1719
J. Org. Chem. 1993,58, 1719-1729
Structural and Electronic Characteristics of the Monoboro-Analogs of the Acetylcholine Cation As Determined by the Semiempirical MNDO Computational Method Michael A. Egan and Robert W.Zoellner' Department of Chemistry, Northern Arizona University, P.O.Box 5698, Flagstaff, Arizona 8601 1-5698 Received September 14, 1992
The semiempirical computational method MNDO (modified neglect of diatomic overlap) has been used to calculate the stable conformations and the electronic properties of each of the five possible monoboro-analogs of the acetylcholine cation, ACH+. The thermodynamicallymost stable analog the 5-boro-analog,5, not the commercially-available was determinedto be (CH~)~NBHZCHZOC(O)CH~, isomer (7-boroacetylcholine,H~BN(CH~)ZCHZCHZOC(O)CH~, 7). In addition, the relative Boltzmann distribution populations of the minimum-energy conformations of each analog, as defined by the torsion angles 03-CeC5-N6 and C2_O3-CeC6,were determined. From the conformational energy maps produced by these torsion angles, the 4-boro-analog, (CH~)~NCHZBHZOC(O)CH~, 4, and 7 appear to exhibit the most similarities to ACH+ in the number and the geometries of accessible conformations. Because the monoboro-analogs of ACH+ are zwitterionic neutral molecules, while ACH+ is cationic, few direct electronic comparisons could be drawn. However, molecules exhibiting regional electronic distributions (such as the overall charge on the cationic head) which are similar to those of ACH+ are identified and discussed. Introduction We have developed an interest in the structure and the electronic properties of the acetylcholine cation (ACH+), [(CH3)3NCHzCHzOC(O)CHsl+,as compared to (2-acetoxyethy1)dimethylamine-borane, its isoelectronic and reportedly' isostructural monoboro-analog,HsBN(CH3)r CHzCHzOC(O)CH3,7. The relatively simple synthesis of this molecule' and other boro derivatives of biological moleculesZs has led to an increased interest in their pharmacological activitie~.~*~ In addition to 7, which is commercially-available, four other monoboro-analogs of ACH+ can be envisioned (see Chart I). The monoboro-analogsof ACH+are zwitterionic, neutral molecular species, whereas ACH+ is cationic. The tetravalent boron atom in the monoboro-analogs carries a formal negative charge which balances the formal positive charge on the tetravalent nitrogen atom. This fundamental difference in charge will undoubtedly play an important role in the physical and chemical properties of the monoboro-analogs of ACH+ and may effect the mechanisms through which the molecules interact with biological systems. Due to the important role ACH+ plays in the transmission of nerve impulses, extensive conformational studies have been conducted using X-ray diffraction techniquess-mas well as by Raman spectroscopic?l electron (1)Spielvogel, B.F.;Ahmed,F. U.; McPhail, A. T. J. Am. Chem. SOC. 1986,108,3824. (2)Spielvogel,B. F.;Ahmed,F. U.; McPhail, A. T. Inorg. Chem. 1986, 25,4395. (3)Malone, L.J.; Parry, R. W. Inorg. Chem. 1967,6,817. (4)Koehler, K. A.;Hess, G. P. Biochemistry 1974,13,6345. (6) Mancilla, T.;Santiesteban,F.; Contrerae, R.; Klaebe, A. Tetrahedron Lett. 1982,23,1561. (6)Brown, H. C.; Murray, L. T.Inorg. Chem. 1984,23,2746. (7)Hall, I. H.;Spielvogel, B. F.; Sood, A. Anti-Cancer Drugs 1990,1, 133. (8)Sood, A.; Sood,C. K.; Spielvogel, B. F.; Hall, I. H.; Wong, 0. T.; Mittakanti, M.; Mom, K. Arch. Pharm. 1991,324,423. (9)&rum, H. Acta Chem. Scand. 1969,13,346. (10)Canepa,F. G.; Pauling, P.; &rum, H. Nature (London) 1966,210, 907. (The resulta in this reference have been reinvestigated and are superceded by the resulta in ref 18.)
and NMRzSz7 techniques. Of particular importance is the ability of ACH+ to bind to receptors of the postsynaptic membrane and the eventual degradation of ACH+by acetylcholinesterase (ACHase),two processes highly dependant upon overall molecular conformation. The results reported herein detail the computationallyderived stable conformations of each of the five possible neutral monoboro-analogsof ACH+ as determined by the semiempirical MNDO (modified neglect of diatomic overlap) method. The calculated structures and atomic charge distributions of these monoboro-analogs are compared to the experimental and calculated structures and atomic charge distributions of the conformatione of ACH+. These results were previously reported in preliminary form.28 Computational Methods
All MNDO calculations were performed wing
Quantum Chemistry Program Exchange program no. 455, version 5.0," runningon Apollo/Hewlett-Packard Domain SeriesDN35M)and (11) Sheftar, E.;Kennard, 0. Science (Washington, D.C.)1966,163, 1389. (12)Chothia, C.; Pauling, P. Nature (London) 1968,219,1166. (13)Herdklotz, J. K.; Sam,R. L. Biochem. Biophys. Res. Commun. 1970,40,583. (14)Mahajan, V.;Sam,R. L. J. Cryst. Mol. Struct. 1974,4,16. (16)Manotto, A.; Graziani, R.; Bombieri, G.; Forsellhi, E. J. Cryst. Mol. Struct. 1974,4,263. (16)Sax,M.; Rodriguea,M.; Blank,G.; Wood, M. K.; Pletcher, J. Acta Crystallogr. 1976,B32, 1963. (17)Jagner, S.;Jenaen, B. Acta Crystallogr. 1977,B33,2767. (18)Svinning, T.;&rum, H.; Acta Crystallogr. 1976,B91.1681. (19)Datta, N.;Mondal, P.; Pauling, P. Acta Crystallogr. 1980,B36, 906. (20)Jenaen, B. Acta Crystallogr. 1982,Bs8,1186. (21) Wilson, K. J.; Derreumam, P.; Vertobn, G.; Peticolan, W. L. J. Phys. Chem. 1989,93,1361. (22)Jack, J. J.; Hercules, D. M. Anal. Chem. 1971,43,729. Chem. Commun. (23)Culvenor, C. C. J.: Ham. N. S.J. Chem. SOC., 1%6,15, 537. (24)Cuehley, R. J.; Mautner, H. G. Tetrahedron 1970,26,2151. (26)Partington, P.; Feeney, J.;Burgen, A. S.V. Mol. Pharmacol. 1972, 5. 269. (26)T e d , Y.;Ueyama, M.; Satoh, S.;Tori, K. Tetrahedron 1974,So, 1465. (27)Lichtenberg, D.;Kroon, P. A.; Chan, S.I. J.Am. Chem. Soc. 1974, 96,6934.
0022-3263/93/1968-1719$04.00/0 (8 1993 American Chemical Society
Egan and Zoellner
1720 J. Org. Chem., Vol. 58, No.7, 1993 Chart I
d'
0
dH3
II
nu+
Figure 1. Atomic numbering scheme and major torsion angles for
0
II
1
H3Ch
,CH3
H3B
2
ACE+ and ita monoboro-analogs.
was plotted the calculated heata of formation for the conformations defined by the two torsion angles OS-CCC6-N6and C" 08-cCC6,hereinafter referred to as Taand T ', respectively (Figures 1 and 2). The data used in the creation of the maps were obtained using a stepwise method in which Tawas held constant while T ' was varied in loo incrementa from Oo through 360° while calculating the heat of formation of each incremental conformation, thus creating a 'slice" of the heat of formation grid. The torsion angle Tawas then itself incremented by IOo and the process repeated until a complete 360° by 360° grid of heata of formation was produced. The fiial grids were plotted using the program SURFER, version 4.1_l.% Once the conformational minima on the maps were identified, each minimum was reoptimized without constraita. The fiial geometries thus obtained are the conformational geometries reported herein.
Results 0
It
0
II
5
C\O/CH2.BH;
H3Ch ,CH3 N*LCH3
H3C
DNlOOOO workstations. This MNDO version makes use of the Broyden-FletcherGoldfarb-Shanno algorithmto locate equilibrium geometries on the MNDO potential energy surfaces. All geometries were calculated using the key word PRECISE, increasing the minimization criteria by a factor of 100. Because the use of a given geometrical input, such as an experimentallydetermined crystal structure, favors the conformation associated with that geometry relative to other minima,us an idealized initial trial geometry (ITG)was used in which all pseudotetrahedral angles were set to 109.So, all peeudotrigonal angles to 120.0°, and all heavy atom-heavy atom and heavy atom-hydrogen bond distances to 1.5 and 1.1A,respectively. All (3n- 6) degrees of freedom were allowed to optimize fully from thia ITG (with the exception of the two torsion angles used in the preparation of the conformational energy maps, vide infra). The thermodynamically most stable conformations for each molecule were found by creating a potential energy map on which ~
(28) Egan, M. A.; Zoellner, R. W . 203d National Meeting of the American Chemical Society, San Francisco,CA, 1992, April 6-10, ORGN15.
(29)Quantum Chemistry Program Exchange (QCPE), Indiana University, Department of Chemistry, Bloomington, IN 47405. (30)Broyden, L. G. J. Zmt. Math. Appl. 1970,6,222. (31) Fletcher, R. Comput. J. 1970, 13, 317. (32) Goldfarb, D. Math. Comput. 1970,24,23. (33) Shanno, D. F. Math. Comput. 1970,24,647. (34) Pullman,B.; Courriere, P. Mol. Pharmacol. 1972, 8, 612. (36) Gelin, B. R.; Karplus, M.J. J. Am. Chem. SOC.1976, 97,6996.
Structural Properties. The conformational energy map for ACH+ is found in Figure 3 with seven minima identified by lower case letters; primed letters indicate that a minimum is related to an unprimed minimum with the same letter by reflection through a plane containing T'. The final optimized geometry of the most stable conformation of ACH+ (ACH+-a)in drawn in Figure 4. Table I summarizes the MNDO-calculated structural properties and lists the Boltzmann distribution populations calculated for the minima of ACH+. The conformational energy maps for each of the monoboro-analogs of ACH+ are depicted in Figures 5,7, 9,11, and 13,with the final optimized geometries of the most stable conformations shown in Figures 6,8, 10, 12, and 14. The structural properties and Boltzmann distribution populations for these moleculesare listed in Table I. Figures 15a-19a illustrate the calculated bond distancea for the most stable conformations for each of the five monoboro-analogs of ACH+ (1-a, 2-a, 4-a, &a, and 7-a). Electronic Properties. Table I1 summarizes the electronicproperties of ACH+ and its monoboro-analogs. The column heading "charge on cationic head" represents the algebraic s u m of the MNDO-calculated atomiccharges of all atoms directly bound to nitrogen, those hydrogen atoms bound to the atoms directly bound to nitrogen, and the calculated charge on the nitrogen atom itself.37 Figures 15b-19b illustrate the heavy atom charge distributions for the thermodynamically most stable conformation of each of the monoboro-analogs of ACH+. Discussion
The Structure of ACH+. From the atom-labeling scheme of ACH+,Figure 1,the possible conformations of ACH+and its monoboro-analogscan be described in terms of four major torsion angles: CcC6-N6-C7 (T'), 086'C"N6 (T*),C2-O3-C4-C6(T'), and C'-C2-03-C4 (T'). However, only T ' and TZwere investigated in the present study. The torsion angle T4 involves rotation about a C-N(CH& bond and is expected to adopt a nearly trans (36) Golden Software,Inc., 809 Fourteenth St., Golden, CO 80401. (37) Beveridge, D. L.; Radna, R. J. J. Am. Chem. SOC.1971,93,3769.
J. Org. Chem., Vol. 58, No.7, 1993 1721
Monoboro-Analogs of Acetylcholine
“313
I
H
OC(O)CH3
H
H H
OC(O)CH3
gauche
trans
Figure 2. Newman projections of the trans and gauche confoimations of ACE+ about the O*-CCCs-NO(Taltorsion angle. Mq
I
I
I
Q 300-
0)
g Q)
3 240-
P
P
a
s
100-
I-
s
+ 120-
,
I
I
,
Figure 4. Final optimized geometry of the most stable conformation of acetylcholine (ACH+-a) m determined by -0. Topdrawing,view perpendicular to,and bottom drawing,parallel to the CcCs bond. and the carbonyl oxygen, O’O. This distance is important for the molecular interaction with the ACH+ receptor of ACHase.& Followingthe example of previous inve~tigators,3~*~*~~* then, we have used only T3 and T2 to describe the conformationsof ACH+ and ita monoboro-analogs. (The orientation of T2and Tsin any molecule will be designated by the ordered pair [T2,Tsl). (40)Wilson, I. B. Neurology 1957,41. (41) Liquori,A. M.; Damiani, A.; DeCoen, J. L. J. Mol. Biol. 1988,sS, (38)Radna, R. J.; Beveridge, D. L.; Bender, A. L. J. Am. Chem. SOC. 1973,95,3831. (39) Baker, R. W.; Chothia,C. H.; Pauling,P. J.; Petcher,T. J. Nature (London)1970,230,439.
446. (42) Froimowitz, M.; Gans, P. J. J. Am. Chem. Soc. 1972, 94,8020. (43) Pullman, A.; Port, G . N. J. Theor. Chem. 1978,32,77. (44)Geneon, D. W.; Chrietoffereen, R. E. J. Am. Chem. SOC.1973, W, 362.
Egan and Zoellner
1722 J. Org. Chem., Vol. 58, No.7, 1993 Table I. Structural Information and Boltzmann Distribution Populations for the Acetylcholine Cation and Its Monoboro-Analogs
torsion anglea (deg) Ta TS T4 conformnb [cq3] [03-C41 [CcCs] [Cs-Ne] ACH+-a 7.6 168.7 78.5 178.3 352.2 190.4 280.9 181.2 ACH+-a' ACH+-b 338.6 96.7 75.9 179.1 21.3 180.5 263.3 283.3 ACH+-b' 268.3 153.9 ACH+-c 13.7 174.5 92.0 206.4 346.3 185.5 ACH+-c' ACH+-d 179.9 180.0 359.9 180.0 TI
Bo1tzmann distribn pop. (5%) 23.41 23.41 14.94 14.94 9.34 9.34 4.51
1-a (1-a')' 1-b 1-b' 1-c 1-I?'
209.0
266.8
310.6
192.8
333.5 26.8 195.5 164.0
200.9 158.2 267.4 92.6
48.6 311.3 153.5 206.4
165.7 194.4 174.9 185.3
27.49 27.49 22.17 22.17 0.34 0.34
2-a 2-8' 2-b 2-b' 2-0 2-c'
327.2 33.6 29.9 331.1 14.1 346.0
80.6 279.4 240.5 119.3 278.4 81.7
47.7 312.1 69.5 290.5 135.6 224.5
166.1 193.9 170.9 189.1 177.4 182.7
27.04 27.04 21.46 21.46 1.50 1.50
4-8 4-a' 4-b (4-b')' 4-c
174.2 185.7 195.8
169.3 191.4 139.5
64.9 295.6 61.4
171.1 189.2 168.0
20.2 339.9 322.8 37.3 359.9
274.7 85.4 84.6 275.1 179.8
135.7 224.4 73.3 285.7 179.8
176.3 183.7 178.2 181.3 179.8
30.97 30.97 13.12 13.12 3.79 3.79 2.08 2.08 0.07
6.9
167.4
67.7
173.9
352.9
191.6
291.6
185.8
7.9
84.6
225.2
181.8
1.8
187.1
271.2
177.4
352.2
93.0
188.0
188.0
354.6 9.4
179.9 267.1
180.0 269.8
180.0 177.2
4-c'
4-d 4-d' 4-e 5-a (5-8')' 6-b (5-b')' 6-c (6-c')c 7-a (7-a')c 7-b (7-b')' 7-c 7-d (7-a')'
el
--da
I$
1%
2ia
300
360
C4-C5 Torsion Angle (degrees)
Figure 8. Conformational energy map for 1 with stable conformationa identified by letters a+. Primed letters indicate mirror image conformations of unprimed letters. n
24.80 24.80 24.74 24.74 0.46 0.46 20.29 20.29 13.90 13.90 13.76 8.93 8.93
Torsion angles have been abbreviated so as to include only the two central atoms containing the bond about which the rotational torsion angle is measured. Thue, [CcCsl represents the torsion angle defined by atoms 03-CLc6-N6,[03-C4]represents the torsion angle defined by a t o m C2-o"ccC6, and 80 on. For the monoboremalags of ACH+, the appropriate atomic substitution is assumed to have been made. T h e "right hand rule" for assigning the positive direction of rotation has been applied to these angles. Primed conformations are related to unprimed conformations by reflection with respect to T* and T*. This primed conformation was not determined to be a minimum on the MNDO potential energy surface. However, because the unprimed mirror image conformation did optimize fully, the primed conformation was assumed to exist, and the Boltzmann distribution population of the primed conformation was calculated as well.
*
U
A comparison of the MNDO-calculated bond lengths
and bond anglesto the most stable conformation of ACH+, ACH+-a,to experimental crystal structure data is found in Tables I11 and IV. The crystal structure data vary over a fairly large range, but the MNDO-calculated results for bond lengths and angles are still generally greater than crystal structure data would suggest. However, since theoretical calculationsdescribemolecules in the gas phase without intermolecular interactions, while crystal geometries reflect crystal packing forces and other environ-
Figure 6. Final optimized geometry of the most stable conformation of 1-boro-acetylcholine (1-a) as determined by MNDO. Top drawing,view perpendicular to,and bottom drawing, parallel to the CcCs bond.
mental effects,the MNDO data for ACH+are remarkably consistent with the crystal data. Table V lists the experimentally-determined conformations about T1 through T4 for ACH+ B r , ACH+ I-, ACH+Cl-,and ACH+C104-. Cholineesters, suchae salte
J. Org. Chem., Vol. 58, No.7, 1993 1723
Monoboro-Analogs of Acetylcholine
I
60
\\v
\\\
,
120
,
180
1
240
300
1
360
C4-C5 Torsion Angle (degrees)
Figure 7. Conformational energy map for 2 with stable conformations identified by lettersa-c. Primed letters indicate mirror image conformations of unprimed letters.
P
60
,
,
1
180
120
300
240
I
360
B4-C5 Torsion Angle (degrees)
Figure 9. Conformational energy map for 4 with stable conformationsidentified by letters 8-8. Primed lettersindicate mirror image conformations of unprimed letters.
i
P
V
Figure 8. Final optimized geometry of the most stable conformation of 2-boro-acetylcholine(2-a) as determined by MNDO. Topdrawing,view perpendicular to,and bottom drawing,parallel to the C4-C6bond. of ACH+, are known to adopt different conformations dependingupon the environment of the measurement.'4J7 This observation may explain the varying results and geometries obtained in the crystal data reported. The ACH+ C1- and ACH+ C l O r structures agree with moat theoretical studies in which the global minimum energy
Figure 10. Final optimized geometry of the moat stable conformation of 4-boroacetylcholine (4-a) as determined by MNDO. Top drawing, view perpendicular to, and bottom drawing, parallel to the BCC6 bond. conformation of ACH+ is calculated to be trans-gauche about [T2,Tsl.The gauche-gaucheconformation of ACH+ B r and ACH+ I- correspond to local minima also found in the theoretical studies. Table VI summarizes some of the accessible conformations of ACH+as determined by various computational methods. The PCILO method used by Pullman and co-
1724 J. Org. Chem., Vol. 58, No.7, 1993
-
Egan and Zoellner
. . . . _____.
360,
i
IM)
C4- B5 Torsion Angle (degrees)
Figure 11. Conformational energy map for 5 with stable conformations identified by letters a-c.
P
1
300
3 0
C4-C5 Torsion Angle (degrees)
Figure 13. Conformational energy map for 7 with stable conformations identified by letters a-d.
P
U
Figure 12. Final optimized geometry of the most stable conformation of S-boroacetylcholine (5-a) as determined by MNDO. Top drawing, view perpendicular to, and bottom drawing, parallel to the CcB6 bond. workers&predicta the global minimum of ACH+ to occur with T1= T2 = T' = 180° and T3 = 60°. This compares favorably with the global minimum predicted by MNDO in the current study (T1= 7.6O, T2 = 168.7O, T3= 78.5O, and T' = 178.3O). In nearly all of the theoretical reports describing the geometry of ACH+ (Table VI), the trans(46) Pullman,B.; Courriere, P.; Coubeils,J. L. Mol. Pharmucol. 1971,
7, 391.
1
240
V
Figure 14. Final optimized geometry of the moet stable conformation of 7-boroacetylcholine (7-a) as determined by MNDO. Top drawing, view perpendicular to, and bottom drawing, parallel to the CcCs bond. gauche conformer ([T2,T31= [180°,80"1)was found to be the most stable structure. Using classical semiempirical methods, Froimowitz and found the trans-gauche conformer, [185°,7501,to be more stable than the transtrans conformer, [180°,18501,by 0.46 kcal/mol. Genson and Christofferaen,4 using an ab initio self-consistentfield (SCF) investigation, originally reported that the tramtrans conformer, [180°,18001,was more stable thaneither of the trans-gauche conformers, [180°,8001or [180°,6001, by 10 and 19 kcal/mol, respectively. However, a reinvee-
J. Org. Chem., Vol. 58, No.7, 1993 1726
Monoboro-Analogs of Acetylcholine 0
CH3
Figure 15. MNDO-oalculated bond lengths (a) and heavy atom charge distribution (b) for 1-a.
Table 11. Thermodynamic and Electronic Properties of the Acetylcholine Cation and its Monoboro-Analogs
conformnb ACH+-a ACH+-a' ACH+-b ACH+-b' ACH+-c ACH+-c' ACH+-d
hestof formn (kcal/mol) 98.719 98.721 98.988 98.988 99.269 99.269 99.704
ionizn potent1 (eV) 14.646 14.645 14.766 14.764 14.782 14.782 14.528
dipole moment
-21.597 -21.468 -2 1.468 -18.973 -18.973
9.074 9.336 9.339 8.903 8.903
18.316 19.260 19.233 19.645 19.646
0.8162 0.8327 0.8325 0.8135 0.8136
-55.964 -55.962 -55.823 -55.824 -54.239 -54.239
7.644 7.644 7.710 7.710 7.594 7.594
15.044 15.040 14.821 14.828 15.938 15.938
0.7763 0.7754 0.7663 0.7664 0.7736 0.7734
-65.184 -65.185 -64.671 -63.933 -63.933 -63.576 -63.578 -61.524
9.244 9.244 9.292 9.473 9.474 9.470 9.468 9.001
10.742 10.726 10.461 9.412 9.417 10.363 10.379 12.538
0.7213 0.7212 0.7133 0.7009 0.7009 0.6946 0.6946 0.7146
-81.894 -81.893 -79.512
10.511 10.514 10.173
7.333 7.308 5.002
0.1192 0.1131
-7 1.589 -71.363 -71.359 -71.103
11.275 11.301 11.294 11.273
6.910 5.099 6.589 5.469
-0.0273 -0.0478 -0.0292 -0.0431
1-a
1-b 1-b' 1-c 1-c' 4 4845
h
e
to
12.2
CH3
2-a 2-a' 2-b 2-b' 2-c
2-c'
Figure 16. MNDO-calculated bond lengths (a) and heavy atom charge distribution (b) for 2-a. 0
CH3
4-a 4a-a' 4-b 4-c 4-c'
4-d 4-d' 4-e 6-a
.01119
n
-0 1214
CH3
6-b 6-c 7-a
Figure 17. MNDO-calculated bond lengths (a) and heavy atom charge distribution (b) for 4-a. 0
Figure 18. MNDO-calculated bond lengths (a) and heavy atom charge distribution (b) for 5-a. 0
7-b 7-c 7-d
(D) d d d d d d d
chargeon cationic head' (e)e 0.9lOg 0.9110 0.8916 0.8920 0.8925 0.8926 0.9137
0.0999
OThe algebraic sum of all of the atomic charges within the -CHzN(CH& portion of the molecule. For the monoboro-analogs of ACH+, the appropriate atomic substitution is assumed to have been made. Primed conformations are related to unprimed conformations by reflection with respect to the torsion anglee T*and F. c Calculated charge is reported in fractions of the electron charge, e. d Undefined for charged species. Table 111. Experimental and Calculated Bond Lengths. for the Acetylcholine Cation and Selected Acetylcholine Salts ACH+ bond (C1-)b (Br-)c (I-)d ACH+-af C1-C2 1.49(1) 1.487(6) 1.48(1) 1.51(1) 1.522 C q 3 1.38(1) 1.358(5) 1.37(1) 1.38(1) 1.382 CW1O 1.18(1) 1.192(4) 1.20(1) 1.20(1) 1.222 Ow' 1.45(1) 1.452(5) 1.43(1) 1.43(1) 1.399 C'-Cs 1.47(1) 1.500(5) 1.50(1) 1.47(1) 1.561 C"Ns 1.49(1) 1.513(4) 1.53(1) 1.52(1) 1.563 NBC' 1.50(1) 1.4966) 1.50(1) 1.49(1) 1.542 Ns-Ca 1.49(1) 1.498(6) 1.49(1) 1.51(1) 1.540 N'3-C9 1.52(1) 1.502(4) 1.52(1) 1.49(1) 1.646 a Bond lengths are given in A with estimated standard deviations in parenthem. Reference 13. Reference 18. Reference 17. Reference 14. f This work.
*
Figure 19. MNDO-calculated bond lengths (a) and heavy atom charge distribution (b) for 7-a.
tigation of their work by Port and Pullman4 reported that the trans-gauche conformer was indeed more stable than the trans-trans conformer by about 0.8 kcal/mol. (46)Port, G.N.J.; Pullman, A. J . Am. Chem. Soc. 1973, 95, 4069.
In past theoretical studies, as many as 11 different minima have been found on the ACH+ potential energy surface. With two exceptions,4'P4 the trans-gauche conformation has been found to be more stable than the fully extended trans-trans conformation. However, the magnitude of the energy difference between the tram-gauche and the trans-trans conformers of ACH+ has varied from as little as 0.69 kcal/mo141to as much as 3.78 kcal/mol,a dependingupon the method used. According to Schulman
1726 J. Org. Chem., Vol. 58, No.7, 1993
Egan and Zoellner
Table IV. Experimental and Calculated Bond Angles. for the Acetylcholine Cation and Selected Acetylcholine Salts ACH+ angle (C1-)b (BrY (I-)d (C104-)e ACH+-af C'-CLo'o 129(1) 125.9(4) 127(0.8) 128(1) 128.2 O3-C"OLo 123(1) 122.8(4) 121(0.8) 121(1) 118.4 113.4 108(1) 111.3(3) 112(0.8) 111(1) C'-CLOs C2-09-C4 115(1) 115.7(3) 116(0.8) 115(1) 124.9 OR-C4-C5 111(1) 111.6(3) lll(0.8) 109(1) 109.8 C4-C5-N6 119(1) 116.4(3) 116(0.8) 119(1) 119.1 C5-N6-C7 111(1) 110.7(3) lll(0.8) 109(1) 112.4 C5-N6-C' 111(1) 112.2(3) llO(O.8) 108(1) 111.6 C5-N6-C9 107(1) 107.1(2) 107(0.8) 112(1) 107.2 C7-N6-C9 109(1) 109.8(3) 107(0.8) llO(1) 109.2 CkN6-C9 111W 108.6(3) 112(0.8) 111(1) 108.2 C7-N6-C8 108(1) 108.3(3) lll(0.8) 107(1) 108.1 ~~~
~
a Estimated standard deviations of bond angles (deg) are given in parentheses. Reference 13. Reference 18. d Reference 17. e Reference 14. / This work.
Table V. Experimentally-Determined Solid-State and MNDO-Derived Conformations of the Acetylcholine Cation ACH+ torsion angle (deg) ( B r T (I-)b ( C W ACH+-ae C'-C"O"C4 (TI) 4.1 0.0 0.8 5.2 7.6 Cz-O"C4-C5 (TZ) 78.9 83.0 179.8 193.1 168.7 0"C4-C5-N6 (T3) 78.4 89.0 73.7 84.7 78.5 C4-C5-N6-C7 (T4) 175.5 53.0 168.3 171.4 178.3 gauche-gauche' trans-gauche' Reference 18. Reference 17. Reference 14. Reference 13. This work. f Conformation with respect to TZ and T3, respectively. Table VI. Minimum Energy Conformations of the Acetylcholine Cation As Determined from Other Theoretical Studies conformational torsion angle (deg) Cl-CLOLC4 C2-03-C4-C5 03
