14.
13C-NMR spectrum of d!equatorial fraction derived
from racemic coupling.
Table 5
13C-NMR spectra of
4-methy!cyclohexanone self-coupling products.
HO OH
HO OH
H3Cch3
37
H3
38
4 aa
4 ae
75.82
75.70
CH3
39
4 ee
75.39
75.24
32.36
32.33
30.80
30.85
30.44
30.41
27.07
27.12
26.19
26.21
24.97
25.10
22.32
16.70
CH3
H3C
16.71
22.32
PO
H
22
U
HO OH
HO OH
----- +»
M.P. (0C)
HOOH
93-94
Figure 15.
104-106
119-120
[Al-Hg]
13
44
43
[Ti]
63
33
4
The reductive coupling of 4-methylcyclohexanone, 40.
optically active, this could not be the case.
It can be seen,
however, that the distinct pseudo-symmetry of _34 could easily
give this initial result.
Once corrected, the solution of the
crystal was obtained by direct methods.
an R value of 6.4%.
Refinement finally gave
The hydrogen atoms, while all were found
during the refinement process, were ultimately given assigned
values.
The computer-generated carbon skeleton, depicted in
Figure 16, clearly shows that both methyl groups are in an axial
orientation and the cyclohexane ring is not distorted from the
chair conformation.
The solution for the 4-methyl diaxial compound, 37, was
generated from the direct methods program Solve.
Again all
hydrogens were found and finally given assigned values.
structure yielded an R value of 6.4%.
The
As in the previous
structure, the computer generated view of Figure 17 shows true
axial orientation and no distortion in either cyclohexane ring.
23
Figure 16.
Crystal structure of diaxial isomer of 3-methylcycIohexy1-3-methyIeyeIohexane-I ,I 1-diol, 34.
24
Figure 17.
Crystal structure of diaxial isomer of 4-methylcyclohexyl-4-methylcyclohexane-1,I 1-diol, 37.
25
It can be seen from the stereo-drawings in Figures 18 and
19 that the 3-methyl diaxial compound exists in three
conformations in the asymmetric unit.
Because of the symmetry
of 21_, two of the would-be conformations are identical, but since
its asymmetric unit contains 1.5 molecules, it is statistically
equivalent to the conformations of 34.
With the product distribution of the self-coupled products
well defined, we next turned our attention to the mixed coupling
reactions of cyclohexanone with R-(+)-3-methylcyclohexanone and
4-methylcyclohexanone. This would further test the generality
of the stereoselectivity of the reactions and provide us with
valuable material for conducting studies on the effect of alkyl
substituents in the.course of pinacol rearrangement.
Again it
was found that the aluminum mediated process yielded
considerable axial orientation, while the titanium formed
products were predominantly equatorial.
tabulated in Figure 20.
These results are
Table 6 compares the 13C-NMR data of -42
to its corresponding self-coupled products.
As a requirement for any further extensions of our work, it
became apparent that a rapid method for differentiating isomers
was highly desirable.
Although carbon NMR proved to be a
powerful tool, we turned our attention to mass spectrometry as
an alternate rapid method for characterizing 1,2-glycols.
Alcohols, particularly tertiary alcohols, typically exhibit
rapid loss of water when ionized by the conventional 70 eV
accelerating v o l t a g e . T h e
!,I'-bicycloalkyl diols
26
Figure 18.
Stereo drawings of 3-methyl diaxial, 34.
27
Figure 19.
Stereo drawings of 4-methyl diaxial, 37.
28
HO OH
Cv O
1
HO OH '
19
M.P.
Figure 20.
90-91
[Al-Hg]
41
[Ti]
91
86-89
59
9
Mixed reductive coupling of 3-methy!cyclohexanone,
with cyclohexanone, 19.
I,
consistently display major cleavage of the carbon-carbon bond
bearing the vicinal hydroxyl groups.
mechanistically by Figure 21.
This is illustrated
Since very little fragmentation
occurs prior to this cleavage, the spectra characteristically
yield little or no parent ions and only small M-18 and M-36
peaks.
This lack of discriminating data rendered EI spectral
comparison virtually useless for these molecules.
This is
illustrated in Table 7 which depicts the prominent masses of the
70 eV EI spectra for the isomeric 4-methylcyclohexyl-4methyIcyclohexane-I,I '-diols.
"/
Figure 21.
+/H
HO'+
HO
zZ
C
I
OH
A,
Z
C
:0H
0
11
♦
C
'c
I
OH
Proposed major cleavage for 1,1'-bicycloalkyl diols.
Table 6.
13C-NMR spectra of axial isomer from mixed coupling products of cyclohexanone
with (+)-3-methylcyclohexaone.
HO OH
HO OH
HO OH
3 a
3 aa
76.58
77.20
20
75.59
76.00
IV
VD
37.04
37.09
31.50
31.38
31.15
31.00
30.61
30.90
27.60
25.84
27.57
25.80
21.81
21.69
21.76
21.20
21.18
17.60
17.42
30
Table 7.
70 eV electron impact spectra of isomeric 4-methylcycIohexyI-4-methyIeyeIohexane-I ,I '-diols.
Diaxial , 37
M/Z
% Base
Axial--Equatorial, 38
M/Z ,
% Base
Diequatorial, 39
M/Z
% Base
208
3.1
208
2.8
208
7.7
190
4.4
190
4.5
190
5.8
151
5.8
151
6.3
151
10.7
133
2.1
133
3.2
133
2.8
114
9.9
114
10.4
114
10.9
113
100.0
113
100.0
113
100.0
112
40.4
112
49.3
112
39.5
95
58.4
95
61.7
95
46.0
81
9.7
81
8.4
81
7.8
67
8.8
67
14.4
67
9.5
55
15.2
55
26.9
55
6.3
In an attempt to promote less fragmentation, it appeared
logical to incorporate chemical ionization as a less harsh
method to induce ion formation.
Chemical ionization occurs when
an ion formed from the reagent gas in the source reacts with the
neutral sample molecules.2^
This generally involves exothermic
proton or hydride transfer.
The excess energy subsequently
promotes dissociation of the reactant product (MH+ or [M - H]+)
yielding a spectrum that is generally different from the
corresponding electron impact process.
By choosing a reagent
gas with the appropriate Bronsted acidity, or proton affinity.
31
one can in principle control the degree of fragmentation of the
sample.
In general, the more exothermic the reaction, or the
greater the difference in proton affinities of the reagent ion
and the sample, the more fragmentation.
By using both methane and isobutane, reagent gases with
differing proton affinities,26'27 it was hoped that the
fragmentation patterns might be altered significantly.
We
found, however, very little change in the spectra of the diols.
Again facile cleavage of the diol carbon—carbon bond dominated
the fragmentation pattern.
Recently Harrison and Lin26 employed charge exchange mass
spectrometry to probe the energy dependence of fragmentation of
the stereoisomeric methyleyeIohexanoIs. Charge exchange
ionization occurs when the charge of the reagent gas is
transferred to the neutral species in the source.
This permits
a soft ionization process of specific energy which is more
precise than simply lowering the ionization potential in the
source.
While charge exchange techniques have been utilized to
construct breakdown diagrams to depict energy dependence of
particular fragmentation patterns,28,29- Harrison also found that
certain cis-trans epimeric pairs could readily be distinguished
from simple observation of the spectra.
The loss of water from alkylated eyeIohexanoIs occurs
either by a stereospecific cis 1,4 elimination from a boat
conformation, or a more general non-specific cleavage.20
Trans
32
1,4-substituted cyclohexanols readily display the 1,4 water
loss.30
This is illustrated in Figure 22.
Figure 22.
Comparison of cis and trans isomers to promote
I ,4-H2O elimination.
Harrison found that at low charge exchange energies
(10-11 eV) the trans isomer exhibited a substantially different
[M-H2Oj+ZM+ ratio than the cis, reflecting the cis-1,4 water
elimination.
negligible.
At higher energies, however, the difference was
This implied that the highly ordered transition
state necessary for the cis water loss quickly gave way to the
general non-stereospecific water loss mechanism.
The 3-methyIcyclohexanoI epimers were also examined.
As
might be expected, these compounds did not exhibit the water
loss differences as noted in the 4-methyIcyclohexanoI examples.
In general Harrison reported identical data for all charge
exchange energies investigated.
Application of charge exchange mass spectrometry to the
I,I'-bicycloalkyI systems seemed to a be a natural extension.
33
With it we had hoped to explore two questions:
Could this give
us information to differentiate diastereomers and could we, with
the proper reagent, examine the energy involved in the facile
cleavage of the diols?
To explore these questions, three reagent gases, argon,
nitrous oxide and carbon disulfide, were utilized.
This would
permit examination of the energy region from 10 eV-16 eV.
Table
8 summarizes the results of the study for the three isomeric
4-methyl eye Iohexy I-4-methy Ieye Iohexane-1,1'-dio Is.
As expected, the spectra produced by the charge exchange
methods displayed less fragmentation than those produced by 70
eV electron impact.
At the same time there were negligible
differences between the spectra within a given isomeric series.
From the table one can readily see that the more energetic
ionizations show very little fragmentation above mass 113.
This
reinforces the facile cleavage mentioned earlier.
Examination of the spectra of the 4-methyIcyclohexylMmethyIeyeIohexane diol series produced by charge exchange with
carbon disulfide readily—shows~the-characteristic diol cleavage
seen in the electron impact spectra.
Although the rupture of
the carbon-carbon bond bearing the vicinal hydroxyls appeared to
be very facile, we had hoped that at a low charge exchange
energy, i.e., carbon disulfide, we would see a significant
increase in the [M-H2O]+ and [M-2H20]+ fragments.
These
34
Table 8.
Major fragmentations for charge exchange spectra of
isomeric 4-methylcyclohexyl-4-methylcyclohexane-1-1
diols.
Ar Charge Exchange
ee
208 (.2) , 190(2.2) , 123(1.1) , 114(3.6) , 113(48.1), 112(30.7) ,
109(1.5) , 97(4.8) , 95(100)
ea
208(5.2), 190(2.4) , 123(5.3), 114(0.8), 113(11.7), 112(100),
109(7.9), 97(53), 95(25.6)
aa
1
208(4.1), 190(1.7), 123(5.3), 114(0.0) , 113(12.1) , 112(100),
109(6.6) , 97(54.0), 95(24.7)
N2O/N2 Charge Exchange
ee
208(0.8), 190(1.4), 140(1.7), 114(2.8), 113(40.0), 112(100),
97(13.4), 94(14.3)
ea
208(0.8), 190(3.5), 140(1.8) , 114(2.5), 113(29.2), 112(100),
97(12.6) , 94(15.4)
aa
208(1.1), 190(3.5), 140(1.9), 114(2.6), 113(30.8), 112(100),
97(13.1) , 94(15.8)
CS2ZN2 Charge Exchange
ee
208(2.7), 190 (-) , 151(2.4), 114(5.3), 113(60.4), 112(100),
95(68.9), 94(14.5)
ea
208(2.2), 190(1.7) , 151(3.8), 114(7.0) , 113(74.9),
112(78.9) , 95(100), 94(13.4)
aa
208(2.2), 190(2.0) , 151(2.3), 114(6.3), 113(72.5),
112(63.0), 95(100), 94(10.1)
I
j
- I:
; j
35
fragments were minorf at best, so we were unable to draw any
conclusions from this portion of the spectrum.
Examination of the fragmentation of the daughter ion at
mass 113 also reveals loss of water represented by mass 95.
In
order for the stereospecific loss of water to be a major
contributor, it must be able to occur while the ring is yet
intact.
If the proposed cleavage described in Figure 20 is
correct, both rings are indeed still intact, but the carbons
bearing the hydroxyls are most likely planar, thereby destroying
the stereoselectivity necessary for the cis 1,4-water
elimination.
Since water loss is prominent in this part of the
spectrum, and the fragmentation pattern very similar among the
corresponding isomers, we are forced to conclude that it occurs
by another route.
Although the stereoselectivity of the two different metalmediated coupling reactions suggest the possibility of new
synthetic potential for the diols formed by these procedures,
the origin of the differences is not well understood.
While our
main concern involved exploration of the applicability of
pinacol chemistry toward synthetic methodology, we were
compelled to address some of the mechanistic implications.
Typically one reference^! is cited during a discussion of
the mechanism of reductive coupling.
This classical description
requires the formation of a radical anion intermediate as
depicted in Figure 23 to accomplish the formation of pinacols.
36
Unfortunately very little work has been conducted to examine
this directly.
0"
0
2 CI.
2
HO
OH
Ii
C
Figure 23.
General mechanism for reductive coupling.
Indirect evidence for this has come from work performed by
McMurry5 in coupling carbonyl compounds with reduced titanium to
yield olefins.
McMurry has proposed several mechanisms to
account for these results, all of which contain the formation of
pinacol dianions prior to the generation of the olefins.
The
mechanism portrayed in Figure 24 is the one he considers most
likely.
More recently Dam52 has bolstered this concept by studying
benzophenone and cyclohexanone as substrates for low-valent
titanium coupling to generate olefins.
Dam's study concurs with
McMurry: the ketone is first transformed to the radical anion,
followed by dimerization to the pinacol dianion and subsequent
37
oxygen abstraction to yield the olefin.
The coupling reaction
occurs on the active metal surface.
Figure 24.
Mechansim proposed by McMurry to form olefins by
reductive coupling.
Although a rigorous study involving the titanium induced
pinacolization has not yet been reported, the generalizations
from the olefin reaction can be used to explain the results
found in the coupling of the alkyl-substituted cyclohexanones.
Figure 25 graphically depicts the formation of the predominate
diequatorial product produced from the self-coupling of (+)-3methy!cyclohexanone.
Formation of the minor product, the
38
axial-equatorial diol, can be rationalized by a "front-to-front"
approach.
The resulting intermediate undergoes immediate
conformational reorganization to minimize the steric congestion.
This initially unfavorable approach would also account for the
smaller amount of 2 formed.
alternate orientation.
Figure 26 illustrates this
Absence of the diaxial isomer follows
the same rationalization.
"Back-to-back" coupling would
encounter even more steric congestion.
The effectiveness of
this kind of approach is minimal at best.
Careful examination
using Dreiding models butresses these assumptions.
Figure 25.
Titanium mediated coupling to form diequatorial
isomer.
This particular mechanistic rationale does not account for
the results of the aluminum mediated coupling.
Based on the
data, one would expect the coupling processes to be different.
It was first thought that the diequatorial isomers were formed
39
as the result of thermodynamic control, while those compounds
with axial methyl groups were driven kinetically.
The elevated
temperatures and extended reaction times employed for the
aluminum coupling would argue against this.
Warnet10 subjected
the diequatorial isomer, 2, to the conditions of the aluminum
procedure for two days at room temperature and found no
conversion to 3^ or
and only minimal alkene production.
This
went along with the assertion by McMurry5 that retropinacol
condensations do not occur for tertiary alcohols.
Figure 26.
Mechanistic rationalization to account for axialequatorial product formation.
To investigate the influence of solvent we ran the aluminum
coupling with refluxing THF. This reaction gave us the same
ratios of isomers as found in benzene.
In an effort to probe whether or not surface effects or
discrete metal complexes were operative, we attempted to carry
out a photopinacolization of (R) - (+)-3-methylcyclohexanone to
40
compare the product ratio to those obtained from the metal bound
reactions.
The photo-induced coupling of ketones is a well-
known reaction.33
In the case of benzophenone, such coupling is
routinely carried out in sophomore organic labs by subjecting
starting material to sunlight for several days.34
Coupling of
aliphatic ketones, however, appears not to be as straight­
forward.
Some simple aliphatic ketones have been dimerized.33
However, cyclic ketones are reportedly prone to a variety of
fragmentations and hydrogenation.
Such a side reaction kept us from observing diol formation.
Analysis of the reaction mixture after three days of exposure to
ultraviolet light yielded 3-methylcyclohexanol, 44,
exclusively.35
Figure 27.
This is summarized in Figure 27.
Photochemical reaction of R-(+)-3-methylcycIohexanone.
41
McMurry et al^ had proposed a dianion intermediate for
certain aromatic ketones that undergo the low valent titanium
pinacol coupling.
MundylO had suggested that since aluminum
reactions often undergo two-electron transfer, perhaps the
aluminum mediated coupling reaction might proceed by this non­
radical process.
Formation of the axial-equatorial isomer by
this process is depicted in Figure 28.
3
Figure 28.
Proposed dianion induced coupling.
Part of the problem with this mechanism involves the
geometry of the dianion intermediate.
Carbanions are generally
considered to assume an sp3 geometry, but the question needed to
be asked:
Could this be extended to the anions derived from the
methyIeyeIohexanones ?
To probe this matter further, we employed the semiemperical
molecular orbital program MNDO (Modified Neglect of Diatomic
Overlap).
This method was developed by Dewar et al36 to yield
molecular properties which were chemically valuable and yet
computationally inexpensive.
This has proven to be quite
valuable for organic chemists since typical analyses require
42
numbers of atoms that are much too large for them to use ab
initio techniques.^7
Average MNDO absolute errors are 9
kcal/mole for heat of formation, 3° for bond angles, 0.025 A for
bond lengths, 0.35 D in dipole moments and 0.5 eV for ionization
potentials.
Using bond lengths and angles typical for simple systems,36
we examined a formaldehyde radical anion complexed with an
aluminum ion having a +1 charge.
This permitted us to optimize
the oxygen-aluminum bond length and examine the geometry about
the carbon atom.
Figure 29 illustrates the molecular structure
of the complex after optimization by MNDO.
IBO
/,0
HjgSlfo
H ^
Figure 29.
Optimized aluminum-formaldehyde complex by MNDO,
At first glance, the nearly linear aluminum-oxygen-carbon
bond may seem surprising, but this is analogous to the situation
observed in the complexation of certain lanthanide metals with
carbonyl compounds.39
The bond angles about the carbon atom
certainly indicate sp2 hybridization, which is quite reasonable
for a radical.
The oxygen-aluminum bond length is somewhat
short,40 but certainly workable.
43
Our next step was to inspect a reasonable model of the
cyclohexanone system.
For this we chose the 3-pentanone
molecule, fixing the geometry to assume a "chair" conformation,
as depicted in Figure 30.
Al
46
Figure 30.
Initial 3-pentanone-aluminum model.
To assure that the final geometry about the carbonyl center
would not fall into a localized minimum, we allowed the angle
to optimize by starting the calculation with the angle at
various positions.
to 120° (Figure 31).
In all cases the final bond angle returned
In short, this system behaved as the
simpler formaldehyde model.
47
Figure 31.
Optimized 3-pentanone-aluminum complex.
44
By adding a second electron to the previously described
3-pentanone system, we were able to investigate its effect on
the geometry.
To our surprise the final geometry of the dianion
was nearly identical to that observed in the radical anion.
This would certainly speak against the idea of a dianion
intermediate.
We were at first skeptical of these results,
however, they are not without precedent.
Gimarc^ points out
that the geometry of related carbonyl systems, while exhibiting
a tendency toward a pyramidal shape, has very low inversion
barriers, and thus appear planar.
In conjunction with the theoretical findings, the selective
formation of a dianion among identical reactants seems quite
unlikely.
For mixed systems, where reactivity can vary between
species, the dianion may be more plausible, but since we see
the same trends in mixed as well as self-coupling reactions, it
appears that an alternate mechanism must be sought.
Certainly
additional work needs to be done in this area.
Pinacol Rearrangement
Tandem mass spectrometry, while finding increasing use as a
powerful analytical tool in identification of selected targets
in complex mixtures, has also been tapped to yield fragmentation
maps and secondary ion spectra.
Coupling chemical ionization
with MS/MS can afford valuable information of gas phase ionic
reaction mechanisms.
49
45
A variety of mass spectrometer geometries has been
assembled to carry out the tandem experiment.^3
Figure 32
illustrates a generic configuration employing a forward geometry
double focusing instrument.
Primary ions are generated in the
ion source, either by conventional electron ionization or
chemical ionization techniques.
The ion of interest is then
filtered out by the first mass analyzer.
As this ion enters the
field—free region between the analyzers, it undergoes secondary
fragmentation by colliding with a neutral gas.
This process is
termed collisional activation or collisional-induced
dissociation.
The second analyzer then scans the mass region of
the daughter ion to yield its spectrum.
With this type of
geometry, several scanning techniques are available, depending
on how the accelerating voltage, magnetic sector and electric
sector are varied.
A very popular linked scan method, called
the B/E scan,43 is performed by maintaining a constant
acceleration voltage while scanning the two sectors such that
the ratio B/E remains constant.
This type of scan gives
daughter ion spectra for a given parent ion.
The pinacol rearrangement, because of its ionic nature, is
quite amenable to study in the gas phase by tandem mass spectro­
metry.44
Cooks and Glish43 first demonstrated by chemical
ionization that the spectrum of the [MH-H20]+ daughter ion of
pinacol corresponded to the spectrum of protonated pinacolone.
Shortly thereafter Maquestiau and co-workers46 provided evidence
that the spectrum of the [MHHE^O]+ daughter ion of protonated
46
D
Figure 32.
Schematic diagram of a tandem mass spectrometer with
forward geometry (S = source, E = electron sector,
C = collisional chamber, B = magnetic sector,
D = detector).
eye Iopen ty lcycl open tane-1,1'-dio 1, 48, correlated well with
that derived from the CAD spectrum produced by the protonated
spiranone 49.
Both of these studies provided valuable insight
into the relationship between the gas phase and solution
mechanisms of the pinacol rearrangement.
With this information in hand, we felt compelled to explore
the possibility of utilizing tandem mass spectrometry as a
possible rapid analytical tool in determining product ratios of
mixed diol rearrangements and, at the same time, attempt to
compare gas phase distribution to the product ratios found by
carrying out the reaction in solution under standard conditions.
Srinivasa^ systematically explored the effect of reaction
conditions on the course of pinacol rearrangement of the
unsymmetrical glycol, eye Iopenty I-eye Iohexane-1,11-d io 1, 4y in
acidic media.
his work.
Table 9 and Figure 33 summarize the findings of
Clearly, increasing the concentration of water and
47
temperature promoted increase of the spiranone, 6, while
concentrated sulfuric acid at 0° showed a marked increase in the
other spiranone, _5.
Refluxing
and j5 individually in 25%
H2SO4, only spiranone 5^ yielded quantitative conversion to 6.
In a similar experiment 5 was reacted with 92% sulfuric acid at
0° but no conversion occurred.
Srinivasa and Mundy47 proposed a
mechanistic rationalization to account for observed secondary
rearrangement, which is depicted by Figure 34.
These results
clearly showed that the spiroketone, jj, is more stable at .
higher temperatures, while the 5-7 spiranone predominates only
at 0° in the presence of concentrated sulfuric acid.
This
would indicate a thermodynamic preference for the 6,6 ring
system.
Table 9.
Brief Summary of Pinacol Rearrangement of 4.
Conditions
Product Composition (in %)
6
5
7
25% H2SO4
7.0
0.8 ■
92.4
96°, 25% HzSO4
50.0
6.6
43.5
0°, 100% H2SO4
31.8
68.2
0°,
20.9
10.9
0°,
92% H2SO4
—
68.2
This work provided impetus for exploring this particular
system in the gas phase by tandem mass spectrometry.
As a
preliminary study, two symmetrical systems were analyzed as a
check.
Both the eye Iopen ty Ieye lopentane-l,l'-diol, j48 and the .
O---O-- O-
5+6
Q 50-
q
Figure 33.
...-.. y
Effect of product distribution as a function of
sulfuric acid concentration.47
49
Figure 34.
Possible mechanism of the secondary rearrangement of
spiranone 5.
eye Iohexy Ieye Iohexane-1,1'~dio I, 20,
and their corresponding
pinacol rearrangement products were ionized by isobutane, the
appropriate ions focused and then fragmented with low energy
collisional activated dissociation, and analyzed using the
conventional B/E scanning procedure.
The spectra of the [MH-
H2O]+ and their corresponding protonated spiroketones are
summarized in Table 10.
Authentic samples of the two spiroketones 5 and 6 were
synthesized and purified along with a sample of their diol
precursor, 4.
These were then analyzed by tandem mass
spectrometry using the same conditions for Cl, CAD and scanning
procedure.
Comparison of the two spiroketone spectra as
tabulated in Table 11 reveal overall similarities.
regions about mass 111 and 125 differ markedly.
However, the
These same
differences occur in the spectra generated from a conventional
70 eV electron ionization experiment.
illustrated in Table 12.
This is graphically
50
Table 10.
CAD spectra of symmetrical diols ^8 and ZO and
spiroketones 49 and 50.
48
49
20
50
M/Z
% Base
M/Z
% Base
M/Z
% Base
M/Z
137
136
135
134
133
124
123
122
121
111
HO
109
108
107
95
93
91
85
81
79
0.78
0.53
100.00
2.19
0.84
1.69
6.88
0.38
0.38
7.19
1.25
0.91
0.41
0.50
0.31
0.25
0.22
0.22
0.13
0.13
0.13
137
136
135
134
133
125
124
123
122
121
119
117
112
111
HO
109
108
107
95
93
91
85
81
79
0.27
' 1.47
100.00
0.91
0.55
0.34
1.38
166
165
164
163
162
161
152
151
150
149
147
145
139
138
137
136
135
134
133
125
124
123
122
121
119
111
HO
109
108
99
97
95
91
82
80
78
1.80
3.08
2.20
100.00
.10.40
2.60
2.92
5.20
2.44
2.32
1.40
1.08
1.36
2.40
14.00
1.72
2.40
1.12
1.56
2.56
2.16
1.00
1.36
1.08
1.16
1.16
0.80
1.52
0.88
3.08
1.32
1.16
1.20
1.28
0.60
0.76
166
165
164
163
162
161
152
151
150
149
148
147
139
138
137
136
135
134
133
126
125
124
123
122
121
120
119
112
111
HO
109
107
99
97
68
68
2.82
0.25
0.34
0.34
0.20
0.80
13.65
1.41
0.89
0.65
0.47
0.41
0.32
0.32
0.24
0.22
0.20
0.20
95
91
82
.
80
% Base
3.82
6.76
4.12
100.00
11.47
■1.56
3.88
3.09
1.09
2.62
1.18
2.24
3.82
6.76
19.41
2.41
2.06
1.65
2.00
2.47
4.41
3.88
1.56
1.00
1.09
0.74
0.88
1.00
0.79
0.56
1.35
0.82
3.74
0.79
1.06
0.62
0.79
0.56
51
Table 11.
70 eV electron impact spectra of spiroketones 5
and 6.
5
M/Z
166
148
125
124
123
119
111
HO
109
98
97
95
82
81
80
79
69
68
67
6
% Base
M/Z
37.1
166
148
125
124
123
122
111
HO
109
29.2
54.4
5.0
18.7
11.4
2.8
8.2
7.5
15.2
11.1
■ 70.1
41.3
38.0
30.2
20.3
14.9
23.1
100.0
98
97
96
95
82
81
80
79
69
68
67
% Base
38.9
10.8
15.1
21.1
8.5
25.9
100.0
7.8
17.9
35.8
9.2
15.3
29.0
25.0
62.1
9.6
18.2
10.7
23.6
79.2
Having a set of discriminating data in hand, we embarked on
an analysis of the unsymmetrical eye Iopenty Ieye Iohexane-1,11diol.
From the comparison of the resultant data as displayed in
Table 13 to that of the two spiranones, it is clear that the
diol spectrum more closely resembles the spectrum of the
unsymmetrical spiroketone than that of the spiro-[5,5]-undecan6-one.
Although we had hoped to establish a quantitative
relationship between the gas phase data, such a marker eluded
us, and we had to settle for a qualitative analysis.
52
CAD spectra of spifoketones
6
and 6.
5
M/Z
% Base
M/Z
% Base
152
151
150
149'
148
147
139
138
137
136
135
134
133
131
126
125
124
123
122
121
120
119
112
111
HO
109
108
107
105
99
3.62
4.77
2.85
100.00
3.92
1.03
0.33
1.92
5.54
0.79
1.01
0.36
1.15
0.30
0.65
4.00
4.77
4.08
2.08
0.88
0.45
0.67
6.71
14.62
1.02
1.05
0.81
0.69
0.45
0.90
0.89
0.52
0.39
0.59
0.38
0.48
0.92
0.28
0.64
0.37
0.31
0.46
152
151
150
149
148
147
139
138
137
136
135
133
126
125
124
123
122
121
119
111
HO
109
108
107
0.33
0.34
3.61
100.00
2.13
0.29
0.27
0.73
0.60
0.14
0.20
0.13
0.68
4.07
0.64
2.96
0.25
0.16
0.15
0.25
0.62
0.16
0.16
0.15
0.49
0.13
0.10
0.17
0.30
0.15
0.11
98
97
96
95
93
91
86
84
82
80
78
67
99
;
98
97
95
86
82
67
53
Table 13.
CAD spectrum of unsymmetrical diol 4.
4
M/Z
% Base
M/Z
% Base
152.
151
150
149
148
147
139
138
137
136
135
133
125
124
123
122
121
120
0.62
2.00
0.94
100.00
4.54
0.69
0.38
1.00
4.69
0.20
0.25
0.22
1.92
0.93
1.00
0.42
0.58
0.12 ,
119
112
111
HO
109
108
107
105
99
0.35
0.15
6.20
0.47
0.28
0.26
0.28
0.13
0.58
0.28
0.22
0.35
0.23
0.15
0.12
0.31
0.25
0.12
0.12
98
97
96
95
93
91
86
82
78
67
The relationship between the gas phase and solution data is
not surprising.
Since reactions that occur readily both in
solution and the gas phase generally display minor solvent
e f f e c t s , one would expect to see a similarity in product
distribution for the two conditions.
Again, although a
quantitative spiroketone product ratio was not established in
the gas phase, the fact that an overall similarity between the
mixed diol and the unsymmetrical spiroketone existed indicates
the fast forming spiranone predominates in both types of
chemistry.
For the pinacol rearrangement of !,I'-bicycloalkyl diols to
be synthetically useful, it became evident that structural
54
effects other thah ring size needed to be studied as directing
influences.
We chose to examine the influence of alkyl
substituents on the course of the rearrangement.
Our previous
work on the coupling of mixed cyclohexanones indicated that the
stereoselectively formed products of these reactions would be
excellent preliminary systems for study.
Analysis of the rearrangement of 41 quickly reveals another
potentially difficult stereochemical problem.
graphically illustrates this.
Figure 35
We felt several aspects of this
particular rearrangement needed to be probed:
Would there be a
preference for certain diastereomers formed; could the
preference, if found, be traced to electronic or steric effects;
finally, could we develop a method to differentiate rapidly the
products formed?
As a point of departure we examined the electronic effects
of the system with the use of MNDO.
If the methyl group exerted
an effect in stabilizing the cationic intermediates, it would be
expressed in a difference in their respective heats of
formation.
We utilized the model cations 5j5 and 57 shown in
Figure 36 as a first approximation, since they could be computed
relatively quickly and, if the methyl group did stabilize the
carbocation, its effect would most likely be greatest when
closest to the charge.
It should also be noted that use of the
charged species without consideration for counter ions or
solvent shell was justified since the pinacol rearrangement
55
readily occurs in the gas phase in a manner similar to its
solution counterpart.
Figure 35.
Possible products from the rearrangement of 41.
'CH
H1CH3C OH
CH3
,CH
H3CH3C
HO CH3
57
Figure 36.
Model carbocations to determine methyl group
influence.
Comparison of the two cations showed that carbocation, _57
with its methyl group nearer to the charge, did exhibit distinct
56
stabilization.
Cation 57 yielded a heat of formation 7
Kcal/mole more than _56.
Assuming that the differences in
entropy between the two systems were negligible, it is possible
to approximate the ratio of the two products at equilibrium.
This approximation shows a distinct preference for carbocation
57.
Since this system did exhibit a difference in energy
between the two models, we next analyzed models that would mimic
differences elicited by a methyl group beta to the charged
center.
Figure 37 shows the models utilized for this.
Figure 37.
Carbocations used to explore stabilizing effect of
methyl group.
Although the MNDO work showed a slight stabilization for
the carbocation in which the methyl group was in closer
proximity to the charge, there was no clear-cut preference.
In
a strange way this was probably advantageous, since it eliminated
any predetermined bias prior to analysis.
The rearrangement of 41 was then carried out under standard
conditions and analyzed by capillary GC-MS.
Along with a
fraction presumed to be the alkene, the crude product mixture
57
showed the presence of four compounds, each possessing parent
ions and fragmentation patterns consistent with the isomeric
spiroketones.
statistical.
The distribution of these spiranones was not
Based on the order of elution, the percent ratio
was 7:12:38:43.
Had the ketones been formed with equal
facility, one would have expected twenty-five percent for each.
Rapid, clean separation of the spiroketones proved to be
elusive.
Collection of three of these ketones was accomplished
by preparative GLC.
Analysis of these compounds revealed
disappointing spectra.
Since the carbonyl group was the only
functionality in any of the compounds, each displayed a broad
complicated methylene envelope between I and 2 parts per
million in the proton-NMR spectrum.
The only readily
distinguishable features were the resonances corresponding to
the protons alpha to the carbonyl and the methyl doublets.
From
this we were confident that at least one of the compounds could
be structurally elucidated.
Geminal protons near a chiral center, particularly those
alpha to that center, often exhibit different chemical shifts.
Since they experience different environments they are indeed
diastereotopic.
Spiroketone 5j2 as depicted in Figure 38 should
be the most easily recognizable by this phenomenon, unless the
alpha protons were fortuitously equivalent.
While all the isomers possess chiral centers, only 52 had a
reasonable chance of being confirmed by this technique.
The
58
others would exhibit differences imbedded in the methylene
envelope.
Figure 38.
Nonequivalence of alpha protons in 52.
Only one compound presented itself as a likely candidate.
In a decoupling experiment the alpha proton centered at 2.58 ppm
was irradiated, which resulted in the collapse of the signal at
2.18 ppm to a broad singlet.
Irradiation at 2.18 ppm caused the
signal at 2.58 ppm to collapse to a doublet (J = 10 Hz).
This
implies that the downfield signal is coupled to a single
adjacent proton at a large dihedral angle.
The upfield
resonance is consistent with interaction with a single vicinal
proton in an axial-equatoriaI like fashion.
Although the
decoupling experiments did not reveal a direct relationship
between the methyl group and adjacent methine proton, the
experiment yielded consistent data to assign spiroketone C as
52.
The decoupling experiments performed on the other two
compounds yielded no conclusive data.
It seemed appropriate, at
this juncture, to expand chemically the spectra of these
compounds by utilizing a lanthanide shift reagent.
These
59
reagents have been used extensively^/50 j_n organic structure
elucidation since they were introduced in 1969.51
A number of
these shift reagents have been employed, but probably the most
commonly used is Eu(fod)3 , illustrated in Figure 39.
Figure 39.
Structure of Eu(fod)3.
(R = CF3CF3CF^")
The lanthanide reagents act as Lewis acids and complex with
an electron pair donor of the substrate.
The complex exhibits
resonances shifted from the original spectrum.
The basis for
this induced shift is considered to be a pseudocontact
interaction, expressed by the McConnel!-Robertson equation
(Figure 40).
The line defining the distance between the proton
and the lanthanide ion (r), along with the angle (6) between the
donor-lanthanide bond and r, define the variables necessary to
calculate the induced shift (v).
60
A v = K(3cos2 e-l) /r3
Figure 40.
Structural parameters involved in the McConnellRobertson equation.
As one incrementally adds more lanthanide reagent, the
resonances continue to shift proportionally.
Done correctly,
the experiment should yield linear relationships for each of the
shifted resonance frequencies.
Analysis of the data can yield several types of
information.
Decoupling experiments performed on the chemically
expanded spectra often provide structural relationships that
were unavailable when signals were hopelessly overlapped in the
original.
It is also possible to discern relative stereo­
chemistry and perform conformational analysis based on the
induced shifts.
The latter two applications are carried out by comparing
the observed lanthanide induced shifts to idealized shifts
calculated from the McConneII-Robertson equation.
The computer
program PDIGM^2 is a convenient method employed to carry out the
comparison.
Searching a spherical region at specified
61
incremental lanthanide-donor distances, the program calculates
the orientation which best correlates with the experimental
induced shift values.
The coordinates and the calculated
agreement factor (R) which compares the experimental shift with
the McConnel!-Robertson derived values are then output.
Typically the agreement factor is used as a negative screening
parameter.
Values of R < 0.10 are generally considered
unreasonable.
The lanthanide-oxygen distance for carbonyls is
in the neighborhood of 2 .3A .39
An additional feature of PDIGM is its auto assignment
capability.
Unknown protons can be entered by their shift
values and these are then arranged to give the best agreement
factor.
This can be useful for structures in which decoupling
experiments are inconclusive.
The LSR experiment on the methyl-substituted spiranone D
was carried out by adding incremental amounts of solid Eu(fod) 3
until one equivalent was introduced.
After addition of
approximately 0.3 equivalents of the shift reagent, thirteen
distinguishable peaks were observed in the spectrum.
experiments were carried out on subsequent additions.
Decoupling
Certain
decoupling patterns were observed, but those protons coupled to
the key structural features could not be traced.
As a result,
it was hoped that the auto assignment function of PDIGM would
show a distinct structural preference for the experimental data.
The induced shifts are listed in Table 14.
62
Table 14.
Slopes from the plot of change in shift versus
tEu(fod)3/d ]
Peak
Integration
I
2
3
4
5
6
7
8
9
10
11
12
12
14
15
16
IH
IH
IH
IH
. IH
IH
IH
3H
IH
IH
3H
IH
IH
IH
IH
3H
Slope
Correlation Coefficient
6.24
5.83
5.53
4.94
4.07
3.89
3.32
2.98
2.71
2.65
1.86
1.67
1.17
0.90
0.75
0.61
.992
.990
.992
.995
.992
.992
.990
.985
.993
.985
.989
.983
.990
.982
.992
.990
Dreiding-derived coordinates of the unsubstituted
spiranone^S were then input to the empirical force field program ■
MMl in an effort to yield an optimum geometry.
Molecular
mechanics is not a. true quantum-mechanical approximation.
Instead it considers the total molecular energy (E) to be a
summation of four empirical force constants: stretching;
bending; torsional and van der Waal.
The idealized constants
were obtained experimentalIy for small molecules.
The program
then attempts to minimize the strain energy of the molecule
under consideration by optimizing the geometry.
The energy
deviation of the real molecule from the idealized system is
called the steric energy.
63
The advantage of molecular mechanics is speed.
For nearly
all of the molecules we have considered (typically 20-40 atoms)
the computation time is only several minutes.
In addition,
final geometries are quite good, but this is restricted to those
functional groups for which constants are defined.
problems with this method, however.
There are
If the initial geometry is
near a localized potential energy well, it will settle there and
not find the true minimum.
can often rectify this.
Perturbation of the initial geometry
Secondly, those properties that rely
heavily on electronic effects are not appropriate for molecular
mechanics.
Once the geometry was optimized for j50, MMl was used to
optimize structures and provide coordinates for 52, 53, 54^ and
55 by replacing the appropriate hydrogen with methyl groups
(Figure 41).
These values, along with the induced shifts, were
used in PDIGM.
The protons alpha to the carbonyl and the methyl
protons were assigned their respective shifts while the
remainder were input to be auto-assigned.
54
55
53
Figure 41.
Numbering scheme of unsubstituted spiroketone 50.
64
Only one of the structures yielded an agreement factor less
than 0.10. This occurred at a base-lanthanide distance of 1.84
O
O
A which is approximately 0.5 A too short. Based on these
results, the PDIGM program was inadequate in providing insight
into the structure of the second major rearrangement product of
41.
It appears that an alternate method must be employed.
Analysis by two-dimensional NMR might prove useful.
Alternatively, production of a suitable crystalline derivative
might allow structure determination by x-ray diffractometry.
Secondary Rearrangements
If the spiranones generated from the rearrangement of
bicycloalkyl diols were to be of general synthetic utility, they
needed to be extended into other systems.
To test this, we
embarked on an exploration of secondary rearrangements to probe
their potential utility.
Krapcho5^ demonstrated that the tosyl spiranone, 6£, could be
rearranged quantitatively to a mixture of unsaturated decalins
(Figure 42).
The decalin ring system is the backbone for a
variety of isoprenoid natural p r o d u c t s . F a c i l e entry into
this system has long been a challenge for synthetic organic
chemists.
While Krapcho's conversion is high yield, it lacks an
angular methyl group, one of the hallmarks for many of the
related terpenes.
A classic approach to this family involves incorporation of
the well-known Robinson annulation5^ reaction.
This involves
65
1,4-Michael addition of cyclohexanone to a vinyl ketone or
related Mannich base.
If 2-methyIeyeIohexanone is employed,
and the experimental conditions such that the thermodynamic
enolate is formed, introduction of the angular methyl group is
readily achieved (Figure 43).
This reaction offers tremendous
flexibility and has been incorporated as a key step in a number
of terpene syntheses.57-59
Other methods of entry, however, may
be more advantageous.
To compensate for the deficiency of the Krapcho
rearrangement, we looked to the spiroketones as an alternative.
It appeared that alkylation of the readily available spiranone,
49, could be a simple, effective method of providing an
intermediate that would overcome the deficiency to produce a
structure with the strategic angular methyl group (Figure 44).
The spiroalcohol J56 was produced cleanly and then stirred
in benzene with a trace of p-toluenesulfonic acid used to
catalyze the rearrangement.
Workup yielded two products, the
desired decalin 67 and an elimination product 68 in a 2:1 ratio.
Characterization of these products was readily accomplished
by proton-NMR.
Compound 68 showed the characteristic resonance
66
of an allylic methyl group doublet at 1.61 ppm (j = 2.1 Hz),
while j67 exhibited the expected sharp methyl singlet
at 1.04 ppm.
Mechanistic rationalization of these products is
shown by Figure 45.
Figure 43.
Robinson annulation of 2-methy!cyclohexanone, 63,
with MVK, 64.
Although the conditions for this reaction were not
optimized, the distinct preference for 61_ was very encouraging.
Fadel and Salaun^O have recently obtained
in high yield by
reacting methyI-1-methyIeyeIopentyIcarboxylate with the
67
diGrignard of 1,4-dibromobutane followed by rearrangement with
FeCl3 .
Figure 45.
Rationalization of cationic rearrangement of 66.
68
Extension of this rearrangement to the mixed diol j69
(Figure 46) may increase its applicability.
From the previously
described work on the electronic effect of a methyl group alpha
to the charge, it is not unreasonable to predict the formation
of the spiranone 70.
Alkylation followed by rearrangement could
lead to any of three products, all of which would be useful as a
terpene intermediate.
With these results in hand, we were anxious to attempt the
rearrangement of the isomeric spiroketone 74. Alkylation and
rearrangement of this compound promised to yield [5-4-0] bicyclo
product, 76^.29
Analysis shows that, if formed, it might prove
to be a novel precursor for a number of unusual sesquiterpenes.
To our consternation the attempted rearrangement of the
spiroalcohol 7j5 yielded only the elimination product T7 (Figure
47).
As an alternate method, stannic chloride was employed as a
catalyst to induce rearrangement.
was formed (Figure 48).
Again only one product, 77,
Although frustrating, the exclusive
elimination product is not an unreasonable result.
Typically
the conversion of a C q to a C7 ring system is energetically less
favorable than other ring expansions.61
We simultaneously became interested in exploring the
feasibility of the Baeyer-Villiger oxidation-^1 to enhance the
versatility of the spiranone products.
This reaction involves
conversion of ketones by peracids to esters (Figure 49).
The
salient aspect of this transformation is that the stereochemical
69
integrity about the original carbonyl is preserved.
Typically
the group which better stabilizes a carbocation will migrate.
Figure 46.
Possible use of j59 to prepare terpene intermediates.
Figure 48.
Attempted rearrangement of spiroalcohol 75.
Rx
R ^ O -tJ -C -F f
Cro . R-CO3H -- ► V
6
R
R7 x On-H
- R-O-C-R
II
0
Figure 49.
Mechanism for the Baeyer-Villiger rearrangement.
71
Spiroketone 74 was chosen as a model to test the migrating
ability of the spiro ring juncture (Figure 50).
The reaction
was carried out using m-chloroperbenzoic acid as the peracid.
Analysis by GC-MS showed two peaks: one corresponding to
starting material (60%); the other exhibiting a molecular ion
consistent with a lactone (40%).
The proton-NMR of the new
product possessed a resonance frequency of 2.21 ppm as its most
downfield signal, which is consistent with structure 7J3.
gated carbon-NMR experiment buttressed our analysis.
A
The
spectrum from this experiment yielded two singlets: one at 216
ppm (the carbonyl carbon); the other at 81 ppm which is
consistent with a quaternary center bonded to an oxygen atom.
Figure 50.
Baeyer-Villiger rearrangement of 74.
This simple experiment opens many new avenues to
investigate.
For example, hydrolysis of the lactone, 79,
followed by dehydration and ozonolysis would yield molecules
which could be reformed by c* - w coupling.
A number of these
large ring systems are precursors for macrolide antibiotics.
Figure 51 illustrates how the mixed diol 4 might prove to be an
entry into patulolide A, jSO,^4 and unsaturated lactone 81,
respective bacterial and fungal metabolites.
72
O
O
80
Figure 51.
Possible macrolide entry via spiroketone 6.
73
CHAPTER 3
EXPERIMENTAL
% - N M R and -^C-NMR spectra were obtained on a Bruker
250 MHz spectrophotometer equipped with an ASPECT 2000 data
processing system.
Deuterochloroform was used as a solvent
and as an internal standard.
Chemical shifts were reported in
parts per million relative to TMS.
GLC-MS analyses were
conducted on a VG MM16 mass spectrometer interfaced with a
Varian Model 3700 gas chromatograph equipped with a 30 m DB-I
capillary column.
Accurate mass measurements were obtained on a
VG 7070E mass spectrometer.
X-ray crystallographic data were
obtained by a Nicolet R3mE diffractometer and processed by
direct methods using Solve or Rant.
Specific rotation was
obtained on a Perkin Elmer 241MC polarimeter measured with the-D
line of sodium through a I dm cell.
Semiempirical quantum
mechanical calculations were performed with the program MNDO
residing on a Honeywell CP6 computer.
were computed using the program M M I.
uncorrected.
ketyl.
Force field calculations
All melting points are
Dry THF was prepared by distillation from benzyl
Dry benzene was prepared by distillation from LiAlH4-
The purity of (+) -3-methylcyclohexanone (Aldrich) .was 98%.
Unless otherwise specified, commonly needed reagents were used
as received.
74
General Preparation of Pinacols
Two general methods were employed to prepare the diols.
Method A:
Dry THF (20 mL), distilled from benzyl ketyl immediately
prior to use, was added to 1.8 g (6.4 mmol) HgCl2 and 5.8 g
(0.24 mol) Mg.
The mixture was stirred under Ar for 30
minutes, after which time the THF was withdrawn through a serum
cap. .The amalgam was washed three times with 20 mL portions of
dry THF, maintaining the mixture under Ar.
To the amalgam was
added 250 mL of dry THF and the mixture cooled by means of a
dry ice-isopropanol bath.
Titanium tetrachloride (13 mL) was
slowly added via syringe to the cooled solution, being careful
to keep the mixture from rising above -10°C.
To the resulting
yellow-green solution was added dropwise the ketone (or 3:1
ketone mixture) totaling 80 mmol in 10 mL of solution.
reaction was then cooled by an ice bath.
The
Once the gelatinous
suspension turned dark purple in color, the reaction was
allowed to stir for an additional two hours, after which time
the reaction was quenched with 25 mL of saturated potassium
carbonate, followed by 50 mL of diethyl ether.
The reaction
was filtered and the filtrate extracted with 3-50 mL aliquots
of ether.
The combined organics were washed with saturated
brine, dried over anhydrous magnesium sulfate and the solvents
stripped.
Purification of products was accomplished by flash
chromatography utilizing a silica gel column and petroleum
ether-diethyl ether as a solvent system.
75
Method B:
Dry benzene, freshly distilled from lithium aluminum
hydride, was added to 0.28 g HgCl2 (0.10 mmol) and 0.56 g (22
mmol) Al powder.
After refluxing the mixture for 30 minutes to
form the amalgam, 22 mmol ketone dissolved in 5 mL benzene were
added and the mixture allowed to reflux overnight.
The
reaction was quenched with 5 mL H2O, filtered through High-flo
Supercel and extracted with three 15 mL portions of ether.
The
combined organics were dried over anhydrous magnesium sulfate,
filtered, and the solvents evaporated.
Preparation of Isomeric (+)-3-MethyIeyeIohexyI-3-Methylcyclohexane- !,I1-Diols____________________________________________
(a)
[Al-Hg] Procedure:
(R) - (+) -3-Methylcyclohexanone (5.0 g, 45 mmol) was added
to a refluxing mixture containing Al (1.1 g, 47 mmol) and
HgCl2 (0.54 g, 2 mmol) in 25 mL of benzene.
The mixture was
refluxed overnight, and subsequently quenched with 5 mL of H2O.
After stirring for 10-15 minutes, the reaction mixture was
filtered, and the filtrate extracted with three portions of
ether.
The combined extracts were dried (MgSo4), filtered and
the solvent stripped to give the crude reaction product.
Column chromatography yielded three diols.
Analysis by GC-MS
showed the diols present in the following percentages:
2 (16.4%), 3 (52.7%), 34 (30.9%)
76
diequatoriaI 2
1H-NMR:
1.28-1.80 (18H, m); 0.88-0.90 (6H, d, J = 6 Hz)
13C-NMR:
76.39, 39.68, 34.66, 30.32, 27.97, 22.76, 21.66
MS:
226 (M+), 208 (M+ - 18), 190, 165, 139, 113 (base),
95, 69, 55
Analysis (HRMS):
calculated for C14H26O2 :
found:
[a ]D = -3.6°
M.P.
226.1931
226.1936
(ethanol)
= 77-78°
equatorial-axial 3
1H-NMR:
1.22-1.79 (18H, m); 1.09-1.12 (3H, d, J = 7 Hz);
0.85 — 0.88 (3H, d, J = 6 Hz)
13C-NMR:
76.83, 76.53, 39.86, 36.97, 34.60, 31.49, 31.25,
30.55, 27.98, 27.61, 22.78, 21.74, 21.22, 17.56
MS:
226 (M+), 208 (M+ - 18), 190, 165, 139, 113 (base),
95, 69, 55
Analysis (HRMS):
CalculatedforC14H26O2 :
found:
226.1931
226.1935
[a ]D = +1.25 (ethanol)
M.P.
= 70-71°
diaxial 34
1H-NMR:
13C-NMR:
1.41-182 (18H, m); 1.10-1.13 (6H, d, J = 7 Hz)
37.09,
31.38, 27.57, 21.18, 17.42
77
MS:
226 (M+), 208 (M+ - 18), 190, 165, 139, 113 (base),
95, 69, 55
Analysis (HRMS):
calculated for C14H26O2 :
found:
226.1932
226.1923
[ a ]D = +6.7 (ethanol)
M.P.
= 100-101°
(b) [Mg-Hg]/TiCl4 Procedure:
Magnesium (2.9 g, 0.12 Mol) and HgCl2 (0.88 g, 3.2 mmol)
were added to a flask containing dry THF and the contents
placed under an Ar atmosphere.
After cooling with a dry
ice/isopropanol bath, TiCl4 (6.6 mL, 60 mmol) was slowly added
via syringe.
After the addition had been completed and the
reaction subsided,
(R)-( + )-3-methylcyclohexanone (4.5 g, 40
mmol) in 10 mL THF was added.
The reaction mixture was allowed
to stir for 3 hours at 0°C, and worked up as in the general
procedure.
The reaction yielded 3.6 g of crude product.
Analysis by GC-MS showed only two diols present in the
ratio 82.7:17.3.
Isolation, characterization by NMR and co­
injection conclusively showed the diols to be 2 and 3^
respectively.
Preparation of Isomeric 4-MethyleyeIohexyI-4-Methylcyclohexane1,1'-Diols_________________________________
■ .(a)
[Al-Hg] Procedure:
4-MethyleyeIohexanone (4.5 g, 40 mmol) was treated in the
same way as previously described.
Workup afforded 3.8 g of
78
crude reaction product, which contained three diols in a ratio
of 11.9:43.9:44.2 percent.
Column chromatography yielded the
isomerically pure diols subsequently characterized as 39/ 38 and
37 respectively.
diequatorial 39
1H-NMR:
13C-NMR:
MS:
1.69-1.24 (18H, m) : 0.89-0.88 (6H, d, J = 4.6 Hz)
75.24, 32.33, 30.85, 30.41, 22.32
208 (M+ - 18), 190 (M+ - 36), 168, 151, 133, 123, 113
(base) 112, 95, 81, 67, 55
Analysis (HRMS) :
calculated for C14H2^ :
208.1826
found:
208.1834
M.P. = 93-94°
axial-equatorial 38
1H-MNR:
13C-NMR:
1.91-1.31 (18H, m) , 0.94-0.91 (6H, d, J = 7)
75.70, 75.39, 32.36, 30.80, 30.44, 22.32, 27.12, 26.21,
25.10, 16.71
MS:
208 (M+ - 18), 190 (M+ - 36), 169, 162, 151, 133, 123,
113 (base), 112, 105, 95, 81, 67, 55
Analysis (HRMS):
M.P. = 104-106°
calculated for C14H 24O:
208.1825
found:
208.1843
79
diaxial 37
1H-NMR:
13C-NMR:
MS:
1.91-1.31 (18H, m) , 0.94-0.91 (6H, d, J = 7)
75.84, 27.07, 26.19, 24.97, 16.70
208 (M+ - 18), 190 (M+ - 36), 169, 162, 151, 133, 123,
113 (base), 112, 105, 95, 81, 67, 55
Analysis (HRMS) :
calculated for
208.1826
found:
208.1836
M.P. = 119-120°
(b)
[Mg-Hg]/TiCl^ Procedure:
Coupling was accomplished using the general procedure with
the following reagents: 4-methylcyclohexanone (4.5 g, 40 mmol);
magnesium (2.9 g, 0.12 mol).; HgCl2 (0.88 g, 3.2 mmol); TiCl4
(6.6 mL, 60 mmol). The reaction was quenched with 10 mL of
saturated K2CC^, filtered, and the filtrate extracted with
diethyl ether.
The combined extracts were dried, filtered,
washed with brine and evaporated to yield 3.78 g of crude
product.
Analysis by GC-MS showed three diols present in the
ratio 63:33:4 percent.
Characterization by 1H-NMR and co­
injection on GC-MS showed the diols to be 39_r 38^ and 37
respectively.
Preparation of Isomeric Cyclohexyl-3-Methylcyclohexanone-l,I 1Diols_________________________________________________________
.(a)
[Al-Hg] Procedure:
To a refluxing mixture containing Al (1.1 g, 40 mmol) and
HgCl2 (0.54 g, 2.0 mmol) in benzene was added a solution of 2.9
80
g (30 mmol) cyclohexanone and 1.1 g (10 mmol)
hexanone in 5 mL benzene.
(+)-3-methy!cyclo­
After refluxing for 12 hours, the
mixture was quenched with 5 mL H^O, filtered, and the filtrate
extracted with three portions of diethyl ether.
The combined
extracts yielded 3.78 g of crude reaction product.
Separation
by flash chromatography yielded, along with the expected '
homogeneously coupled products, two mixed diols 41 and _42.
Relative percentages of these two diols based on GC-MS analysis
were 41:59 percent.
equatorial 41
1H-NMR:
13C-NMR:
1.77-1.32 (19H, m); 0.88-0.86 (3H, d, J = 6 Hz)
76.55, 75.58, 39.59, 34.65, 30.79, 30.71, 30.30,
25.84, 22.71, 21.75, 21.66
MS:
176 (M+ - 18), 167, 151, 137, 123, 113 (base), 112,
99, 98, 95, 81, 69, 67, 55, 42, 41
Analysis (HRMS) :
calculated for C13H2z^O2:
found:
212.1766
212.1770
[a]D = -2.2 (ethanol)
M.P. = 90-91°
axial 42
1H-NMR:
13C-NMR:
1.95-1.33 (19H, m); 1.11-1.08 (3H, d, J = 7)
76.54, 76.00, 37.04, 31.49, 31.15, 31.02, 30.91,
27.59, 25.78, 21.81, 21.76, 21.20, 17.62
81
MS:
194 (M+ - 18) , 176, 167, 151, 128, 123, 113 (base),
112, 99, 98, 95, 81, 69, 67, 55, 43, 41
Analysis (HRMS) :
calculated for C13H2^ 2 :
found:
212.1767
212.1771
M.P. = 86-89°
(b)
[Mg-Hg]/TiCl^ Procedure:
Following the general procedure, the following quantities
of reagents were utilized: 2.9 g (30 mmol) cyclohexanone? 1.1 g
(10 mmol) (+)-3-methylcyclohexanone;
6.6 mL (60 mmol) titanium
tetrachloride; 2.9 g (0.12 mol); 0.88 g (3.2 mmol) HgCl2Workup afforded 3.6 g crude product.
Analysis by capillary GC-
MS confirmed the presence of two diols, 4JL and 42 in a ratio of
91:9.
Preparation of Spiro-[5,5]-6-Oxadecan-7-one, 78
Spiro-[4,5]— decan-2-one (470 mg, 3.1 mmol) was dissolved in .
30 mL CH2C12 at 0°c.
To this was added 0.26 g (3.1 mmol) NaHCOg
and the system purged with argon.
M-chloroperbenzoic acid (0.59
g, 3.4 mmol) dissolved in CH2Cl2 was added dropwise via syringe
to the stirred solution.
The mixture was allowed to stir
overnight at room temperature.
The reaction mixture was then
quenched with Na2S2Og and washed with 5% NaHCOg.
The organic
layer was dried, filtered and the solvent evaporated to yield
460 mg crude product.
Analysis by GC-MS showed only two peaks:
unreacted starting material (41%) and the spirolactone (59%).
82
spirolactone 78
1H-NMR:
2.49-2.43 (2H, t, J = 7); 1.84-1.65 (8H, m); 1.58-1.39
(6H, m)
13C-NMR:
171.24 (s)/ 82.96 (s) , 37.43 (t) , 32.55 (t) ,
29.55 (t), 25.40 (t), 21.71 (t), 16.13 (t)
MS:
168 (M+), 125, 112, 97, 83, 81, 67, 55
Analysis (HRMS) : ■ calculated for C1QH-LgO2 ^
168.1154
found:
168.1152
Preparation of Isomeric CycIohexy1-4-Methylcyclohexane-II 1-Didls_______________________________
(a)
[Al-Hg] Procedure:
Cyclohexanone ((2.9 g, 30 mmol) and 4-methyIcyclohexanone
(1.12 g, 10 mmol) dissolved in 5 mL dry benzene were introduced,
via syringe, to a refluxing mixture of Al (1.07 g, 40 mmol) and
HgCl2 (0.54 g, 2.0 mmol) in 30 mL dry benzene.
Reaction and
workup followed as described in the general procedure.
Flash
chromatography yielded two mixed diols 82^ and _83 along with the
corresponding homogeneous diols.
Analysis of GC-MS showed their
relative percentages as 41:59.
equatorial 82
1H-NMR:
13C-NMR:
1.68-1.25 (19H, m), 0.90-0.88 (3H, d, J = 5.1)
76.82, 76.72, 32.35, 30.83, 30.73, 30.42, 25.89,
22.32, 21.80
83
MS:
194 (M+ - 18), 176, 151, 137, 113 (base), 112, 99, 98,
95, 81, 67, 55, 43, 41
Analysis (HRMS):
calculated for C13h 220:
194.1624
found:
194.1647
M.P. = 88-90°
axial 83
1H-NMR:
13C-NMR:
MS:
1.79-1.10 (19H, m); 0.93-0.90 (3H, d, J = 7.1)
75.74, 75.65, 32.33, 30.40, 27.08, 26.17, 24.95, 16.69
194 (M+ - 18), 176, 168, 151, 137, 113 (base), 112,
99, 98, 95, 81, 69, 67, 55, 43, 41
Analysis (HRMS):
calculated for Gi3H2^C=
194.1626
found:
194.1638
M.P. = 96-99°
Preparation of Cyclopentylcyclopentane-I,I 1-Diol (48)
By the general titanium preparation of pinacols, 4j8 was
prepared using the following reagents: eyelopentanone (6.7 g, 80
mmol); magnesium (5.67 g, 0.24 mol); mercuric chloride (1.76 g,
6.4 mmol); titanium tetrachloride (13.2 mL, 120 mmol).
workup, 6.2 g of crude product was obtained.
Analysis by GC-MS
showed only one product which was confirmed as
with previously prepared authentic samples.
1H-NMR:
13C-NMR:
1.98-1.56 (16H, m)
80.07, 36.41, 24.83
After
by comparison
84
MS:
152 (M+ - 18) , 135, 123, 111, 96, 95, 85 (base) , 84,
67, 55, 41
Analysis (HRMS):
calculated for c i o h 18°2:
found:
170.1313
170.1310
Preparation of Spiro-[4,5]-Decan-6-one, 49
To 100 mL of concentrated sulfuric acid stirred at 0° were
added 2 grams (12 mmol) of 48.
The mixture was stirred at 0°
for two hours, followed by quenching over ice.
The organics
were extracted with three portions of diethyl ether, washed with
saturated sodium bicarbonate, followed by brine and dried with
magnesium sulfate.
crude (77%).
Evaporation of the solvent yielded 1.55 g of
Analysis by GC-MS showed only one product
identified as 49.
1H-NMR:
2.39-2.34 (2H, t, J - 6.5); 2.04-1.99 (2H, m) ; 1.791.33 (12H, m)
13C-NMR:
MS:
56.82, 39.89, 39.36, 35.41, 27.27, 25.16, 22.79
152 (M+), 134, 124, 123, 111, 108, 95, 93, 91, 82, 81,
79, 77, 67 (base), 55, 53, 41
Analysis (HRMS):
calculated for Cio^l60:
152.1199
Found:
152.1200
Preparation of Spiro-[4,5]-6-Methyldecan-6-ol, J56
To 100 mL of dry THF, at 0° and under an argon atmosphere,
were added 13 mmol of 1.4 M methyl lithium.
While still at 0°,
85
1.4 g (10 mmol) of _49 were slowly added via syringe through the
serum cap.
The reaction was allowed to come to room temperature
and stirred overnight.
The reaction was guenched with 5 mL
water, and the organics extracted with ether.
The dried
(magnesium sulfate) ether fraction yielded 1.14 grams of crude
product, which upon analysis by GC-MS showed only one product
identified as 66.
1H-NMR:
13C-NMR:
1.82-1.22 (16H, m); 1.13 (3H, s)
74.05, 50.80, 38.16, 35.68, 34.40, 33.02, 26.17,
26.02, 24.39, 22.64, 22.12
MS:
168 (M+), 153, 150, 135, 121, 108, 93, 71 (base), 67,
58, 55, 43, 41
Analysis (HRMS):
calculated for C11H 2QO:
168.1518
found:
168.1516
Rearrangement of Spiro- [4,5] -6-Methyldecan-6-^ol, ^6
To 15 mL of dry benzene were added 150 mg spiranol j[6 and a
trace of tosic acid.
The solution was allowed to stir at room
temperature for 14 hours.
Analysis by GC-MS revealed low
conversion, so the reaction was continued under reflux for an
additional 6 hours.
The reaction was then quenched with sodium
bicarbonate solution and extracted with ether.
The organic
fraction yielded 140 mg crude product which contained two
products, 67 and 68 in a ratio of 67:33.
86
9 - m e t h y l - '^^-octalin
1H-NMR:
13C-NMR:
5.27 (1H, brs; 2.16-1.12 (14H, m); 1.04 (3H, s)
143.87, 119.28, 42.23, 40.11, 34.81, 32.69, 28.58,
25.98, 24.37, 22.48, 19.08
MS:
150 (M+), 135 (base), 121, 109, 108, 107, 93, 91, 82,
79, 77, 67, 55, 41
Analysis (HRMS):
calculated for C11Hlg:
found:
150.1408
150.1407
spiro-[4,5]-6-methyl-6-decene, 68
1H-NMR:
5.35 (1H, br s); 192-1.89 (2H, br s); 1.61-1.60
(3H, d, J = 3); 1.68-1.28 (14H, m)
MS:
150 (M+), 135, 121, 109, 108, 107, 93 (base), 91, 79,
77, 68, 67, 55, 41
Analysis (HRMS):
calculated for C11Hlg:
found:
150.1409
150.1410
Preparation of Spiro-[4,5]-I-Methyldecan-1-ol, 75,
To 100 mL dry THF, at 0° and under an argon atmosphere,
were added 13 ,mmol of 1.4 M methyl lithium.
While still at 0°,
1.50 g of spiranone _74 were slowly added via syringe through the
serum cap.
The reaction was allowed to come to room temperature
and stirred overnight.
The reaction was quenched with 5 mL
water, and the organics extracted with ether.
The dried
I
87
(magnesium sulfate) ether fraction yielded 1.34 g crude product,
which yielded a single product identified as 75.
spiro-[4,5]-1-methyldecan-l-ol, 75
13C-NMR:
76.51, 48.55, 39.57, 32.98, 32.66, 31.54, 27.74,
24.82, 24.27, 23.50, 20.47
MS:
168 (M+), 153, 150, 135, 125, 120, 108 (base), 107,
94, 93, 80, 78, 71, 67, 58, 55, 43, 4.1 ■
Analysis (HRMS):
calculated for C11H2OOi=
168.1511
found:
168.1512
Rearrangement of Spiro-[4,5]-1-Methyldecan-l-ol, 75
Method A:
To 20 mL of dry benzene were added 150 mg spiranol 18 and a
trace of tosic acid.
then quenched.
The solution was refluxed for 12 hours and
Extraction with ether yielded 1.44 g crude which
upon analysis showed a single product, 77.
spiro- [4,5] -1-methyl-A1-decene, 77
1H-NMR:
5.24 (1H, br s); 2.15-2.13 (2H, m) ; 1.75-1.17
(12H, m), 1.58-1.57 (3H, d, J = 1.6)
MS:
150 (M+), 135, 121, 107 (base), 94, 93, 91, 81, 80,
79, 77, 55, 53, 41
Analysis (HRMS):
calculated for C11H1O=
150.1409
found:
150.1393
I,
88
Method B :
To 20 mL of methylene chloride and a trace of stannic
chloride at room temperature and under an argon atmosphere, were
added 140 mg of the spiranol 75..
The reaction was stirred
overnight, quenched with water and extracted with ether.
The
combined organic fractions were dried with anhydrous magnesium
sulfate, and the solvent stripped leaving 130 mg crude product.
Analysis showed one product, identified as 77.
Product Ratio Study on the Coupling of R - (+)-3Methylcyclohexanone, I
Reactions were carried out in triplicate in accordance
with the general coupling procedures.
used for Method A were as follows:
Quantities of reagents
1.25 g (11 mmol) R - (+)-3-
methyIcyclohexanone; 0.14 (0.05 mmol) mercuric chloride; 0.28 g
aluminum powder (11 mmol).
After workup the reactions yielded
1.1 g, 1.0 g and 1.2 g crude product respectively which were
analyzed by GC-MS to yield integrated peak areas of the
background subtracted spectra.
Method B was carried out with the following reagent
quantities:
0.22 (0.8 mmol) mercuric chloride; 0.72 g (30
mmol) magnesium powder; 1.6 mL titanium tetrachloride; 1.1 g
(10 mmol) R - (+)-3-methylcyclohexanone.
Workup afforded 1.1 g,
0.96 g and 1.0 g crude product which again were analyzed (in
triplicate) by GC-MS to obtain product ratios based on
integrated peak areas.
89
Preparation of CyclopentyIcyclohexane-I,I1-Diol, 4
Mixed coupling of eyelopentanone and cyclohexanone was
carried out by the general procedure utilizing low valent
titanium.
Quantities of reagents employed were: cyclohexanone
(5.8 g, 60 mmol); eyelopentanone (1.68 g, 20 mmol); mercuric
chloride (1.76 g, 6.4 mmol); titanium tetrachloride (13.2 mL,
120 mmol); magnesium (5.76 g, 0.24 mol).
g crude product.
chromatography.
The mixed diol _4 was purified by flash
Coinjection with authentic sample yielded only
one peak on GC-MS.
13C-NMR:
MS:
Workup afforded 7.10
Pertinent spectral data follow.
87.71, 74.98, 34.81, 25.78, 24.29, 21.65
166 (M+ - 18), 148, 137, 123, 111, 99 (base), 98, 85,
84, 81, 67, 55, 41
Preparation of Isomeric Spiroundecanones 5_ and 6^
To 20 mL of concentrated sulfuric acid stirred at 0° were
added 230 mg (1.74 mmol) eyelopentyIcyclohexane-I ,I '-diol, _4.
The mixture was stirred at 0° for 2 hours, then quenched by
slowly dropping onto ice.
The organics were extracted with
three portions of diethyl ether and washed with bicarbonate
followed by brine.
The combined organics were dried with
anhydrous magnesium sulfate, filtered and the solvent removed by
rotary-evaporation to yield 230 mg of crude product.
Samples of
the purified spiranones were prepared by GLC (20 ft, 1/4 in
0V17) and characterized by GC-MS.
90
spiro- [4-6] -undecan^6-one, _5
MS:
166 (M+) , 148, 135, 125, 109, 95, 80, 67 (base), 55, 4.1
Analysis (HRMS):
calculated for C 11HlgO:
166.1350
found:
166.1354
spiro- [5-5] -undecan-7-one, 6^
MS:
166 (M + ) , 151, 148, 137, 133, 124, 122, 111 (base), 109,
97, 95, 81, 67, 55, 53, 41
Analysis (HRMS):
calculated for C11HlgO:
166.1355
found:
166.1356
Attempted Photopinacolization of R- (+)-3-Methylcyc Iohexanone, JL
A solution of 150 mL dry isopropanol (freshly distilled
from lime) and 3 g (27 mmol) of R- (+)-3-methylcyclohexanone
was irradiated with a 500 watt Hanovia lamp for 64 hours.
was taken to maintain the temperature at 55-60°.
Care
At the end of
the reaction time the mixture was analyzed by GC-MS.
Only two
compounds were found: 14% starting material and 86% 3-methylcyclohexanol,
44.^
Solvent Effect Test on Aluminum Coupling of R-(+)-3Methylcyclohexanone, _1
To a refluxing mixture containing 0.56 g (24 mmol) Al and
0.27 g (1.0 mmol) HgCl2 in dry THE were added 2.5 g (23 mmol)
(R)-(+)-3-methylcyclohexanone.
The mixture was refluxed
91
overnight, after which time it was quenched with 3 mL of water.
The reaction mixture was then filtered and the filtrate
extracted with diethyl ether.
The organics were dried over
anhydrous magnesium sulfate, filtered and the solvent
evaporated.
I,
2 and 3,
Analysis by capillary GC-MS revealed three, dioIs,,
in a percent ratio of 17.4:53.5:29.1.
Charge Exchange Mass Spectral Analyses of 1,1'-Bicycloalkyl
Diols______________
Electron impact (70 eV) mass spectra were obtained on a
VG7070 mass spectrometer with a source temperature of 100°
and ion source pressure 0.2 torr.
Samples were introduced from
the interfaced Varian 3700 capillary chromatograph.
Reagent gas
mixtures were prepared by pressure and oscilloscope height
measurements.
The charge exchange reagent ions utilized were
[CS2]+ (10.2 eV) , [N2O]+ (12.9 eV) and [Ar]+ (15.8 eV) .
The
method of production of these ions followed the procedures of
Harrison et al.16,17
All spectra obtained were background
subtracted.
Reductive Coupling of Racemic 3-Methyl-Cyclohexanone
Following the general procedure of the aluminum mediated
reductive coupling, the following quantities of reagents were
used: aluminum (0.56 g, 22 mmol); mercuric chloride (0.28 g,
0.10 mmol); 3-methylcyclohexanone (2.5 g, 22 mmol).
The
reaction mixture was refluxed overnight and subsequently
quenched with 5 mL of water.
After filtration and extraction.
92
2-1 g of crude product were obtained.
Analysis by GC-MS
revealed three diols, which when co-injected with authentic
samples, corresponded to 2^, _3 and 3jl.
No meso products could be
isolated.
Semiemperical (MNDO) Studies on Model Carbonyl-Aluminum
Complexes______________
The geometry and bond lengths involving the formaldehyde
radical anion complexed with aluminum (net charge = 0) were
calculated using the semiemperical quantum mechanical method
MNDO.36
Standard parameters were employed for bond lengths and
bond angles.
models.
Torsional angles were derived from Dreiding
All parameters remained fixed unless marked by an
asterisk (*).
Only final non-hydrogen values are listed here.
Final cartesian coordinates for all atoms are listed in the
Appendix.
Numbering of the atoms corresponds to the structure
presented below.
Table 15.
MNDO Summary of 45.
H
45
Heat of Formation: -32.94450 I cal/mol
Atom #
1
2
3
4
5
Net Atomic Charge
6.3892
3.9953
0.9535
0.9535
2.7085
93
Table 16.
Atom
Number
(I)
I
2
3
4
5
6
MNDO parameters of 45.
Atomic
Number
Bond Length
(Angstroms)
J :I
99
8
6
I
I
13
—
—
Bond Angle
(Degrees)
K :J: I
—
1.2500
1.2993*
1.0954*
1.0954*
1.6056*
—
W- _
—
—
—
90.000
120.661*
120.660*
174.567*
Twist Angle
(Degrees)
L:K:J:I
J
K
I
2
3
3
2
I
2
2
3
—
—
—
90.000
-90,000
90.138*
L
—
I
I
4
Comparison of Radical Anion and Dianion Geometries of the 3Pentanone-Al Complex Model, 46.
a)
Analysis of 46^ was carried out utilizing MNDO.
The net
charge of the model radical anion aluminum system was assumed to
be zero.
Structural parameters are standard or previously
optimized unless marked with an asterisk.
Pertinent final
parameters are presented below while all final cartesian
coordinates are listed in the Appendix.
Table 17.
MNDO Summary of 46.
J80
/ . 0
111/1";
"
120
46
Heat of formation: -32.94450 Kcal/mole
Atom #
3
4
7
Net Electron Density
4.0404
6.3606
2.7023
94
Table 18.
Atom
Number
(I)
MNDO parameters of 46.
Atomic
Number
1
2
3
4
5
6
7
Bond Length
(Angstroms)
J :I
6
6
6
8
6
6
13
b)
Bond Angle
(Degrees)
K: J: I
—
1.5400
1.5400
1.2800
1.5400
1.5400
1.6050
Twist Angle
(Degrees)
L:K:J:I
J
—
125.713*
122.536*
114.100
114.100
179.273*
—
121.981*
-60.000
60.000
15.812*
K
L
-
-
I
—
I
2
3
2
3
5
4
2
3
3
I
I
2
2
The basic structure and parameters of 46^ were employed
to examine the geometry of its dianion (net charge = -I).
As
before, pertinent final data are presented below with final
coordinates listed in the Appendix.
Table 19.
MNDO summary and parameters of _46 anion.
Heat of formation: -34.08047 Kcal/mole
Atom
Number
(I)
I
2
3
4
5
6
7
Atomic
Number
6
6
6
8
6
6
13
Atom #
Net Electron Density
3
4
7
4.5020
6.2303
3.1777
■
Bond Length
(Angstroms)
J :I
1.5400
1.5400
1.2800
1.5400
1.5400
1.6050
Bond Angle
(Degrees)
K: J: I
—
126.104*
122.569*.
114.100
114.100
180.122*
Twist Angle
(Degrees)
L:K:J:I
J
I
2
122.159 * 3
-60.000
3
60.000
5
-12.399* 4
—
—
Analysis of Carbocation _56 by MNDO
Bond lengths and angles of the model system 56 were
assigned standard values as described previously.
The bond
K L
-
I
2
2
3
3
-
I
I
2
2
95
between the carbon bearing the hydroxyl group and the carbon
bearing the charge was optimized.
Final pertinent parameters
are listed below while all cartesian coordinates are listed in
the appendix.
Table 20.
MNDO summary and parameters of 56.
H3C-- <
/CH3
H3C OH
CH3
56
Heat of formation: 200.16798 Kcal/mol
Atom
Number
(I)
Atomic
Number
I
2
3
4
5
6
7
8
6
6
6
6
6
6
6
8
Bond Length
(Angstroms)
J :I
Bond Angle
(Degrees)
K: J: I
1.5400
1.6441*
1.5400
1.5400
1.5400
1.5400
1.3900
120.000
114.100
114.100 .
120.000
• 114.100
114.00
—
Twist Angle
(Degrees)
L:K:J:I
J
—
—
120.000
-120.000
70.000
10.000
.000
K
I
2
3
3
2
6
3
L
—
I
2
2
3
2
2
—
-
I
I
5
3
I
Analysis of Carbocation _57 by MNDO
Standard bond lengths and angles were employed for initial
parameters of the model system 5^7 to facilitate calculations by
MNDO.
57.
Torsional angles were calculated from a Dreiding model of
The bond length between the carbon bearing the hydroxyl
group and the carbon bearing the charge was optimized as in
model 56^ for consistency.
follow.
Final carbon skeleton parameters
The cartesian coordinates of the complete system are
tabulated in the Appendix.
96
Table 21.
MNDO summary and parameters of 57.
H3C
3
H3Cy HO CH 3
Heat of formation: 193.41493 Kcal/mole
Atom
Number
(I)
Atomic
Number
I
2
3
4
5
6
7
8
6
6
6
6
6
6
6
8
Bond Length
(Angstroms)
J :I
1.5400
1.5909*
1.5400
1.5400
1.5400
1.5400
1.3900
Bond Angle
(Degrees)
K: J: I
—
—
—
120.000
114.100
114.100
120.000
114.100
114.100
Twist Angle
(Degrees)
L:K:J:I
J K L
—
-----
—
—
—
25.000
-90.000
70.000
10.000 •
160.000
I
2
3
3
2
6
3
—
—
I
2
2
3
2
2
—
I
I
5
3
I
Preparation of Isomeric Spiro-[5,6]-Methyldocecan-7-ones
To 20 mL of concentrated sulfuric acid was slowly added 200
mg of eye Iohexy I- 3-m ethy Ieye Iohexane-1,11-dio 1, 41, at 0°C.
The
mixture was stirred for two hours at this temperature and poured
over ice.
The organics were extracted with 3 portions of ether,
washed with saturated sodium bicarbonate and brine.
The
combined organic layer was dried over anhydrous magnesium
sulfate.
Evaporation of the ether yielded 160 mg of crude
product.
Analysis by GC-MS revealed four peaks corresponding to
ketones 84% in a relative percent ratio of 7:12:38:43 and an
alkene fraction (16%).
97
spiroketone A
MS:
195 (M+ + I), 1 9 4 (M+), 176, 161, 151, 138, 125 (base),
95, 812, 67, 55, 41
Analysis (HRMS):
calculated for C13H22O:
194.1671
found:
194.1666
spiroketone B
1H-NMR:
2.47-2.42 (2H, m) ; 2.05-1.96 (2H, m); 1.67-1.16
(15H, m); 0.83-0.81 (3H, d, J = 5.9 Hz)
MS:
195 (M+ + I), 194 (M+), 176, 172, 161, 151, 148, 139,
123, 95, 94, 81 (base), 67, 55, 41
Analysis (HRMS):
calculated for C13H22O:
194.1671
found:
194.1658
spiroketone C, 52^
1H-NMR:
2.63-2.54 (IH m) ; 2.18-2.12 (m, 1H); 1.91-1.09
(19H, m) ; 0.98-0.95 (3H,.d, J = 5 Hz)
MS:
195 (M+ + I), 194 (M + ), 176, 161, 151, 133, 126, 121,
112, 109, 95, 94, 93, 81 (base), 67, 55, 41
Analysis (HRMS):
calculated for C13H22O:
194.1671
found:
194.1678
spiroketone D
1H-NMR:
2.51-2.48 (2H, m); 1.76-1.13 (19H, m); 0.86-0.84
(3H, d, J =
6.4)
98
MS:
195 (M+ + I), 194 (M + ), 176, 161, 151, 138, 125, 123,
121, 108, 95 (base), 81, 67, 55, 41
Analysis (HRMS):
calculated for C^gH220:
194.1671
found:
194.1678
X-ray Diffractometry on Diol 34
Suitable white plates were grown from hexane by slow
evaporation.
A crystal approximately 0.8 x 0.4 x 0.04 mm was
mounted on a glass fiber and the cell constants were obtained.
The structure was solved by direct methods and refined by full
matrix least squares.
Final atomic coordinates, bond lengths
and angles and temperature factors are tabulated in the
Appendix.
Table 22.
X-ray data for 34.
a =
10.453(3)A
b =
10.616(3)A
C =
11.057(3)A
=
97.47(3)°
=
104.23(3)°
=
118.77(3)°
V =
Z = 3
Dc = 1.131 g/cm3
X = 0.71069A
= 0.68 cm"--*T = 24°C
F(OOO) = 377.96
997.6(10)A3
R = 0.0640
X-ray Diffractometry on Diol 37
White platelets crystalized from hexane by slow evaporation
were used for analysis.
A crystal approximately 0.8 x 0.4 x
99
0.04 mm was mounted on a glass fiber and the cell constants were
obtained.
The structure was solved by direct methods and
refined by full matrix least squares.
Final atomic coordinates,
bond lengths and angles and temperature factors are tabulated in
the Appendix.
Table 23.
X-ray data for 6.
a =
10.352(2)A
b =
19.010(6)A
C =
11.114 (3)A
=
90.000°
=
109.01(2)°
=
90.000°
V =
Z = 6
Dc = 1.089
X = 0.71069A
= 0.66 cm"I
T = 24°C
F(OOO) = 755.92
R = 0.0638
2067.9(8)A3
Lanthanide Induced Shift Study on Spiroketone D
A solution of 1.6 mg (0.0075 mMol) of spiroketone D in
CDClg was placed in an NMR tube.
Eu(fod) g. was added in
increments of approximately 0.1 equivalents until one equivalent
was added.
After each addition, the proton-NMR spectrum was
obtained and decoupling experiments were performed.
The
chemical shifts and changes in chemical shift were recorded for
each [Eu(fod)3]/D ratio.
Linear least squares slopes and
correlation coefficients were obtained by a calculator program
for each discernable shift.
computer program PDIGM.
This data was utilized with the
100
MNDO Analysis of Carbocations 5J3 and 59
Standard bond lengths and angles were input to facilitate
optimization.
models.
Torsional angles were calculated from Dreiding
The bond between the carbocation center and the carbon
bearing the hydroxyl group was used as the optimization
parameter.
Final values associated with- the corresponding
carbon skeletons are reproduced below, while the cartesian
coordinates are listed in the Appendix.
Table 24.
MNDO summary and parameters of 58
58
Heat of Formation:
Atom
Number
(I)
I
2
3
4
5
6
7
8
Atomic
Number
6
6
6
6
' 6
6
6
8
Bond Length
(Angstroms)
J :I
1.5161*
1.5400
1.5400
1.5400
1.5400
1.5400
1.3900
163.38693 Kcal/mol
Bond Angle
(Degrees)
K: J: I
—
114.100
114.100
114.100
120.000
114.100
114.100
Twist Angle
(Degrees)
L:K:J:I
J K L
—
—
—
—
180.000
180.000
180.000
180.000
60.000
I
2
3
4
I
6
2
-
-
I
2
3
2
I
I
I
2
3
2
6
101
Table 25.
MNDO summary and parameters of 59.
H HO H
59
Heat ■of Formation:
Atom
Number
(I)
Atomic
Number
I
2
3
4
5
6
7
8
6
6
6
6
6
6
6
8
Bond Length
(Angstroms)
J: I
1.5165*
1.5400
1.5400
1.5400
1.5400
1.5400
1.3900
V
163.09367 Kcal/mol
Bond Angle
(Degrees)
K: J: I
—
120.100
114.100
114.100
114.000
114.100
114.100
Twist Angle
(Degrees)
L:K:J:I
J K L
—
----—
180.000
180.000
180.000
180.000
60.000
I
2
3
4
I
6
I
-
-
I
2
3
2
I
2
—
I
2
3
2
3
102
CHAPTER 4
SUMMARY
This work has clearly demonstrated—that -the-method o f --- —
pinacol coupling influences the stereochemistry of the products
formed.
Of the systems examined, coupling by aluminum amalgam
consistently yielded predominately axial orientation of the
alkyl substituents while coupling by low^valent titanium
demonstrated preference for equatorial orientation.
Separation
of the closely related isomeric mixtures was achieved with a
simple flash chromatography system, permitting preparative
purification for further work.
While both of the developments
may help to bring this methodology into synthetic focus,
considerable work needs yet to be done to capitalize on these
coupling techniques for natural product synthesis.
In
particular, a clear understanding of the mechanistic differences
of the aluminum and titanium coupling reactions needs to be
addressed.
While formation of radical anions on a titanium
surface is consistent with the products observed by this
reaction, the results of the aluminum process are poorly
understood.
Isolation and characterization of the metal
complexes would most likely prove helpful in analyzing these
mechanisms.
103
There appears to be a pronounced alkyl group effect on the
course of pinacol rearrangement of bicycloalkyl diols, since the
product ratio for the rearrangement of
statistical.
was far from
Characterization of d2 as one of the two major
products buttressed the MNDO model study finding which indicated
that electronic effects from the alkyl group would play a minor
role in influencing product formation.
Unambiguous
characterization and rapid separation of the remaining products
need to be accomplished so that the specific nature of the
alkyl influence might be understood.
At the same time, a study
involving the influence of acid type on the distribution of
products may help fine-tune the manipulation of product ratios.
The successful secondary rearrangements carried out on the
spiroketones will hopefully extend this chemistry into other
areas of interest.
This, coupled with the stereo-consequences
of the coupling reactions and the alkyl group influence,
exhibited in the course of the pinacol rearrangement, should
lay the groundwork for product control.
If achieved, the
synthetic utility of pinacol chemistry as a whole would be
greatly enhanced.
104
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105
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----
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—
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-----------------—
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---
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C.C. Hinkley, J l Am. Chem. Soc., 91, 5160 (1969).
52.
M.R. Wilcott III, R.E. Davis and R.W. Holder, J. Org.
Chem., 40, 1952 (1975).
108
53.
Y. Kim, Ph.D. Thesis, Montana State University (1982).
54.
A.P. Krapcho and M. Benson, J. Am. Chem. Soc., 84, 1036,
1962? A.P. Krapcho, J.E. McCullough, K.V. Nahabenadian, J.
Org. Chem., 30, 139, (1965); and A.P. Krapcho and J.E.
McCullough,
Org. Chem., 32, 2453 (1967).
55.
T.K. Devon and A.I. Scott, Handbook of Naturally Occurring
Compounds, Vol. II, Academic Press, New York, 19721
56.
M.E. Jung, Tetrahedron, 32, 3 (1976).
57.
C.H. Heathcock and Y . Amano, Can. J. Chem., 50, 340 (1972).
58.
J.E. McMurry, L.C. Blaszczak, J. Org. Chem., 39, 2217
(1974).
—
59.
J.A. Marshall, H. Fauble and T.M. War n e , Chem. Commun., 753
(1967) .
-------------
60.
A. Fadel and J. Salaun, Tetrahedron, 41, 1267 (1985).
61.
B.P. Mundy, Concepts of Organic Synthesis, Marcel Dekker,
NY, 1979, p. 123.
62.
L.H. Zalkow, F.X. Markley and Carl Djerassi, J. Am. Chem.
Soc., 82, 6354 (1960).
63.
W.A. Ayer and W.I. Taylor, J. Chem. Soc., 3027 (1955).
64.
O.J. Sekiguchi, H. Kuroda, Y. Yamada, H. Okada, Tetrahedron
Lett., 2341, 1985.
65.
R.F. Vesonder, F.H. Stodola, L.J. Wickerham, J.J. Ellis and
W.K. Rohwedder, Can. J. Chem., 49, 2029 (1971).
109
APPENDIX
HO
STRUCTURAL COORDINATES
MNDO Coordinates
46
ATOM
NUMBER
I
I
2
3
4
5
6
7
8._
9
10
11
J 2
13
14
15
1A
I 7
C OOR D I N A T E S
„0 0 0 0 0
1,54000
2.43893
3.30484
2.23529
.80503
4.38923
-.30145
-.30145
-.30145
1.75910
... 1 . 7 7 3 0 9
2.90414
2.43793
.91854
.377(54
.27898
.00000
.00000
1.25041
I .47574
2.17128
2.72553
1 .73886
.5367?
.53622
- I .07244
-.52878
- .53884
3.04606
I .53829
3.82785
7-73661
2.43762
’
.
o
■
OOOOO
I.
I .
- 2 . 06897
92876
«*»^ 9 2 8 7 6
S 00000
— o9 5 5 7 1
.94674
T I 04894
2.
I .
7. 25954
41 5 5 7
47
ATOM
NUMBER
I
I
3
4
5
6
7
8
9
o
” 1'
I I
I 2
13
14
I 5
I 6
.17
_
y
X
.00000
...." ' 1 . 5 4 0 0 0
2.44745
3.31737
2.25010
...... . 8 2 3 6 6
4.40956
-.30145
-.30145
-.30145
.....
1.75788
I .76703
2.92736
.... .... 2 . 4 4 5 2 0
.94468
.3931 3
.29552 _
.
, C O O R D I N A T E S ____
.00000
I
.00000'
“ '.OOOOO
I
=00000
:
-.91321
;
1.21743
i........... ' 1 . 3 5 4 3 8
-2.05637
I
'
.92876
-.92876
.00000
-.95419
.94830
'
1.05054
:
2.11155
....
1.46798
2.25982
.41578
;
’
...
.ooooo ;
-----
1.24424
1.46261
2.16648
2.73049
1.73890
.53622
C *2 Z p O
....... - 1 . 0 7 2 4 4
-.53201
-.53868
3.03508
’ - .... 1 . 5 3 1 2 8
3.83205
2.24487
2.44576
Z
I
...
Ill
56
• ATOM
NUMBER
I
COORDINATES
X
I
.00000
1.54000
2.36205
3.28518
3.28518
2.29245
3.75282
1,54700
-.30145
-.30145
-.30145
2.27605
1.63001
4.23585
3.69828
4,15289
2.60750
3.90085
3.88929
3.88929
2.60750
3,90085
.93138
2
3
4
5
6
7
8
9
I O
I I
I 2
I 3
14
15
I 6
I 7
I 8
19
20
21
22
23
57
Y
.00000
.00000
1.42384
1.61698
1.61698
-1.32355
-1.14534
2.54979
—. 3 6 6 8 0
1,05615
-.68935
-1.85492
- 1o 9 3 6 6 6
-.51117
-.73279
-2.17559
1.76375
2.51688
.68372
.68372
1,76375
2.51688
2.53408
Z
.
.00000
.00000
.00000
-1.21743
I .21743
-.23159
-.68676
.00000
I ,00776
-.18623
-.82154
.74738
-.88447
,09139
- I . 7201 1
-.82645
2.08932
.98914
I .28874
-1.28874
-2.08932
-^98914
-.71812
•
ATOM
NUMBER
I
X
I
2
3
4
5
6
7
8
9
I O
I I
I 2
13
I 4
I 5
I 6
17
I 8
I 9
20
21
22
23
.00000
1,54000
2.33547
1.54652
2.64989
2,24034
3.76140
3.65184
-.30145
-.30145
- . 3 0 1 45
I .77086
1.89160
3.89574
4.18374
4.12200
I .67127
3.35475
3.10827
1.15721
.73828
2.28078
3.70159
COORDINATES
Y
.00000
.00000
1.37780
2.55941
1.92238
-1.29346
-1.15029
1.27318
-,36680
1,05615
-.68935
-1.56324
-2.08769
-.31481
-1.01306
-2.15775
2.24290
2.77079
1.07326
2.19971
2.78156
3.39085
.94162
Z
.00000
.00000
.00000
-.59410
I .40576
. ; 45615
.'64976
-.43397
I .00776
-.18623
-.82154
1.42970
-.24283
1.37427
- i 37190
.95958
I ,83071
I .24968
I .96242
- I .57392
.13965
“- . 6 9 6 9 2
-1.31856
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H3SWAN
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S i I VN TOSO- O T
ZTT
113
MMl Coordinates
-JLl-NAL-A JUlMI-C— C-OOR-OINA T-ES -AM-O-8 OND EO-A-TO M -T A BL-EATOM
X
-0.63580
0.82882
-0.98173
0.36798
-C-C—31--------- = 2 -, 9-9-36 6
— 0 .-1 90-83- 0 .-1 3 1 23—
C< 4 )
-2.51771
la 5 9 4 6 0
0.52060
C< 5 )
-1.5021 4
2.11987
-0.50204
C( 6)
-0.59254
1.04074
-1.06226
-C <— 7 )— 0 „ 2 8 2 4 3- 0.1 4314—- 0 . - 1 7 0 1 6 __
C( 8)
1.30656
0.97555
0.63023
C( 9 )
2.55392
1.30379
- 0 . I 9532
C(IO)
3.35821
0.02461
-0.48530
-C -U J L L
-Z U S O Z -Q -U -U L 7 6 Q — 0 . - 5 3 6 3 5 __
C d 2)
1.07142
-0.83912
-1.07688
H( 13 )
-0.05806
-1.55039
I . I 2377
H( I 4)
-0.68210
-0.10794
1.78660
-H-U-SJl
- - U -9 4 1 6 2 - 1 . 6 1 - 9 91-^ 0 .5 2 6 1 -7 —
H( 1 6 )
-2.45745
-1.65476
1.12348
H( 1 7 )
-3.27917
0.23676
-0.93155
H(Ig)
-3.94933
-0.00772
0.64615
-H U 9 L
— Z .4 4 - 8 2 6 - L U 0 -4 4 6
— 1 ,-5 4 2 4 -1 ___
H( 2 0 )
- 3 „ 36033
2.30535
0.57226
H( 2 T )
-2.02526
2.51853
-1=38284
H( 2 2 )
-0.90307
2.95690
-0.12113
-O C2-3 JA824T— 0 .-7 8 4 9 3 - - 2 = 4 2 6 7 -2 H( 2 4 )
1.66901
0.44050
I .51968
H( 2 5 )
0.83974
1.88454
1.03242
H ( 26)
2.21691
1=79351
-1.12171
H( 27)
3.19075
2.05066
0.30741
H( 2 8 )
4.13139
-0.13356
0.28377
H( 2 9 )
3.91053
0.1 5043
-1=43052
-HX 3 0 L
—2 .3 2 2 9 3 ,
- - I . 6 7 1 .1 6 - 0.45750 .
H( 3 1 )
2.92947
-2.01649
- I . I 2821
H( 32)
-1.72512
-1.30713
H( 3 3 )
-0=43263
-2.05988 ■
H I;
-hiun
114
MMl Coordinates (continued)
C(
C( Ii
-Ci- -3-XC(
C(
Ii
C ( 6)
-C C -Z )-
C< 8)
C( 9 )
C(IO)
_C U - U C U 2)
H U 3)
H U 4)
—H U - 5 ) —
H( 1 6 )
H (IZ ),
H U 8)
-H U -S O H( 2 0 )
H( 2 1 )
H( 2 2 )
—O C 2 3 ) H( 2 4 )
H( 2 5 )
H( 26)
H ( 2 Z)
H ( 2 8)
H( 2 9 )
_H ( 3 0 ) _
H( 3 1 )
H( 3 2 )
H( 3 3 )
TYPE
C I)
( I )
( 14)
( I )
< n
< 3>
-- ^ I v--( I)
( P
( 1)
BOUND TO ATOMS
2f
Zz
I 3z
14
I ^
3,
15,
16
-•2#
4 z - - I Z z - —18
3»
19»
5z
20
4-#6>— -21 z
22
5,
23, „
Zz
I , — . — — 8 f —- I 2
7,
9,
25
24,
8z
26,
2Z
I Oz
9z
Ilz
28z
29
(-40- - 10, —12 z— - 3 0 , - - 3 1
( I)
Zz
Ilz
32,
33
( 5)
I f
( 5)
I /
_ ( - 5 1 —— 2 z —
( 5)
2z
( 5)
3z
( 5)
3z
—(... 5 )__
4 »( 5)
( 5)
( 5)
7}
( 5)
( 5)
( 5)
( 5)
( 5)
( 5)
. ( 51.
( 5)
( 5)
( 5)
4,
5,
5,
6,
8 z
8 f
9,
9,
10,
I Qz
IIZ
IIZ
1 2,
12,
115
34
Atomic coordinates
cl
CxlO ) and isotropic
thermaI parameters
(S"1"xlO3 )
X
C(Ia)
C C2a)
C C3a)
C C4a)
C C5a)
C C6a)
C C7a)
Oa
Hoa
C(Ib)
C (2b)
C (3b)
C (4b)
C (5b)
C C6b)
C C7b)
Ob
Hob
C(Ic)
C (6c)
C (5c)
C C4c)
C C3c)
C C2c)
C (7c)
Oc
Hoc
C(Id)
C(6d)
C(Sd)
C(4d>
C (3d)
C (2d)
C C7d)
Od
Hod
C(Ie)
C(6e>
C (Se)
C (4e)
C (3e)
C (2e)
C (7e)
1355
-218(6)
-376(7)
1025(7)
2556(6)
2708(6)
-563(9)
1642(4)
845(45)
1394(5)
2906(6)
3174(8)
3025(7)
1472(8)
1297(8)
2251(10)
128(5)
-419(62)
8647(5)
10245(6)
10346(7)
9123(8)
7476(7)
7379(6)
6982(8)
8503(2)
9529(27)
8541(5)
7078(7)
6819(7)
6876(8)
8399(6)
8728(5)
9735(7)
9832(5)
10680(45)
5412(6)
4476(6)
4923(10)
5004(7)
6142(7)
5742(6)
7826(7)
y
7623
7149(6)
6956(7).
835517)
8690(7)
8947(6)
5497(8)
6418(2)
5476(30)
7925(5)
8209(7)
8697(8)
10025(7)
9735(8)
9349(6)
7427(9)
6668(4)
6076(57)
2375(5)
2778(7)
3031(8)
1699(9)
1276(7)
1101(6)
2310(7)
3643(4)
4215(51)
2010(5)
1861(7)
1373(8)
-32(8)
207(5)
721(5)
1195(7)
3400(4)
3246(64)
5187(6)
3993(7)
4346(8)
5781(6)
7091(6)
6734(5)
7628(7)
Z
9396
8438(5)
7020(6)
-6856(7)
7760(7)
9186(5)
6330(7)
9185(4)
9220(54)
10833(5)
11795(5)
13235(6)
13575(7)
12692(7)
11260(7)
13770(7)
10938(4)
10040(16)
10587(5)
I 1532(5)
12957(6)
13123(7)
12304(6)
10881(6)
12761(7)
10886(4)
10850(57)
9119(5)
8228(6)
6769(7)
6384(7)
7201(5)
8693(5)
6819(6)
9041(4)
9138(58)
10771(6)
11325(6)
12737(8)
13321(6)
12947(5)
11491(5)
13698(6)
LI
47(3) *
52(3)*
70(3)*
-7-2(4)*
72(3)*
52(3)*
88(4)*
62(2)*
75(2)
46(3)*
55(3)*
74(4)*
76(4)*
71(4)*
71(4)*
86(5)*
54(2)*
75(2)
38(2)*
55 (3) *
68(4)*
79(4)*
57(3)*
59(3)*
73(4) *
53(2)*
75(2)
39(2)*
66(3) *
73(4)*
75(4)*
53(3)*
41(2)*
65(3)*
54(2) *
75 (2)
42(3) *
43(3)*
74(5)*
56(3)*
53(3)*
44(3)*
65(3)*
116
Atomic Coordinates (continued)
_
5401(4)
4478(34)
4793(7)
61 14(7)
5696(7)
4242(7).
2959(7) 3323(5)
5762(8)
4593(2)
5600(22)
Bond lengths
C (la)- C (2a)
C (la)-Oa
C (2a)-C (3a) ,
C (3a)-C (7a)
C (5a)-C (6a)
C (lb)- C (2b)
C(Ib)-Ob
C (3b)- C (4b)
C (4b)- C (5b)
Ob-Hob
C(Ic)-C(2c)
C(Ic)-C(Id)
C (5c)- C (4c)
C (3c)- C (2c)
Oc-Hoc
C (Id)- C (2d)
C (6d)—C (5d)
C (4d)—C (3d)
C (3d)- C (7d)
C (Ie)-C (6e)
C(Ie)-Oe
C (6e)- C (Se)
C (4e)- C (3e)
C (3e)—C (7e)
C (If) - C (2f)
C(If)-Of
C (3f)- C (4f)
C (4f);—C (5f)
Of-Hof
1.513(7)
1.452(6)
1.512(10)
1.532(13)
I, 519(1 I)
1.533(9)
1.402(8)
1.502(14)
1.531 (12)
0.960(22)
1.515(9)
1.582(9)
I.454(11)
I.532(11)
0. 960(36)
I.506(10)
I.543(11)
1.503 (11)
I. 492(10)
1.498(10)
I.463(10)
I.455(11)
1.524(9)
1.519(10)
1.556(10)
1.428(9)
1.500(12)
1.514(10)
0.960(32)
11042(4)
11029(60)
9240(5)
8780(6)
7229(6)
6680(7)
7051(5)
8558(5)
6569(6)
8973(4)
9443(48)
52(2)*
75 (2)
37(3)*
47(3)*
47(3)*
71(4)*
59(3)*
5.4 (3) *
75(4)*
51(2)*
75(2)
r»
(S)
C(Ia)-C(6a)
C(Ia)-C(Ib)
C (3 a )—C (4 a )
C (4a)-C (5a)
Oa-Hoa
C (lb)- C (6b)
C (2b)- C (3b)
C (3b)- C (7b)
C (5b)-C (6b)
C(Ic)-C(6c)
C(Ic)-Oc
C (6c)—C (5c)
C (4c)- C (3c)
C (3c)- C (7c)
C(Id)-C(6d)
C(Id)-Od
C(Sd)-CC4d)
C (3d)- C (2d)
Od-Hod
C(Ie)-C(2e)
C (Ie)- C (If)
C (Se)- C (4e)
C (3e)- C (2e)
Oe-Hoe
C (If)- C (6f)
C (2f)—C (3f)
O
Q
6956(5)
6919(69)
4614(6)
5674(7)
5180(7)
5030(8)
3873(7)
4384(7)
3773(8)
3109(4)
3477(62)
O
Q
**+»
Oe
Hoe
C (If)
C(2f)
C(3f)
C (4 f)
C(5f)
C (6 f)
C (7 f)
Of
Hof
C (5f)—C (6f)
1.538(7)
1.566(8)
I. 579(10)
1.503(11)
0.960(35)
I.583(11)
I.520(10)
1.528(12)
1.525(12)
I.550(9)
1.431(8)
1.532(10)
I. 539(12)
1.503(14)
I.523(10)
I.478(7)
I.531(14)
1.563(9)
0.960(64)
1.559(10)
I.589(10)
1.529(13)
1.506(9)
0.960(48)
1.519(11)
1.597(10)
I. 512(13)
1.551(9)
117
Bond angles
C (2a)-C Cla)-C (6a)
C (6 a )—C (la) -Oa
C (6 a ) — C ( l a ) — C (lb)
C (la)-C (2a) -C (3a)
C (2a) —C (3a) -C (7a)
C (3a)-C (4a)-C (5a)
C (la)-C (6a)-C (5a)
C (la)- C (lb)- C (2b)
C (2b)- C (lb)- C (6b)
C (2b)- C (lb)-Ob
C (lb)- C (2b)- C (3b)
C (2b)- C (3b)- C (7b)
C (3b)- C (4b)- C (5b)
C (lb)- C (6b)- C (5b)
C (6c)—C(Ic)-C(2c)
C (2c)-C(Ic)-Oc
C (2c)-C(Ic)-C(Id)
C(Ic)-C(6c)- C (5c)
C (5c)-C (4c)-C (3c)
C (4c)- C (3c)- C (7c)
C(Ic)-C(2c)- C (3c)
C(Ic)-C(Id)-C (6d)
C (6d)- C (Id)- C (2d)
C (6d)- C (Id)-Od
C(Id) —C (6d)- C (5d)
C (5d)—C (4d)—C (3d)
C (4d)- C (3d)- C (7d)
C (Id)- C (2d)- C (3d)
C (6e) -C (Ie) -C (2e)
C (2e)-C(Ie)-Oe
C (2e) -C (Ie)-C (I f)
C(Ie)-C(6e)- C (Se)
C (Se)- C (4e)- C (3e)
C (4e) —C (3e) —C (7e.)
C (Ie) —C (2e) -C (3e)
C(Ie)- C d f)-C(2f)
C(2f)-C(If)-C (6f)
C(2f)-C(If)-Of
C(If) —C (2f)- C (3f)
J C(2f)-C(Sf)-C (7f)
C (3f)- C (4f)- C (5f)
CClf )-C(6f)-C(Sf)
c'J)
112.3(4)C (2a)- C (la)-Oa
104. 3 (4) C (2a)-C (la)-C (lb)
112.9(3) Oa-C (la) -C (Ib )
116.6(5)C (2a)- C (3a)- C (4a)
114.5(7)C (4a)- C (3a)- C (7a)
110.3(6)C (4a)- C (5a)- C (6a)
111.8(4)C (la)-Oa-Hoa
111.2(5)C(Ia)-C(Ib)-C(6b)
107. 3 (5) C(Ia)-C(Ib) -Ob
IOS.6(5)C (6b)-C(Ib)-Ob
116.3(7)C (2b)- C (3b)- C (4b)
114.7(5)C (4b )- C (3b)- C (7 b )
111.3(5)C (4b)- C (5b)- C (6b)
112.4(7)CClb)-Ob-Ho b
107.9(5)C (6c)- C (Ic)-Oc
107.0(5)C (6c)-C(Ic)-C(Id)
113.7(4) Oc-C(Ic)-C(Id)
112.4(6)C (6c)- C (5c)- C (4c)
112.6(8)C (4c)- C (3c)- C (2c)
115. 4 (6) C (2c) -C (3c) -C (7c)
117. 8(4)C(Ic)-Oc-Hoc
109.8(S)1C(Ic)-C(Id)-C(2d)
113.8 (4) C(Ic)-C(Id) -Od
104.0(5)C (2d)- C (Id)-Od
112.8(7)C(6d)- C (5d)- C (4d)
110.6(5)C (4d)- C (3d)- C (2d)
113. I (6) C (2d)- C (3d)- C (7d)
115.0(5)C (Id)-Od-Hod
110.3(6) C (6e)-C (Ie)-Oe
104.5(4)C (6e)-C(Ie)-C(If)
110.9(6)'Oe-C(Ie)-C(If)
117.8 (5),C (6e) -C (Se) -C C4e)
110.3 (7): C (4e) -C (Se) -C (2e)
111.7 (6) C C2e) -C (Se) -C (7e)
116.7(6)C(Ie) —Oe-Hoe
108.2(4)C ( I e ) - C d f )-C(6f)
111.5(6) C ( I e ) - C d f )-0f
111.0(6)C (6f)-C(If)-Of
112.4(4) C (2f)- C (3f)- C (4f)
113.0(7)C (4f)- C (3f)- C (7f)
112. I (7)C(4f)-C(Sf)-C(6f)
114. 3(6)C (If)-Of-Hof
109.9(3)
111.0(4)
106.I (3)
111.0(5)
I 10.4(7)
113.8(7)
114.5(31)
111.7(5)
109.I (4)
108.8(6)
I 12. 0(7)
113.2(8)
110.9(7)
100.4(27)
107.8(4)
110.9(5)
109.3(5)
110.6(5)
107.4(6)
112.7(7)
85.2(33)
I 14.5(5)
104.7(4)
109.2(5)
I 12.9(7)
111.9(6)
112.9(4)
105.7(34)
109.6(6)
112.8(4)
108.4(6)
111.5(8)
111.4(4)
113.5(6)
111.8(39)
109.8(6)
108.5(6)
107.8(4)
111.2 (6 )
I 13.6(5)
109.9(4)
96. I (37)
118
A n isotropic thermal parameters
Un
C(Ia)
C (2a)
C (3a)
C (4a)
C(5a)
C (6a)
C (7a) •
Oa
C(Ib)
C (2b)
C (3b)
C (4b)
C(Sb)
C (6b)
C (7b)
Ob
C(Ic)
C (6c)
C(Sc)
C (4c)
C (3c)
C (2c)
C (7c)
Oc
C(Id)
C (6d)
C(Sd)
C (4d)
C (3d)
C (2d)
C(7d)
Od
C(Ie)
C (6e)
C(Se)
C (4e)
C (3e)
C(2e)
C (7e)
Oe
C(If)
C(2f)
C (3f)
C (4f)
C(Sf)
C(6f)
C(7f)
Of
49(3)
41 (3)
54(3)
76(4)
40(3)
55(3)
90(5)
59(3)
39(3)
53(3)
75(4)
57(4)
87(5)
73(4) ■
120(6)
55(3)
21 (2)
50(3)
61 (4)
82 (4)
80(4)
39(3)
. 80(4)
70(3)
24(2)
53(3)
45(3)
79(4)
48(3)
38(3)
77(4)
43(2)
27(3)
38(3)
91 (6)
64(3)
72(4)
36(3)
62(4)
51 (2)
42(3)
63(4)
44(3)
68(4)
56(3)
72(4)
88(5)
37(2)
U22
38(3)
47(3)
63(4)
63(4)
63(4)
45(3)
79(5)
36(2)
28(2)
67(3)
111(5)
72(4)
85(4)
49(3)
109(5)
37(2)
28(2)
69(4)
114(5)
133(6)
55(3)
41 (3)
70(4)
50(2)
33(2)
.66(4)
87(5)
74(4)
30 (3)
33(2)
64(4)
46 (2)
27(3)
49(3)
66(5)
61 (3)
42(3)
53(3)
71 (4)
67(3)
54(3)
40 (3)
59(4)
98(5)
66(4)
41 (3)
106(5)
56(2)
U33
68(4)
59(4)
7414)
93(5)
111(5)
52(3)
67(4)
80 (3)
80 (4)
62(4)
49 (4)
65(4)
87(5)
106(5)
63(4)
66(3)
59(3)
63(4)
50(4)
63(4)
67(4)
93(4)
84(5)
70 (3)
50(3)
72(4)
80 (5)
65(4)
65(4)
56 (3)
65(4)
72(3)
■ 76(4)
45(4)
86(6)
47(3)
53(3)
46(3)
54(4)
64(3)
25(3)
48(4)
44(4)
66(4)
45(3)
63(4)
61 (4)
54(3)
(S2XlO3)
U23
22(2)
8(3)
16(3)
41 (4)
47(4)
17(2)
11 (4)
3(2)
I I (2)
10(3)
4(3)
-6(3)
35(4)
22(3)
34(4)
22(2)
13(2)
33(3)
34(3)
50 (4)
30 (3)
18(3)
28(3)
28 (2X
20(2)
20 (3)
27(4)
9(3)
-0(2)
20 (2)
15(3)
22(2)
13(3)
10(3)
34(4)
17(3)
11(2)
I (2)
15(3)
29 (2)
15(2)
26 (3)
28(3)
24(3)
7(3)
26(3)
44(4)
6(2)
U 13
33(3)
6(2)
0(3)
43(4)
41 (3)
22(3)
23(4)
15(2)
25(3)
14(3)
10(3)
14(3)
49(4)
52(4)
32(4)
32 (2)
6(2)
31 (3)
29(3)
42(3)
50(3)
34(3)
46(4)
. 42(2)
10(2)
17(3)
6(3)
19(3)
15(3)
9(2)
31 (3)
21 (2)
22(3)
20 (3)
44(5)
21 (3)
35 (3)
6(2)
15(3)
33 (2)
16(2)
24(3)
29(3)
48(3)
14(3)
45(3)
29 (3)
10(2)
The anisotropic temperature factor exponent takes the form:'.
-2^(h^a*^U1 ^ + ... + 2hka*b*U^0 )
'
U 12
26(2)
24(2)
__ 27(3)
38(3)
15(3)
21 (3)
31 (4)
25(2)
24(2)
49(3)
69(4)
20 (3)
68(4)
35(3)
83(5)
14(2)
11(2)
34(3)
54(4)
75(4)
44(3)
15(2)
42(4)
45(2)
8(2)
28(3)
38(3)
41 (4)
16(2)
23(2)
43(3)
20(2)
15(2)
22 (3)
48(4)
35(3)
31 (3)
33(2)
35 (3)
41(2)
28 (3)
29(3)
22(3)
46(4)
31 (3)
30 (3)
66(4)
25(2)
119
H-Atom coo r d inates
(xlO^) and
thermaL parameters
(.SjSclO'*)
X
H(2aa)
H (2ab)
H (3a)
H <4aa)
H(4ab)
H(Saa)
H(Sab)
H (6aa)
H(6ab)
H (7aa)
H (7ab)
H (7ac)
H(2ba)
H (2bb)
H (3b)
H (4ba)
H (4bb)
H(Sba)
H(Sbb)
H (6ba)
H (6bb)
H(7ba)
H (7bb)
H(7bc)
H (6ca)
H (6cb)
H(Sca)
H(Scb)
H (4ea)
H(4cb>
H (3c)
H (2ca)
H(2cb)
H (7ca)
H (7eb)
H (7cc)
H C6da)
H (6db)
H(Sda)
H(Sdb)
-445
-979
-1335
940
983
2662
3380
3673
2712
—740
-1436
367
3764
2899
4240
3081
3866
1438
630
302
2113
2556
1156
2461
11 053
10397
10234
I 1344
9242
9233
6735
6402
7392
6884
5995
7750
6191
7170
7616
5815
Y
7896
6206
6888.
9213
8143
7856
9576
9071
9843
5419
4656
5500
8980
7295
9021
10220
I0884
10622
8915
9148
10192
6709
6943
7832
3681
1971
3862
3253
874
1883
347
959
217
2245
2024
3323
1126
2815
2181
1168
Z
8695
8503
6594
7059
5972
7503
7674
9689
9476
5422
6418
6718
11629
I 1623
13685
14465
13475
12908
12831
10735
11118
13684
13289
14674
11450
11295
13210
13499
12865
14026
12405
10387
10586
13595
12142
12837
8390
8429
6578
6263
isotropic
Li
75(2)
75(2)
75 (2)
75(2)
75(2)
75(2)
75 (2)
75(2)
75 (2)
75(2)
75(2)
75(2)
75 (2)
75 (2)
75(2)
75(2)
75(2)
75(2)
75(2)
75 (2)
75(2)
75(2)
75 (2)
75 (2)
. 75 (2)
75(2)
75(2)
75(2)
75 (2)
75(2)
75 (2)
75(2)
75(2)
75(2)
75 (2)
75(2)
75 (2)
75(2)
75 (2)
75(2)
120
H-Atom Coordinates (continued)
H(4da>
H(4db)
H (3d)
H(2da)
H (2db)
H (7da)
H (7db)
H (7dc)
H (6ea)
H (6eb)
H (5ea)
H(Seb)
H (4ea)
H(4eb)
H (3e)
H(2ea)
H (2eb)
H (7 ea)
H C7eb)
H (7ec)
H (2 fa )
H (2 fb)
H(3f)
H (4fa)
H C4 fb)
H(Sfa)
H(Sfb)
H (6fa)
H (6 fb)
H C7 fa )
H C7 fb)
H(7fc)
6769
6035
8292
9781
8020
9539
10674
9851
4533
3416
4170
5930
5347
3986
6034
4828
6602
8509
8038
7995
5602
6732
6014
4686
6032
2860
3830
5352
3598
3821
2839
3765
-248
-865
-755
1019
-120
745
1315
2160
3137
3734
3529
4482
6007
5632
7924
6765
7502
8546
6878
7800
6960
6375
6462
4006
4358
2815
2059
3373
2524
6591
4844
5893
5481
6512
7022
9159
- 8919
5930
7377
6904
11027
I0978
12954
13100
14255
12995
13200
I I 125
11325
13545
13411
14613
9079
9153
7035
5747
7007
6703
6698
8882
8766
7090
6472
. 5725
75(2)
75(2)
75(2)
75(2)
'75(2)
75(2)
75(2)
75(2)
75(2)
75(2)
75(2)
75 (2)
75 (2)
75(2)
75(2)
75 (2)
75(2)
75(2)
75(2)
75(2)
75(2)
75(2)
75 (2)
75(2)
75(2)
75 (2)
75(2)
75(2)
75 (2)
75(2)
75(2)
75(2)
121
Atomic coordinates
37
thermaI parameters
X
C CI)
C (2)
C (3)
C (4)
C (5)
C (6)
C (7)
C(S)
C (9)
C(IO)
C(Il)
C (12)
M (I)
M (2)
Ox CI)
Ox (2)
C (13)
C (14)
C C15)
C C16)
C C17)
C C18)
M (3)
Ox (3)
5538(4)
4377(5)
4888(6)
5933(6)
7089(5)
6590(4)
5024(4)
4241(4)
3788(5)
4961(6)
5680(5)
6172(4)
5291(6)
• 5916(6)
6152(3)
4047(3)
359(4)
-250(4)
377(4)
316(4)
971(5)
331(4)
-1137
1765
CxlO4') and
)2 , 3 ,
isotropic
-
■
Y
8697(2)
8493(3)
8288(3)
7689(3)
7889(2)
8105(2)
8904(2)
8323(2)
8515(3)
8759(3)
9363(3)
9167(2)
6987(3)
8162(3)
9326(2)
9 4 6 6 CI)
178(2)
899(2)
1240(2)
776(3)
69(3)
-285(2)
698
315
542(5)
—646(5)
-1749(4)
-1381(5)
-200(5)
888(4)
'1657(4)
2053(4)
3177(5)
4333(5)
3920(5)
2810(4)
-1247(5)
4969(5)
270(3)
1216(3)
650(3)
758(4)
2056(5)
3150(4)
3051(4)
I760(4)
3195
742
'
5 0 (2 )*
78(3)+
I05(3)*
83(3)*
6 6 (2 )*
50(2)*
46(2)*
51(2)*
74(3)*
91(3)*
95(3)*
69(2)*
■119(3)*
123(3)*
98(2)*
" 78(2)*
39(2)*
52(2)*
64(2)*
64(2)*
67(2)*
54(2)*
90*
58*
* E q u ivalent isotropic U defined as one third of the
trace of the orthogonalised U
tensor
ij
122
Bond lengths (8)
C d ) -C (2)
1.523(7)
C d ) -C (7)
1.552(8)
C (2)-C (3)
1.537(9)
C (4)-C (5)
1.513(7)
C (5)-C (6) __-.1.520(8) .
C (7)-C (12)
' I. 524(6)" "
C (8)-C (9)
1.517(8)
C ( I O ) - C d I)
1.516(9)
1.529(9)
C (11)-C C12)
0.771(4)
O x (2)- H (52)
C (13)-C (18)
I.526(7)
C (13)- C (13a)
1.554(7)
I.522(8)
C (15)- C (16)
C (16)- M (3)
1.528(6)
O x (3)- H (53)
0.747(1)
Bond angles
C (2)-C (I)-C (6)
C (6) -C <I)-C (7) C (6)-C (I)-Ox (I)
C (I)-C (2) -C (3)
C (3)-C (4)-C (5)
C (5) -C (4) -M <I)
C(I)-C(6)- C (5)
C (I>-C (7) -C <12)
C d ) -C (7) -Ox (2)
C (12)-C (7)-Ox (2)
C (8)- C (9)- C (10)
C (9) -C(IO)-M(Z)
C ( I O ) - C d I)-C(12)
C (I)-Ox (I)-H (51)
C (14)-C (13)-C (18)
C (18)-C (13)-Ox (3)
C (18)- C '(13)-C (13a)
C (13)-C (14)-C (15)
C (15)-C (16)-C (17)
C (17)-C (16)-M (3)
C(IS)-C (18)-C (17)
C(I) —C (6)
C d ) -Ox (I)
C (3)- C (4)
C (4)- M (I)
C (7)-C (8)
“ C (7)—O x (2)
C (9)- C (10)
C (10)- M (2)
Ox(I)-H(Sl)
C (13)-C (14)
C (13)- O x (3)
C (14)-C (15)
C (16)-C (17)
C (17)-C (18)
1.524(6)
1.431 (6)
I.530(8)
1.518(8)
■ 1.516(7)
1.444(5)
I.529(7)
1.520(8)
0.681(4)
1.528(6)
1.449(5)
I.524(7)
1.524(7)
I.531(7)
(°)
109. 3(4) C (2) - C d ) -U (7)
112.7(4) C (2)- C (I)- O x (I)
109.8 (4) C (7)- C (I)-Ox (I)
112.4(4) C (2)- C (3)- C (4)
I09. 7 (4) C (3) -C (4) -M (I)
112.5 (4) 0(4) -C (5) -C (6)
113.4(4) C C I)- C (7)- C (8)
112.4(4) C (8)- C (7)- C (12)
107.4(3) C ( S ) - C (7)- O x (2)
108.3(3) C (7)- C (8)- C (9)
113.2(5) C (9)- C (10)- C (11)
112.7(5) C(Il)-C(IO)-M(2)
112.7(4) C (7)- C (12)- C d I)
118.0(4) C (7)- O x (2)- H (52)
109.7(4) C (14)- C (13)-Ux (3)
109.I (3) C (14)- C (13)- C (13a)
112.I (4) O x (3)- C (13)- C (13a)
113.3(3) C (14)- C (15)- C (16)
108. 5 (4), C (15) -C (16) -M (3)
I 12. 5 (4): C (16) -C (17) -C (18)
113. I (4) C (13) -Ox (3) -H (53)
i
112.5(4)
107.9(4)
104.4(3)
111.7(4)
I 12.6(5)
112.6(4)
113.7(3)
109.7(4)
104.8(3)
113.7(4)
107.9(4)
113.4(5)
I 12.9(4)
104.6(4)
105.3(3)
112.3(4)
108.I (4)
113.5(4)
112.3(3)
112.8(3)
HO. I (2)
A n isotropic thermaI parameters
'
U22
U33
47 (3)
70 (4)
109(5)
93(4)
68(4)
44(3)
40(3)
47(3)
79(4)
I 12(5)
108(5)
66(3)
103(5)
127(5)
I 16(3)
82(2)
34(3)
56(3)
69(4)
58(3)
74(4)
63(3)
80
40
42(3)
104(5)
149(6)
104(4)
58(3)
52(3)
34(3)
51 (3)
79(4)
99(5)
95(4)
57(3)
I 16(5)
159(6)
■59(2)
56(2)
39 (3)
44(3)
53(3)
78(4)
68(4)
46(3)
120
60
70 (3)
54(3)
53(4)
55(4)
80 (4)
55(3)
69(3)
53(3)
78(4)
81 (4)
87(4)
93(4)
I 19(5)
71 (4)
163(4)
116(3)
46(3)
61 (3)
70(4)
54(3)
56(3)
54(3)
76
75
U23
13(3)
20 (3)
17(4)
6 (3)
10(3)
-3(2)
13(2)
6 (2)
16(3)
-17(4)
-38(4)
-14(3)
-54(4)
23(4)
32(2)
32(2)
0 (2)
-3(3)
-13(3)
-20(3)
0 (3)
I (3)
-10
-9
U 13
29(3)
12(3)
23(4)
29(3)
34(3)
17(2)
25(3)
16(2)
45 (3)
56(4)
40 (4)
35(3)
11 (4)
14(4)
106(3)
62(2)
16(2)
24(3)
24(3)
15(3)
18(3)
22(3)
35
19
The anisotropic temperature factor exponent takes the forms
?
7
"7
-2- Ch"a*"-IJ11 +
+ 2hka*b*U10)
U 12
9(2)
40 (3)
60 (4)
38(4)
19(3)
5(2)
7(2)
-7(2)
2(3)
-10(4)
-17(4)
-16(3)
-13(4)
10(5)
10(2)
24(2)
—4 (2)
4(2)
-I (3)
-7(3)
-0(3)
2(2)
—0
-3
123
C(I)
C (2)
0(3)
0(4)
0(5)
0(6)
0(7)
0(8)
0(9)
0(10)
0(11)
0(12)
M CI)
M (2)
Ox (I)
Ox (2)
0(13)
0(14)
0(15)
0(16)
0(17)
0(18)
M (3)
Ox (3)
uH
(S-zXlO3 )
124
H-Atom coordinates
(x IO4 ) and
thermaI parameters
cR^xlO')
X
H CSa)
H C2b)
H C3a)
H (3b)
H(4)
H(Sa)
H(Sb)
H (6a)
H (6b)
H(Sa)
H(Sb)
H (9a)
H (9b)
H(IO)
H(Ha)
H(Ilb)
H (12a)
H (12b)
H(Ia)
H(Ib)
H(Ic)
H (2c)
H (2d)
H (2e)
H(Sl)
H (52)
H (14a)
H (14b)
H(ISa)
H(ISb)
H (16)
H (17a)
H (17b)
H(ISa)
H(ISb)
H (3c)
H (3d)
H (Se)
H (S3)
3897
3765
5307
4124
630 I
7688
7581
6184
7360
3445
4817
3128
3372
4606
5057
6455
6848
6575 •
4572
4923
5973
6629
6309
5412
6743
4393
-1213
-103
-106
1317
818
1925
867
—601
826
-I 129
-1707
-1488
2192
Y
8099
8885
'8691
8139
7624
7492
8276
7703
8260
8215
7915
8888
8109
8923
9751
9500
8803
9576
6881
7012
6624
8342
7961
7808
9295
9725
844
1205
1669
1345
996
143
-238
-398
-710
400
493
1153
-3
Z
-451
-904
-1989
-2454
-2061
63
-400
I 145
1582
1347
2273
2927
3413
4979
3670
4626
3081
2568
-2020
-560
-1076
5689
4377
5243
130
881
602
128
2075
2170
3939
3183
3698
1663
1742
3892
2417
3304
986
isotropic
U
102
102
133
133
95
82
82
65
65
64
64
96
96
105
I 19
I 19
89
89
140
140
140
149
149
149
47
65
66
66
82
82
73
88
88
72
72
106
106
106
72
MONTANA STATE UNIVERSITY LIBRARIES
762 10005047 3
D378
B838
Bruss, Dan R
Studies on rinacol
chemistry
cop.2
date
.. f
-i~
4
-
i
.I
D378
B838
cop.2