With the increasing power and sophistication of experimental

and theoretical methods for assigning chemical structures, it seems almost incredible that the structure of any reasonably stable organic entity with a small number of carbons could remain enigmatic for very long. Nonetheless, this is true of C_4H_7^+-one of the first "nonclassical" cations to be discovered, which has some of the characteristics expected for a very rapidly equilibrating

mixture of classical cyclopropylmethyl, cyclobutyl, and 3-butenyl cations and yet other characteristics which wholly belie any description that implies conventional charge distributions or geometries derived from structural representations using solid lines representing

two-electron bonds

Brittain, William J.

Roberts, John D.

Squillacoate, Michael E.

Caltech Authors - Main

7280 J .  Am. Chem. SOC. 1984, 106, 7280-7282 
Figure 1. Stereoplot of the X-ray structure of dilithium tribenzylidenemethane-2TMEDA. 
Figure 2. Schematic view of the structure in Figure 1. Important bond 
lengths in A: C(8)-C(27) 1.460 (3), C(8)-C(17) 1.443 (3), C(8)-C(7) 
1.434 (4), Li(4)-C(21) 2.667 (4), Li(4)-C(27) 2.234 (5), Li(4)-C(8) 
2.287 (6), Li(4)-C(17) 2.304 (5),  Li(3)-C(7) 2.297 (5), Li(3)-C(8) 
2.337 (6), Li(3)-C(17) 2.626 (61, Li(3)-C(11) 2.784 (6), Li(3)-C(12) 
1.388 (4), C(l1)-C(17) 1.441 (3). C(7)-C(1) 1.420 (3), C(27)-C(21) 
2.673 (5), C(l)-C(2) 1.395 (4), C(2)-C(3) 1.372 (4), C(3)-C(4) 1.437 
(3), C(4)-C(5) 1.369 (4), C(5)-C(6) 1.371 (4), C(l)-C(6) 1.462 (3). 
Lithium-nitrogen distances vary between 2,025 and 2.1 18 A. 
dianion'* and confirms this interpretation. The phenyl groups are 
twisted from the trimethylenemethane plane, as suggested by 
MNDO calculations on the d i a n i ~ n . ~  The entire structure, with 
lithium atoms above and below the dianion plane in bridging 
positions between the carbon atoms with the highest negative 
charges, is electrostatically very favorable. The quinonoid dis- 
tortions of the phenyl substituents (indicative of delocalization 
of the negative charge) are most pronounced for the ring bound 
to C(7), although the differences are not large. Finally, we note 
that the orientation of the TMEDA ligand coordinated to Li(4) 
is that expected from Stucky's orbital arguments5.12 but that the 
orientation of the other diamine moiety is consistent with an 
interaction with C(7) and C(l2).I3 
The X-ray structure of a related Y-conjugated 1,3-acetone 
"dianion" derivative (dilithiated dibenzyl ketone) has just been 
reported.I4 We have now been able to obtain the X-ray structure 
of another Y-conjugated system, dilithium dibenzylidine- 
thylene-2-tetramethylpr0panediamine.~~ The geometry resembles 
5 more closely than does 2. 
Acknowledgment. This work was supported by the Deutsche 
Forschungsgemeinschaft and the Fonds der Chemischen Industrie. 
We thank G. Boche and J. Klein for related discussions. 
Registry No. 1, 13001-05-3; 2, 92314-26-6. 
(14) Dietrich, H.; Mahdi, W.; Wilhelm, D.; Clark, T.; Schleyer, P. v. R. 
Angew. Chem. 1984, 96, 623; Angew. Chem., Int. Ed. Engl. 1984,23,621. 
Also see: Kos, A. J.; Clark, T.; Schleyer, P. v. R. Angew. Chem. 1984, 96, 
622; Angew. Chem., Int. Ed. Engl., 1984, 23, 620. 
(15)  Wilhelm, D.; Dietrich, H.; Mahdi, W.; Clark, T.; Schleyer, P. v. R., 
to be published. 
13C, 'H, and *H NMR Observation of Trideuterated 
Cyclopropylmethyl-Cyclobutyl Carbocation: A 
Configurationally Stable SpeciedB 
William J. Brittain, Michael E. Squillacote,Ib and 
John D. Roberts* 
Contribution No. 701 6 
Gates and Crellin Laboratories of Chemistry 
California Institute of Technology 
Pasadena, California 91 125 
Received April 18, 1984 
. Revised Manuscript Received September 8, 1984 
With the increasing power and sophistication of experimental 
and theoretical methods for assigning chemical structures, it seems 
almost incredible that the structure of any reasonably stable 
organic entity with a small number of carbons could remain 
enigmatic for very long. Nonetheless, this is true of C,H7+-one 
of the first "nonclassical" cations to be discovered, which has some 
of the characteristics expected for a very rapidly equilibrating 
mixture of classical cyclopropylmethyl, cyclobutyl, and 3-butenyl 
cations and yet other characteristics which wholly belie any de- 
scription that implies conventional charge distriutions or geometries 
derived from structural representations using solid lines repre- 
senting two-electron bonds.* 
(12) Walczak, M.; Stucky, G .  J .  A m .  Chem. SOC. 1976, 98, 5531. 
(13) See Bushby et al. (Bushby, R. J.; Tytko, M. P. J .  Organornet. G e m .  
1984, 270, 265) for an electrostatic interpretation of lithiated n-carbanion 
structures. 
(1) (a) Supported by the National Science Foundation. (b) NSF Fellow, 
(2) Staral, J. S.; Roberts, J. D.; Prakash, E. K. S.; Donovan, D. J.; Olah, 
1979-1 980. 
G. A. J .  Am. Chem. SOC. 1978, ZOO, 8016,8018. 
0 1984 American Chemical Society 
Communications to the Editor J. Am. Chem. SOC., Vol. 106, No. 23, 1984 7281 
PP" 
Figure 1. Methylene-shift region of the proton-decoupled 125.7-MHz 
I3C FT N M R  spectrum of endo-C4H4D3+ (3a) a t  -95 OC in SbF5- 
S02CIF-S02F2 solution. (* corresponds to an unknown resonance.) 
Further evidence bearing on the nature of C4H4D3+ in 
SbF5-SO2C1F-SO2F2 ("~uperacid")~ has been obtained from I3C, 
'H, and 2H N M R  spectroscopy4 a t  temperatures ranging from 
-121 to -80 OC. Specifically, (2E)-, (22)-, (3E-cyclopropyl- 
d3)methanol (2)s affords a long-lived, quite stereochemically stable 
C4H4D3+ species (3a), while (cyclopropyl-2,2-d2)methan-d-01 (4): 
under the same conditions, produces 3a and its stereoisomeric 
species 3b. These stereoisomeric species, the likelihood of which 
H 
I 
2 
H 
I 
CHDOH suparocid 
-130 'C - C4H4D3' endo and exo 
3 a . b  
4 
was earlier recognized by Saunders and Siehl: will be here 
designated as endo (3a) and exo (3b), although it is abundantly 
clear from earlier that they are very rapidly equilibrating 
mixtures of C4H4D3+. 
Figure 1 shows the three nonequivalent methylene resonances 
of the 125.7-MHz I3C N M R  spectrum of 3a at  -95 "C, each of 
which can be identified by its 'JcD splitting pattern. Smaller peaks 
~~ ~ ~~~ 
(3) Olah, G. A.; Kelly, D. P.; Jeuell, C. H.; Porter, R. D. J .  Am. Chem. 
SOC. 1970, 92, 2544; 1972, 94, 146. 
(4) Chemical shifts are relative to external tetramethylsilane and are ac- 
curate to fO.01 ppm for carbon and f0.001 ppm for deuterium and hydrogen. 
For complete experimental details, see: Brittain, W. J. Ph.D. Dissertation, 
California Institute of Technology, Pasadena, CA, 1982. 
( 5 )  Prepared by lithium aluminum hydride reduction of the corresponding 
carboxylic acid; see: Kobayashi, K.; Lambert, J. B. J .  Org. Chem. 1972, 42, 
1254. 
(6) Synthesized starting from prop2-en-1-al. Protection of the carbonyl, 
cyclopropanation with CD,N,, vacuum pyrolysis of pyrazolines, deprotection, 
and lithium aluminum deuteride reduction gave a mixture of deuterated 
3-butenyl and cyclopropylmethyl alcohols which could easily be separated by 
preparative gas chromatography. 
(7) Saunders, M.; Siehl, H. J .  Am. Chem. SOC. 1980, 102, 6868-6869. 
Table I. "C Chemical Shifts (ppm/Me,Si) Assigned to C4H4D,' 
(3a and 3b) at  -95 OC 
13CH, "CHD I3CD2 13CH 
3a 51.35 56.69 53.68 109.81 
3b 53.68 50.5 1 55.70 110.28 
5 kOI&+) 
I 
I-t,O+ 
I 
5 cp-ri, C C l 4  SDJ+ ye thylene -Id , 
5 PP" 
Figure 2. F T  500-MHz 'H NMR spectrum of 3a containing some 3b, 
a t  -121 "C in SbF5-S02C1F-S02F2 solution; the proton resonances as- 
signed to cyclobutyloxonium ion (5 )  are so labeled. The methylene 
proton resonances (in ppm): 3a, 4.49, 4.12, 3.83; 3b, 4.49, 4.44, 3.94. 
(Figure 1) arising from the stereoisomer 3b could be identified 
by comparison with the corresponding equimolar mixture of 3a 
and 3b prepared from 4. Still other peaks correspond to cyclo- 
butyloxonium ion (5).2 
The pattern of I3C shift differences between 3a and 3b, as well 
as between these moieties and the shifts3 for C4H7+ (1) is quite 
striking. Relative to the corresponding I3C resonances of 1 as 
internal standard, the following are the I3C shifts, in ppm at -94 
"C, of 3a and 3b, respectively: (CH,) -3.0, -0.7; (CHD) 2.2, -3.6; 
(CDJ -0.8, 1.0 (?);* (CH) 0.0, 0.4. Whatever else can be said 
about these shifts, the influence of the endo-exo configuration 
at  the CHD carbon is indeed significant (Table I ) .  
In the 500-MHz 'H spectrum of 3a (admixed with some 3b) 
shown in Figure 2, the endo-methylene protons (the protons trans 
to the methine) have chemical shifts more toward lower fields (4.64 
ppm3) than do the exo-methylene protons (4.21 ppm3). This 
suggests different shift assignments than derived previ~usly.~ 
Several 76.7-MHz 'H NMR spectra of C4H4D,+ samples prepared 
from 2 and 4 were taken to assess the extent of deuterium mi- 
gration from methylene to the methine position. Even after ex- 
tended periods above -80 "C, no 2H resonance was observed in 
the methine region. 
Conversion of 3a to 3b was not clearly observed at -90 "C in 
4 h. The outside limit of reaction was about 12%, which would 
correspond to a lower limit for the free energy of activation of 
around 14 kcal/mol. This, then, must be the lower limit for the 
free energy of C4H7+, either for conversion to the planar cyclobutyl 
cation or for rotation about a methylene to methine carbon-carbon 
bond. This fact, along with the small isotopic perturbations of 
the 13C chemcial shifts reported here and by Saunders and Siehl' 
provide compelling evidence that C4H7+ cannot be regarded as 
a rapidly equilibrating mixture of classical cations. 
The remarkable difference in the direction of the isotope shifts 
in the I3C resonances of 3a and 3b and the much larger isotopic 
perturbations of the exo-proton shifts compared to the endo-proton 
shifts (Figure 2) indicates that one or more of the equilibrating 
structures of C4H7+ must have an exo-methylene proton located 
in a unique environment compared to the other protons. If the 
(8) Uncertain because of poor signal-to-noise ratio and overlap with the 
resonances of C4H7+, which was present in the solution as internal standard. 
7282 J .  Am. Chem. Soc. 1984, 106, 7282-7283 
particular C4H7+ structure has a pentacoordinated carbon with 
the elements of square-pyramidal geometry and possesses an 
exo-methylene proton at the apical position, this could account 
for the observed isotopic perturbations. The bicyclobutonium 
cation structure has a pentacoordinated carbon which could possess 
this configuration. 
Acknowledgment. We are pleased to acknowledge use of the 
Southern California Regional N M R  Center facilities (Bruker 
WM-500 spectrometer) supported by the National Science 
Foundation, Grant CHE79- 16324, and helpful discussions with 
Professor Martin Saunders of Yale University. 
Registry No. 2, 92365-85-0; 4, 92346-36-6. 
Estrogen Biosynthesis. Concerning the Obligatory 
Intermediacy of 
20-Hydroxy- 10~-formylandrost-4-ene-3,17-dione 
Eliahu Caspi,*+ Jerzy Wicha,+.* Thangavel Arunachalam,+ 
Peter and Gerhardt Spitellerl 
The Worcester Foundation for  Experimental 
Biology, Inc., Shrewsbury, Massachusetts 01 545 
Department of Chemistry, University of Bayreuth 
Bayreuth, German Federal Republic 
Received May 7,  I984 
The transformation of an androgen (1) to an estrogen (5) by 
human placental aromatase was shown to involve three oxidative 
steps, each of which requires 1 mol of O2 and 1 mol of NADPH.I 
The process is initiated by (2-19 hydroxylation2s3 (2) in the re- 
tention mode4 and is followed by the introduction of a second C-19 
hydroxyl5 (3). The second hydroxylation proceeds with the ste- 
reospecific abstraction of 19-pro-R hydrogen atom of the 19- 
alcohol"s 2. The obtained diol 3 is then dehydrated with the loss 
of the "second" hydroxyl9 to give the 19-aldehyde 4. The aldehyde 
is subsequently aromatized with the consumption of a (third) mole 
each of oxygen and NADPH, and C-19 is extruded as formic 
a ~ i d . ~ . ~  
Fishman et aI.'*l3 proposed that the "third" mole of oxygen 
and of NADPH are utilized for the enzymatic 2P-hydroxylation 
of a 19-aldehyde intermediate to give, e.g., 2P-hydroxy-1OP- 
forrnylandrost-4-ene-3,17-dione (6b) (Scheme I). They proved 
'Worcester Foundation for Experimental Biology. 
*Visiting scientist, summer 1983. Permanent address: Institute of Organic 
Chemistry, Polish Academy of Science, 44 ul. Kasprzaka, Warsaw, Poland. 
*Present address: Metabolism and Radiation Research Laboratories, State 
University Station, USDA-ARS, Fargo, ND 58105. 
University of Bayreuth. 
(1) Thompson, E. A., Jr.; Siiteri, P. K. J .  Eiol. Chem. 1974, 249, 5364. 
(2) Meyer, A. S .  Experientia 1955, 11, 99. Meyer, A. S. Eiochem. Eio- 
phys. Acta 1955, 17, 441. 
(3) Wilcox, R. B.; Engel, L. L. Steroids, Suppl. 1965, No. I ,  49. 
(4) Casui, E.; Arunachalam, T.; Nelson, P. A. J .  Am. Chem. Sot .  1983. 
105, 6987.' 
S. J. M.; Akhtar, M. Ibid. 1969, 114 ,  75. 
Commun. 1975, 185. 
Chem. Soc. 1975, 97, 4400. 
Am. Chem. Sor. 1978, 100, 5223. 
1982, 201, 569. 
(5) Akhtar, M.; Skinner, S. J. M. Eiochem. J .  1968, 109, 318. Skinner, 
( 6 )  Arigoni, D.; Bataglia, R.; Akhtar, M.; Smith, T. J .  Chem. Soc., Chem. 
(7) Osawa, Y.;  Shibata, K.; Rohrer, D.; Weeks, C.; Duax, W. L. J .  Am. 
(8) Caspi, E.; Santaniello, E.; Patel, K.; Arunachalam, T.; Eck, C. R. J .  
(9) Akhtar, M.; Calder, M. R.; Corina, D. L.; Wright, J .  N. Eiochem. J .  
(10) Hosoda, H.; Fishman, J .  J .  Am.  Chem. Soc. 1974, 96, 7325. 
(1 1) Goto, J.; Fishman, J .  Science (Washington, D.C.) 1977, 195, 80. 
(12) Fishman, J.; Raju, M. S.  J .  Eiol. Chem. 1981, 256, 4472. 
(13) Hahn, E. F.; Fishman, J. J .  Eiol. Chem. 1984, 259, 1689. 
Scheme I 
OH 
N A D P H  N A D P H  
2 3 
L n  \ 
Scheme I1 
Table I. Aromatization of 
[2fl-'80,19-3H]-2fl-hydroxy- lOfl-formylandrost-4-ene-3,17-dione (6b): 
GC-MS Analyses of the Derived Benzyl Formates 
relative intensities of M+ ions 
source of HCOOCH,CIH, rnlz 136 mlz 137 mlz  138 
(1) authentic, ref 100 9.2 0.94 
(2) nonenzymaticn aromatization of 100 9.6 0.87 
(3) enzymatica aromatization of 6b 100 11.6 0.94 
6b 
"See text for details. 
that the 20-hydroxy- lOB-formyl 6b collapses nonenzymatically 
even at pH 7 with the loss of the 10-hydrogen to give estrone and 
formic acid. On the basis of these and other  observation^,'*'^ 
they postulated that the last step of estrogen biosynthesis is the 
nonenzymatic aromatization of the presumably "not enzyme 
bound" 6b. Accordingly they showed "that there is no end-product 
inhibition of aromatization by estrogens"." 
The collapse of the 2P-hydroxy-1OP-formyl 6b can be ration- 
alized in terms of the mechanisms (A, B, C) outlined in Scheme 
11. Pathway A provides for a "stepwise" aromatization of 6b, 
while pathway B is a concerted process. It should be noted that 
according to mechanisms A and B, the oxygen atom of the 2P- 
hydroxyl of 6b is incorporated into the formic acid produced in 
the aromatization process. In contrast, in mechanism C, the 
aromatization process is initiated by a hydroxyl group attack on 
the 10P-formyl moiety, and the oxygen of the 2P-hydroxyl group 
is eliminated as water. 
Akhtar et aL9 proved that the third mole of oxygen, required 
for completion of the aromatization process, is incorporated into 
the formic acid derived from C-19. It follows therefore that if 
6b is an obligatory intermediate in estrogen biosynthesis, the 
oxygen (e.g., l 8 0 )  atom of the 2P-hydroxyl must be incorporated 
into the extruded formic acid, a point that was recognized by Hahn 
and Fishman.I3 
To test the Fishman et al. hypothesis, we have prepared [2p- 
I8O, 1 9-3H] -2P-hydroxy- 10~-formylandrost-4-ene-3,17-dione 2- 
(tert-butyldimethylsilyl) ether14 (6a). The mass spectrum showed 
0002-7863/84/1506-7282$01.50/0 0 1984 American Chemical Society 


^(13)C, ^1H, and ^2H NMR Observation of Trideuterated Cyclopropylmethyl-Cyclobutyl Carbocation: A Configurationally Stable Species

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^(13)C, ^1H, and ^2H NMR Observation of Trideuterated Cyclopropylmethyl-Cyclobutyl Carbocation: A Configurationally Stable Species

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