Reaction of aziridinium ions with organometallic reagents: Optimization of the key step of ecopipam synthesis

Article abstract of DOI:10.1016/S0040-4039(02)01337-0

Formation, stability and reactivity of aziridinium ions 3 towards organometallic reagents was explored and optimized for the efficient preparation of key drug intermediate 5c.

Full text of DOI:10.1016/S0040-4039(02)01337-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6121–6125
Reaction of aziridinium ions with organometallic reagents:
optimization of the key step of ecopipam synthesis
David R. Andrews, Vilas H. Dahanukar,* Jeffrey M. Eckert, Dinesh Gala, Brian S. Lucas,
Doris P. Schumacher and Ilia A. Zavialov*
Department of Synthetic Chemistry, Schering-Plough Research Institute, 1011 Morris Avenue, Union, NJ 07083, USA
Received 29 May 2002; revised 2 July 2002; accepted 3 July 2002
Abstract—Formation, stability and reactivity of aziridinium ions 3 towards organometallic reagents was explored and optimized
for the efficient preparation of key drug intermediate 5c. © 2002 Elsevier Science Ltd. All rights reserved.
Aziridinium ions are versatile synthetic intermediates
with a rapidly expanding scope of applications.
Efficient methods for their in situ generation and cap-
ture by a variety of heteroatomic nucleophiles such as
amines, alcohols, halides, thiols and phosphines have
N,N-dialkylated aziridinium ions could offer an attrac-
tive alternative as versatile precursors to the various
functionalized amine derivatives.
As a part of our ongoing program on the synthesis of
1
recently been reported. In contrast, the synthetically
novel dopamine D antagonists, we required the prepa-
1
useful reaction of aziridinium ions with carbon nucle-
ophiles such as organometallic reagents remains largely
ration of large quantities of drug candidate ecopipam 1
(Scheme 1). A number of different synthetic approaches
to prepare 1 were proposed and evaluated in our labo-
ratories. In the most direct and efficient route, the
2
unexplored. While the direct addition of organometal-
1
a,b
lics to N-alkyl aziridines is difficult,
more reactive
R
N
Cl
Cl
2a R = Me
MeO
HO
2b R = CH2CH(OMe)2
Cl
R1
N
HCl
MeO
N
R2
Me
4a
or
MgBr
OMe
Sch 39166
1
5
5
5
a R1 = H, R2 = Me
OMe
b R1 = H, R2 = CH2CH(OMe)2
c R1 = Me, R2 = CH2CH(OMe)2
N Me
X
3a X = BF4
3b X = OTf
3c X = Cl
Scheme 1.
Keywords: aziridinium ions; aziridines; Grignard reagents; electron affinity; SET mechanism.
*
Corresponding authors. Fax: (908) 820-6640; e-mail: vilas.dahanukar@spcorp.com; ilia.zavialov@spcorp.com
0
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01337-0

6
122
D. R. Andrews et al. / Tetrahedron Letters 43 (2002) 6121–6125
desired trans-ring stereochemistry was envisioned to be
set at the key step by regio- and diastereoselective
opening of either aziridine 2 or aziridinium ion 3 with3
p-chloro-m-methoxyphenylmagnesium bromide 4a.
While aziridines 2a and 2b proved to be unreactive
towards 4a under a variety of conditions screened,
aziridinium ions 3 did react as expected to furnish 5c as
a single isomer, albeit in low yields and poor overall
piperazinium dimers whose facile generation from
N,N-disubstituted aziridinium ions is well documented
5
in the literature. The rate of aziridinium ion decay in
this case did not appear to depend on the reaction
solvent and was strongly accelerated at higher tempera-
tures. Such instability of 3a and 3b in solution rendered
their handling on scale difficult and resulted in unac-
ceptably low yields (40–45%) of product 5c contami-
nated with piperazinium impurities.
4
mass balance. Our initial attempts to increase the yield
of the desired product by standard variation of reaction
parameters (e.g. temperature, solvent, order of addi-
tion) were not successful, prompting us to undertake a
more detailed study of the formation of aziridinium
ions 3, their stability and reactivity with organometallic
reagents.
Interestingly, when aziridinium chloride 3c was used in
the reaction with 4a, consistently higher yields of 5c
were obtained (55–60%) with no detectable piper-
azinium impurities. The most common way of prepar-
ing aziridinium chlorides from amino alcohols is via
treatment of the latter with MsCl or TsCl in the
Aziridinium ions 3a and 3b could be prepared in good
yields by the direct methylation of aziridine 2b at
1
presence of triethylamine. These conditions were not
readily applicable in our case due to the presence of
byproduct triethylamine hydrochloride which was
incompatible with organometallics. Therefore, our ini-
tial experimental protocol for the preparation of 5c
through aziridinium chloride 3c involved deprotonation
of b-amino alcohol precursor 6 with HexLi in the
presence of 1,10-phenanthroline indicator, treatment of
the resulting lithium alkoxide with TsCl at −20°C to
give tosylate 7a, followed by addition of 7a to the
solution of Grignard reagent 4a kept at 25°C (Scheme
2). NMR spectroscopy studies of the tosylate formation
−20°C. Moreover, aziridinium tetrafluoroborate 3a was
isolated out of reaction solution by precipitation with
diethyl ether and proved quite stable as a solid even
4
upon prolonged storage. To assess the stability of the
aziridinium ions 3a and 3b in solution under the typical
reaction conditions (THF, −20°C), corresponding ion
solutions in several deuterated solvents were prepared
1
and monitored by H NMR. The results of these exper-
iments indicated that both aziridinium tetra-
fluoroborate 3a and aziridinium triflate 3b decomposed
in solution over the course of several hours even at
−
20°C. Among the aziridinium decomposition prod-
ucts, the major ones were identified as cis- and trans-
step in THF-d indicated that 7a was quite stable at
8
−20°C but quickly decomposed upon warming with the
Scheme 2.

D. R. Andrews et al. / Tetrahedron Letters 43 (2002) 6121–6125
6123
elimination of lithium tosylate to give two new species
of 11 obtained upon the methanolysis of a small reac-
9
whose spectra were consistent with chloroamines 8 and
tion aliquot. Using this assay, we established that
13
9
5
(characteristic C NMR signals for 8: 68.2, 61.2,
7.6, 53.9 ppm; for 9: 70.7, 59.3, 58.3, 53.3 ppm).
formation of aziridinium chloride from 6 in our HexLi/
TsCl procedure proceeded in 90–92% solution yields,
and that once formed, the ‘total aziridinium’ concentra-
tion in solution remained constant over several weeks
at 25°C. Besides TsCl, we also examined a range of
other activating reagents containing chloride such as
MsCl, ClPO(OPh) , ClPO(OEt) , SOCl , and (COCl) .
1
13
Inspection of H and C NMR spectra of the reaction
mixture taken at different temperatures during the
warm up of 7a and comparison to the spectra of
authentic aziridinium tetrafluoroborate 3a confirmed
the absence of detectable quantities of aziridinium chlo-
ride intermediate 3c at any point during the reaction.
After ageing the chloroamine mixture at 25°C for sev-
2
2
2
2
The highest solution yields of aziridinium chloride of
95–97% were obtained using ClPO(OPh) , which there-
2
1
13
eral days, H and C NMR indicated complete rear-
rangement of chloroamine into more stable
fore was selected as the preferred reagent. Better yields
8
of aziridinium chloride obtained in ClPO(OPh) proce-
2
chloroamine 9. The identity of chloroamine 9 was
dure were primarily due to improved reaction conver-
sion and reduced amount of unreacted 6. With TsCl
and MsCl, 3–5% of 6 remained unreacted even when
using large excesses of these reagents. Another advan-
further ascertained by its isolation and complete spec-
6
troscopic characterization. These results are consistent
with the findings of other workers in structurally simi-
lar pseudoephedrine and ephedrine systems where ben-
zylic chloroamine was proposed to be the initially
formed kinetic product which then slowly rearranged
into the more stable non-benzylic chloroamine via
tage of ClPO(OPh) compared to TsCl and MsCl was
2
that the rate of phosphate adduct 7b conversion to
chloroamines was relatively slow below −10°C, allowing
for smooth transfers on scale without the risk of line
plugging by precipitating lithium salt.
7
intermediate aziridinium chloride.
Although aziridinium chloride 3c could not be detected
spectroscopically, it clearly was a common reaction
intermediate on the path from 7a, 8 and 9 to the
product 5c (Scheme 2). Neither tosylate 7a nor
With a robust and high yielding procedure for the
generation of aziridinium chloride 3c in hand, we next
turned our attention to the optimization of the Grig-
nard addition step. Despite the benefits realized on
switching from aziridinium triflate and tetra-
fluoroborate to aziridinium chloride, overall solution
yields of 5c from 6 remained below 60%. In order to
establish the causes behind the depressed product yield,
we added phosphate 7b preformed at −20°C to 4a in
THF at 25°C and monitored the progress of the reac-
tion by taking aliquotes of reaction mixture at specified
time intervals, quenching them with methanol and
assaying for the concentration of 5c and 11. As the
solution yield of 5c peaked at 55–60% after approxi-
8
chloroamines 8/9 coupled with 4a directly. Instead,
1e,f
chloroamines 8/9 served as a stable latent form
of
aziridinium chloride 3c, capturing it on formation and
releasing it on demand in a low steady-state concentra-
tion. The benefit of such ‘chloroamine sink’ in the
reaction with 4a was apparently in preventing the
buildup of aziridinium chloride in solution and its
unproductive dimerization. Indeed, in comparison to
‘
naked’ aziridinium ions 3a and 3b, reaction of pre-
formed tosylate 7a with 4a resulted in about 10%
increase in solution yields of 5c and minimized piper-
azinium impurity formation.
mately
4 h reaction time, concentration of 11
approached zero indicating that there was no more
unreacted aziridinium species left in the reaction mix-
ture. Apparently, the remaining 40% of aziridinium
species was consumed in some unproductive side reac-
tions. A thorough analysis of reaction mixture revealed
the presence of three dimeric impurities 12, 13 and 14
In order to assess the efficiency of aziridinium chloride
formation step, we needed a reliable assay method for
the ‘total aziridinium’ concentration in solution. After
screening several derivatizing agents, we found that
reaction of a mixture of 7a, 8 and 9 with methanol at
ambient temperature was rapid, quantitative and gave
10
(Scheme 3). The presence of these dimeric impurities
points to the operation of the SET mechanism, which is
typical for reactions of Grignard reagents with elec-
trophiles possessing low reduction potential (e.g. ben-
11 as the sole reaction product. Given the ready
availability and stability of analytical standards of 11,
we developed a simple and convenient HPLC assay
method whereby the ‘total aziridinium’ concentration in
the reaction mixture was determined from the amount
11
12
zophenone). Indeed, ab initio calculations predict
for cation 3c adiabatic electron affinity E =5.25 eV
ad
and vertical electron affinity E =2.10 eV in the gas
v
OMe
MeO
MeO
Cl
OMe
Cl
Me OMe
N
Me N
N Me
OMe
OMe
OMe
12
13
14
Scheme 3.

6
124
D. R. Andrews et al. / Tetrahedron Letters 43 (2002) 6121–6125
a
Table 1. Effect of Cu(I) salt additives on the rate and yield of reactions of Grignard reagents 4a and 4b with phosphate 7b
Entry
Grignard reagent
Cu(I) salt added
Reaction time (h)
Product (solution yield, %)
1
2
3
4
5
4a
4b
4a
4a
4b
None
None
5 mol% CuCN·2LiCl
5 mol% CuCl·2LiCl
5 mol% CuCl·2LiCl
4
5c (58)
10 (95)
5c (82)
5c (80)
10 (94)
0.5
0.5
0.5
0.5
Product ratio 5c/10
6
7
8
4a+4b
4a+4b
4a+4b
None
5 mol% CuCl·2LiCl
5 mol% CuCN·2LiCl
1
1
1
1/5.4
1/1.7
1/1.5
a
See Ref. 18 for experimental procedure. Experiments on competition kinetics performed using equimolar mixtures of 4a (2.5 equiv.) and 4b (2.5
equiv.).
phase, demonstrating that aziridinium ion 3c is a better
pared p-chloro-m-methoxyphenylzinc bromide and
commercially available phenylzinc bromide proved to
be unreactive towards 7b and 8/9, with none of the
expected product observed even after 48 h reaction time
at 40°C.
13
electron acceptor than benzophenone (E =0.64 eV)
ad
1
4
and even p-benzoquinone (E =1.85 eV). Thus, the
ad
electron transfer from Grignard reagent to aziridinium
ion is expected to be fast and the subsequent car-
15
bonꢀcarbon bond formation to be rate limiting. Lack
of intermediate aziridinium radical racemization on for-
mation of 5c is apparently a consequence of close
In summary, we have explored the formation, stability
and reactivity of aziridinium ions
3
towards
organometallic reagents and identified the optimum
reaction conditions necessary for the preparation of
ecopipam intermediate 5c in high yield and stereoselec-
tivity. Existing in equilibrium with chloroamines 8/9,
aziridinium chloride 3c proved superior to unstable
dimerization-prone ‘naked’ aziridinium triflate and tet-
rafluoroborate. Efficient generation of aziridinium chlo-
ride 3c in solution from b-amino alcohol 6 was
1
6
radical association within a solvent cage.
In contrast to slow reaction with deactivated 4a (Table
, entry 1), we found that reaction of 7b with more
1
nucleophilic p-methoxyphenylmagnesium bromide 4b
proceeded almost instantaneously to give 10 quantita-
tively as a single isomer with very small amounts (<1%
17
combined) of dimeric radical impurities (entry 2).
achieved using HexLi/ClPO(OPh) method. While reac-
2
Following this lead, we attempted to increase the nucle-
ophilicity of reagent 4a by adding catalytic amounts of
copper(I) salts. Gratifyingly, addition of just 5 mol% of
CuCN·2LiCl or CuCl·2LiCl salt to the solution of
organomagnesium reagent 4a prior to its coupling with
tive organomagnesium reagents added to aziridinium
chloride 3c quantitatively, the use of catalytic amounts
of copper(I) salts was necessary to accelerate the addi-
tion of deactivated p-chloro-m-methoxyphenylmagne-
sium bromide and minimize the amount of radical
byproducts. Reaction of aziridinium precursors 7b and
8/9 with aryllithium and arylzinc reagents failed to
provide any of the expected product. Further investiga-
tions of this interesting and useful reaction are cur-
rently underway and will be reported in due course.
7
b dramatically increased the rate of the reaction and
18
yield of 5c by at least 20% (entries 3 and 4). The
amount of impurities 12–14 was also significantly
reduced. Apparently, copper(I) catalysts accelerated the
rate limiting recombination of intermediate aryl-aziri-
dinium radical pair, thereby shifting the mechanism
towards more polar and reducing the chances for radi-
cal pair diffusive breakup and dimerization. This postu-
late was also supported by simple competition kinetics
experiments where equimolar mixtures of 4a and 4b
were reacted with 7b (entries 6–8). In the presence of
catalytic amounts of copper(I) salts, the difference in
reaction rates between the two organomagnesium
reagents became significantly smaller.
Acknowledgements
We would like to thank Professors David B. Collum
and Ronald Breslow for helpful discussions. Drs. Larry
Heimark, Mohindar Puar and Charlie Evans are
thanked for help with LCMS and NMR analyses.
Besides organomagnesium reagents, other organometal-
lic reagents examined in the present reaction failed to
provide any of the desired product. Thus, reactions of
References
19
phenyllithium and p-chloro-m-methoxyphenyllithium
with 7b at −20°C resulted in exclusive attack at the
phosphorus atom of phosphate moiety to give back
starting material 6, while reactions of these aryllithiums
with chloroamine mixture 8/9 at 0–25°C resulted in
deprotonation and formation of various elimination
byproducts (mostly naphthalene). Both freshly pre-
1. (a) McCoull, W.; Davis, F. A. Synthesis 2000, 10, 1347–
1365; (b) Comprehensive Heterocyclic Chemistry II;
Padwa, A., Ed.; Pergamon Press: Oxford, 1996; Vol. 1A,
pp. 1–505; (c) Rayner, C. M. Synlett 1997, 11–20; (d) De
Sousa, S. E.; O’Brien, P. Tetrahedron Lett. 1997, 27,
4885–4888; (e) Sharpless, K. B.; Chuang, T.-H. Org. Lett.

D. R. Andrews et al. / Tetrahedron Letters 43 (2002) 6121–6125
6125
1
999, 1, 1435–1437; (f) Sharpless, K. B.; Chuang, T.-H.
described in Ref. 12b with the following modifications:
global conformation minima were located using MMFF
conformational driver and their geometries optimized at
HF/3-21G(*) level; B3LYP/6-31G(d) method was used
for final single-point energy calculations; (b) Beveridge,
A. J.; Williams, M.; Jenkins, T. C. J. Chem. Soc., Fara-
day Trans. 1996, 92, 763–768.
Org. Lett. 2000, 2, 3555–3557.
2
. (a) Ganellin, R. C.; Hollyman, D. R.; Ridley, H. F. J.
Chem. Soc. (C) 1967, 2220–2225; (b) Tanner, D.; Somfai,
P. Tetrahedron 1986, 42, 5657–5664; (c) Katagiri, T.;
Takahashi, M.; Fujiwara, Y.; Ihara, H.; Uneyama, K. J.
Org. Chem. 1999, 64, 7323–7329; (d) Graham, M. A.;
Wadsworth, A. H.; Thornton-Pett, M.; Rayner, C. M.
Chem. Commun. 2001, 11, 966–967; (e) Overman, L. E.;
Sharp, M. J. J. Org. Chem. 1992, 57, 1035–1038; (f)
Grieco, P. A.; Carroll, W. A. Tetrahedron Lett. 1992, 33,
13. Chen, E. C. M.; Wentworth, W. E. J. Chem. Phys. 1983,
87, 45–49.
4. Briegleb, G. Angew. Chem. 1964, 76, 326–341.
5. Yamataka, H.; Matsuyama, T.; Hanafusa, T. J. Am.
Chem. Soc. 1989, 111, 4912–4918.
1
1
4
401–4404.
. Hou, D.; Schumacher, D. Curr. Opin. Drug Discov. Dev.
001, 4, 792–799.
3
4
1
6. Smith, M. B.; March, J. March’s Advanced Organic
Chemistry; John Wiley and Sons: New York, 2001; pp.
2
. Draper, R. W.; Hou, D.; Iyer, R.; Lee, G. M.; Liang, J.
T.; Zmas, J. L.; Tormos, W.; Vater, E. J.; Gunter, F.;
Mergelsberg, I.; Scherer, D. Org. Process Res. Dev. 1998,
402–404.
1
7. We have also examined a range of other substituted
phenylmagnesium bromides in reaction with 7b. Overall,
good Hammett correlation of relative rates log krel with
S| was obtained (z=−1.7). Increase in respective reac-
tion yields generally paralleled the increase in log krel.
8. Typical experimental procedure: To compound 6 (10.0 g,
2
, 175–185.
5
6
. (a) Leonard, N. J.; Paukstelis, J. V. J. Org. Chem. 1965,
3
0, 821; (b) Olah, G. A.; Szilagyi, P. J. J. Am. Chem. Soc.
1
969, 91, 2949–2955; (c) Golding, B. T.; Kebbell, M. J.;
1
Lockhart, I. M. J. Chem. Soc., Perkin Trans. 2 1987,
05–713.
. Compound 9 data: H NMR (THF-d , 400 MHz) l:
37.7 mmol, 1 equiv.) were added 1,10-phenanthroline (5
7
mg) and anhydrous THF (60 mL). The solution was
cooled to −20°C and n-hexyl lithium (16 mL, 2.5 M
solution in hexanes, 40 mmol, 1.05 equiv.) was added
dropwise. Towards the end of addition, the red-brown
colored reaction mixture turned dark red in color. After
stirring the reaction mixture at −20°C for 10 min,
diphenyl chlorophosphate (8.6 mL, 41.5 mol, 1.1 equiv.)
was added dropwise and the reaction mixture was held at
1
8
7
.60–7.10 (m, 4H), 4.55 (m, 1H), 4.45 (m, 1H), 4.05 (d,
J=6.5 Hz, 1H), 3.30 (s, 3H), 3.25 (s, 3H), 3.00–2.90 (m,
1
3
4
H), 2.31 (s, 3H), 2.28 (m, 1H), 2.15 (m, 1H). C NMR
(
THF-d , 100.6 MHz) l: 137.4, 130.6, 129.6, 128.9, 127.7,
8
1
25.8, 104.8, 70.7, 59.3, 58.3, 53.3, 53.2, 38.2, 32.5, 28.1.
HRMS-FAB calcd for C H ClNO 284.1417, found
2
15
23
2
84.1411.
−
20°C for 1 h. Separately, a solution of CuCl·2LiCl was
7
8
. Dieter, K. R.; Deo, N.; Lagu, B.; Dieter, J. W. J. Org.
Chem. 1992, 57, 1663–1671.
. We were able to find only one documented example of
reaction of b-chloroamines with Grignard reagents, see
Ref. 2a. The authors speculated that the reaction pro-
ceeded at least in part through the attack of Grignard
reagent on isomeric chloroamines and not on the inter-
prepared by adding anhydrous THF (5 mL) to a mixture
of copper(I) chloride (0.19 g, 1.9 mmol, 0.05 equiv.) and
lithium chloride (0.16 g, 3.8 mol, 0.10 equiv.) and this
solution was cannulated to the p-chloro-m-methoxy-
phenylmagnesium bromide (54 mL, 56.6 mmol, 1.5
equiv., 1.05 M in THF) held at 25°C. The mixture was
stirred for 5 min, and the aziridinium ion solution held at
−20°C was added to the Grignard solution via a cannula
and then heated to 40–45°C for 1 h. The reaction mixture
was cooled to 0°C, quenched with aqueous ammonium
chloride solution, extracted with methyl tert-butyl ether
and subjected to acid–base workup. Crude product was
mediate aziridinium ion.
. Compound 11 data: H NMR (CDCl , 400 MHz) l: 7.38
1
9
3
(m, 1H), 7.18 (m, 2H), 7.05 (m, 1H), 4.50 (d, J=7.0 Hz,
1
3
2
H), 4.50 (m, 1H), 3.41 (s, 3H), 3.40 (s, 3H), 3.38 (s, 3H),
.05 (ddd, J=10.5 Hz, 7.0 Hz, 4.5 Hz, 1H), 2.78 (m, 2H),
.70 (m, 2H), 2.41 (s, 3H), 2.05 (m, 1H), 1.65 (m, 1H).
1
3
purified by chromatography to provide analytical sample
C NMR (CDCl , 100.6 MHz) l: 138.1, 136.5, 128.6,
3
1
of 5c (12.1 g, 75.0% isolated yield). H NMR (CDCl , 400
1
5
2
28.0, 127.1, 125.7, 103.6, 78.1, 63.6, 56.2, 55.7, 53.7,
3.2, 38.7, 28.2, 22.7. HRMS-FAB calcd for C H NO
3
3
MHz) l: 7.30–6.65 (m, 7H), 4.12 (t, J=5.6 Hz, 1H), 4.09
16
26
(
d, J=11.3 Hz, 1H), 3.82 (s, 3H), 3.21 (s, 3H), 3.12 (s,
H), 2.95 (m, 3H), 2.60 (dd, J=5.6, 11.3 Hz, 2H), 2.31 (s,
H), 2.08 (m, 1H), 1.80–1.70 (m, 1H); C NMR (CDCl3,
00.6 MHz) l: 154.3, 146.3, 139.2, 136.5, 130.2, 129.2,
28.1, 125.7, 125.6, 122.2, 119.5, 113.3, 103.7, 67.2, 56.3,
5.8, 53.9, 52.6, 49.2, 37.7, 29.6, 22.3; FABMS: 235, 271,
80.1913, found 280.1910.
3
3
1
1
5
3
7
1
1
1
0. Impurity 12 was obtained as a single trans-diastereomer,
while impurity 13 was a mixture of three diastereomers.
Formation of impurity 14 was strongly enhanced when
TsCl was used in place of ClPO(OPh)2.
1. (a) Ashby, E. C. Pure Appl. Chem. 1980, 52, 545–569; (b)
Ashby, E. C.; Laemmle, J.; Neumann, H. M. Acc. Chem.
Res. 1974, 7, 272–280; (c) Hoffman, R. W.; Holzer, B.
Chem. Commun. 2001, 5, 491–492.
13
14, 358, 390. Anal. calcd for C H ClNO : C, 67.77; H,
22 28
3
.24; N, 3.59. Found: C, 67.77; H, 7.29; N, 3.69.
1
9. p-Chloro-m-methoxyphenyllithium was found to undergo
facile dimerization even at low temperatures and was
utilized immediately on preparation.
2. (a) Calculations performed using Spartan’02; Wavefunc-
tion Inc., Irvine, CA. We employed the procedure