New-dimensional cyclam. Synthesis, crystal structure, and chemical

New-dimensional cyclam. Synthesis, crystal structure, and chemical properties of macrocyclic tetraamines bearing a phenol pendant. Eiichi Kimura, Tohr...
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Inorg. Chem. 1987, 26, 2975-2983

2975

Contribution from the Department of Medicinal Chemistry, Hiroshima University School of Medicine, Kasumi, Minami-ku, Hiroshima 734, Japan, Department of Chemistry, College of General Education, Hirosaki University, Bunkyo, Hirosaki 036, Japan, and Faculty of Pharmaceutical Sciences, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113, Japan

New-Dimensional Cyclam. Synthesis, Crystal Structure, and Chemical Properties of Macrocyclic Tetraamines Bearing a Phenol Pendant Eiichi Kimura,*+ Tohru Koike,t Keiji Uenishi,t Markus Hediger,t Miyuki Kuramoto,+ Shuzo Joko,t Yoko Arai,+ Mutsuo Kodama,l and Yoichi Iitakae Received A p r i l 15, 1987

Newly devised 13-15-membered macrocyclic tetraamine (N4)ligands attached with a phenolic pendant (10, 11, 13, and 15) have been synthesized to determine the influence of the phenol on the cation-enclosure properties of the macrocyclic N 4 and, conversely, the influence of the proximate cations encompassed in N 4 macrocycles on the chemical behavior of the phenolate pendant. The synthesis involves a novel annelation reaction between coumarin and suitable tetraamines. The favorable location of phenol in the periphery of the macrocycle has been confirmed by the X-ray crystal structure of the phenol-pendant 14-membered N4 (cyclam) l l b . Dissociation of the phenolic protons is facilitated by incorporation of metal ions into the macrocycle, and the resulting phenolate ion atop stabilizes otherwise unstable complexes. The crystal structures of I l b and its Cu" complex 17a have been determined. The crystals of l l b (C16H28N40) are monoclinic, space group P2,/a, with four molecules in the unit cell of dimensions u = 15.335 (8) A, b = 8.535 (5) A, c = 13.331 (7) A, and 0 = 105.17 (5)'. Crystals of l7a(CIO4).H2O (C16H27N,0CuC104~H,0) are also monoclinic, space group P 2 , / n , with four molecules in the unit cell of dimensions a = 30.943 ( 2 0 ) A, b = 8.188 (4) A, c = 7.936 (4) A, and /3 = 95.89 (5)O. The structures were solved by the direct method for l l b and the heavy-atom method for 17a and refined by block-diagonal least-squares calculations: for I l b , R = 0.061 for 2635 independent reflections, and for 17a, R = 0.066 for 3703 independent reflections. The five-coordinate, square-pyramidal geometry around copper is illustrated with the phenolate oxygen at nearly the apex of the pyramid. The pH-metric and polarographic titration of Cu"-llb revealed a complexation constant ([CuH_,L+]/[Cul'][H-,L-]) of 1.0 X M-I (H_,L is the phenolate species) and stability enhancement of IO2 by the phenolate coordination. Its strong u donation contributes to stabilization of higher oxidation states of metal ions.

-

S a t u r a t e d polyamine macrocycles possess cavities capable of providing a favorable environment for the reception of guest cation and anion species.' The strength of the ion binding is determined by ion size, macrocyclic cavity size, and ligand conformation.2 Typically, t h e 14-membered t e t r a a m i n e cyclam incorporates transition- and heavy-metal ions into its cavity t o form stable, square-planar N4 complexes with several configuration^.^ The realization t h a t t h e ion-binding characteristics of t h e macrocyclic ligand can be significantly modified by attaching additional binding sites t o t h e periphery of t h e macrocycle has been an important feature of recent developments in macrocyclic ~ h e l a t e s . The ~ molecular design, however, has not been extensive as yet both in synthetic tactics and in variation of additional donor functions. Few systemsS have evolved in which t h e reception of guest cation species is triggered or facilitated by a reversible chemical change in a strategically placed new functional group. Were such synergism t o occur, it might be revealed by a change in ion-binding characteristics or modified reactivity of t h e functional group. We have now developed a novel synthetic method t h a t yields the new series of macrocyclic tetraamines 11, 13, and 15 bearing a p e n d a n t phenolic group t h a t is able t o ideally project into the cavity. We have found t h a t this phenolic group indeed influences t h e ion-incorporating properties of N, macrocycles a n d t h a t , conversely, t h e chemical activity of the phenol functions attached to N4 is changed. The idea of apical phenolate coordination has come in part from an active center of catalases6 or abnormal heme' t h a t contain iron(II1) complexes of square-planar macrocyclic N, porphyrins cofunctionalyzed with an apical phenolate donor from t h e surrounding proteins. Although a number of synthetic efforts have been m a d e t o intramolecularly a t t a c h an imidazole or other heterocyclic donors t o porphyrinss or saturated N4macro cycle^,^ there were none that have disclosed t h e effect of t h e distinct apical coordination of phenol on t h e chemistry of square-planar N4 complexes. Earlier communications briefly reported synthesis of t h e phenol-pendant c y c l a m l l b from coumarin,'O an X - r a y structure of its Nil1complex," and t h e 13-membered N4 complex

Hiroshima University School of Medicine.

* Hirosaki University. 5 University of

Tokyo.

0020-1669/87/1326-2975$0l.50/0

with Ni11.12313 Also reported was t h e phenol-pendant N, system.I4

Experimental Section General Methods. All materials were obtained commercially and were used without further purification. Melting points were determined by using a Yanako micro melting point apparatus and were uncorrected. UV-visible spectra were recorded on a Hitachi U-3200 double-beam spectrophotometer at 25.0 0.1 OC using matched quartz cells of 2- or 10-mm path length, I R spectra on a Shimazu IR-408 spectrometer, ' H N M R spectra on a Hitachi R-40 high-resolution N M R spectrometer (90 MHz, 35 OC, Me4Si reference), and I3C N M R spectra on a JEOL JNM-FX100S FT-NMR spectrometer (100 MHz, 22.5 O C , Me4Si reference). Splitting patterns are indicated as follows: s, singlet; d, doublet, dd, AB quartet; m, multiplet. The ESR spectra were recorded on a JES-FElX spectrometer using a small sample of MnO as reference at 77 K. For TLC analysis throughout this work, Merck precoated T L C plates (silica gel 60 F254) were used. Potentiometric Titrations. Aqueous solutions (50 mL) of ligands (1 .OO X M) with four equivalent HC104 groups were titrated with carbonate-free 0.100 M NaOH aqueous solution. pH values were read with an Orion 8 11 digital pH meter. The temperature was maintained at

*

(1) Kimura, E. Yuki Gosei Kagaku Kyokaishi 1986, 44, 871-882. (2) (a) Martin, L. Y.; DeHayes, L. CZompa, L. J.; Busch, D. H. J . Am. Chem. SOC.1974,96,4046-4048. (b) Thom, V. J.; Fox, C. C.; Boeyens, J. C. A,; Hancock, R. D. J . A m . Chem. SOC.1984, 106, 5947-5955. (3) (a) Thom, V. J.; Boeyens, J. C. A,; McDougall, G. J.; Hancock, R. D. J . Am. Chem. SOC.1984,106,3198-3207. (b) Barefield, E. K.; Bianchi, A,; Billo, E. J.; Connolly, P. J.; Paoletti, P.; Summers, J. S.; Van Derveer, D. G. Inorg. Chem. 1986, 25, 4197-4202. (4) Kimura, E. Pure Appl. Chem. 1986, 58, 1461-1466. (5) Takagi, M.; Nakamura, H. J . Coord. Chem. 1986, 15, 53-82. (6) Reid, T. J., 111; Murthy, M. R. N.; Sicignano, A.; Tanaka, N.; Musick, W. D. L.; Rossmann, M. G. Proc. Natl. Acad. Sci. U.S.A. 1981, 78, 4767-4771. (7) Pulsinelli, P. D.; Perutz, M. F.; Nagel, R. L. Proc. Nutl. Acad. Sci. U.S.A. 1973, 70, 3870-3874. (8) (a) Momenteau, M. Pure Appl. Chem. 1986, 58, 1493-1502. (b) Collman, J. P.; Brauman, J. I.: Doxsee, K. M.: Sessler, J. L.;Morris, R. M.; Gibson, Q.H. Inorg. Chem. 1983, 22, 1427-1432. (c) Traylor, T.G. Arc. Chem. Res. 1981, 14, 102-109. (9) Kaden, T. A. Top. Curr. Chem. 1984, 121, 157. (10) Kimura, E.; Koike, T.; Takahashi, M. J . Chem. Soc., Chem. Commun. 1985, 385-386. (11) Iitaka, Y.; Koike, T.; Kimura, E. Inorg. Chem. 1986, 25, 402-404. (12) Kimura, E.; Uenishi, K.; Koike, T.; Iitaka, Y. Chem. Lett. 1986, 1137-1 140. (13) Kimura, E.; Koike, T.; Uenishi, K.; Davidson, R. B. J . Chem. SOC., Chem Commun. 1986. 11 10-1 1 1 1. (14) Kimura, E.; Yamaoka, M.;Morioka, M ; Koike, T. Inorg. Chem 1986, 25, 3883-3886.

0 1987 A m e r i c a n Chemical Society

2976 Inorganic Chemistry, Vol. 26, No. 18, 1987

-A+---

Kimura et al. Table 11. Final Fractional Coordinates (X104) for l l b with Estimated Standard Deviations in Parentheses X

Y

Z

Ben,A2

4630 ( I ) 5016 (2) 5812 (2) 5500 ( I ) 6239 (2) 5855 (2) 5513 (2) 4646 (2) 4244 (2) 3435 (2) 3741 (1) 2999 (2) 3357 (2) 3795 (2) 6643 (2) 6106 (2) 6484 (2) 7399 (2) 7945 2) 7558 (2) 5196 (1)

1928 (2) 3224 (3) 2658 (3) 1514 (3) 784 (3) -634 (4) -1993 (4) -1586 (3) -2882 (3) -2295 (4) -1137 (3) -278 (4) 969 (4) 2371 (4) 1994 (3) 3129 (4) 4207 (4) 4158 (4) 3040 (4) 1978 (4) 3181 (3)

4208 (2) 3752 (2) 3363 (2) 2517 (2) 2154 (2) 1449 (2) 1961 (2) 2162 (2) 2609 (2) 2958 (3) 3793 (2) 4040 (3) 4866 (2) 4484 (2) 1570 (2) 935 (2) 390 (2) 469 (3) 1082 (3) 1626 (2) 837 (2)

3.8 (0.0) 4.3 (0.0) 4.2 (0.0) 3.7 (0.0) 3.9 (0.0) 4.9 (0.1) 5.2 (0.1) 4.5 (0.0) 5.4 (0.1) 5.8 (0.1) 4.3 (0.0) 5.5 (0.1) 5.2 (0.1) 4.7 (0.1) 3.8 (0.0) 4.6 (0.0) 5.4 (0.1) 5.6 (0.1) 5.4 (0.1) 4.4 (0.0) 6.4 (0.0)

atom

[

\

3 (OH.)

Figure 1. Calculated titration curves with the obtained values of pK,, K F ~ I I ~ . and , L , K c u ~ ~ H(L - , L= l l b ) from experimental values (0, X, and z) for (a) 1.00 X IO" M Ilb.4HC104 and for (b) in the presence of 1.00 X IO" M Fe" and (c) Cu". Table I. Crvstal Data and Data Collection Summarv free ligand llb formula M r

cryst syst space group cryst color cell dimens a,

A

b, A c.

A

Z calcd density, g cm-3 cryst dimens, mm radiation (graphite monoc hromated) p, cm-l 28 range, deg scan speed, deg min-' phasing no. of measd reflcns no. of indep reflcns ( I > 2.(fl) final R

C,,H,,N,O 292.4 monoclinic P21la colorless

Cu" complex 17a(CI04).H20

Table 111. Final Fractional Coordinates ( X IO4) for 17a(CI0,).H20 with Estimated Standard Deviations in Parentheses X

C~,H~,N,OCUCIO,*H,O 472.4 monoclinic P2,lfl blue

1152.4 (2) 1066 ( I ) 1435 (2) 1835 (2) 1731 (1) 2077 (2) 1935 (2) 1556 (2) 1145 (1) 766 (3) 476 (3) 556 (1) 196 (2) 264 (2) 630 (2) 2205 (1) 1903 (2) 2077 (2) 2505 (2) 2795 (2) 2639 (2) 1489 (1) 869 (2) 863 (1) 1041 (2) 1074 (4) 684 (6) 420 (4) 516 (5) 935 (6) 1216 (5)

15.335 (8) 30.943 (20) 8.535 (5) 8.188 (4) 13.331 (7) 7.936 (4) 105.17 (5) 95.89 (5) 1684 2000 4 4 1.153 1.569 0.3 X 0.3 X 0.1 0.2 X 0.2 X 1 Cu K a Cu K a 5.52 6-1 56 6 direct method 2750 2635

31.3 6-156 6 heavy-atom method 4579 3703

0.06 I

0.066

25.00 i 0.05 "C, and the ionic strength was adjusted to 0.10 M with NaCIO,. -log [Hc] values were estimated with a correction of -0.08 pH unit to the pH meter readings.I5 All the solutions were carefully protected from air by a stream of humidified argon. The electrode system was calibrated with pH 7.00 and 4.01 buffer solutions and checked by the duplicate theoretical titration curves of 4.00 X M HCIO, with a 0.100 M NaOH solution at 25 " C and I = 0.10 M (NaCIO,) in highand low-pH regions. Calculated titration curves are shown in Figure 1 with the obtained values of pK, and complex stability constants (for 17) from experimental values. Electrochemical Measurements. Cyclic voltammetry and dc polarography were performed with a Yanaco P-1100 polarographic analyzer system at 25.00 i 0.05 "C. A three-electrode system was employed: a 3-mm glassy-carbon rod (Tokai Electrode Co. GC-30), a Yanagimoto P10-RE rotary glassy-carbon-disk electrode, or a Yanagimoto dropping mercury electrode as the working electrode, a Pt wire as the counter electrode, and a saturated calomel electrode (SCE) as the reference electrode. The cyclic voltammograms with scan rates of 10-100 mV SKI and the dc polarograms with scan rates of 2-10 mV s-] were evaluated graphically ( 1 5 ) Kagaku Binran, 3rd ed.; Chemical Society of Japan: Tokyo, 1984; Vol. 11. (16) Johnson, C. K. "ORTEP"; Report ORNL-3794; Oak Ridge National

Laboratory: Oak Ridge, TN, 1965.

Y 2355.1 (9) 3897 (5) 3645 (7) 3249 (7) 1841 (5) 1414 (6) -130 (7) 67 (7) 325 (6) 528 (13) 1551 (16) 2802 (7) 2867 (8) 4155 (8) 3803 (8) 2827 (6) 3978 (7) 5182 (7) 5220 (8) 4089 (8) 2924 (7) 3952 (5) 6029 (9) -1564 (2) 2 (6) -2516 (12) -2394 (15) -1619 (20) -1226 (27) -2332 (12) -2306 (16)

Z

1541.1 (9) 3489 (5) 4808 (7) 3953 (7) 2803 (5) 1712 (7) 673 (7) -685 (7) 53 (6) -1213 (12) -990 (15) 351 (7) 1402 (9) 2774 (9) 4137 (8) 607 (6) -182 (6) -1211 (7) -1473 (7) -722 (7) 329 (7) -25 (5) -1086 (7) 4239 (2) 4583 (8) 5648 (12) 5458 (14) 4403 (18) 3002 (23) 2762 (12) 3449 (23)

Be,, A2 2.54 (0.01) 2.9 (0.1) 3.4 (0.1) 3.2 (0.1) 2.6 (0.1) 2.9 (0.1) 3.4 (0.1) 3.4 (0.1) 3.3 (0.1) 9.4 (0.2) 13.3 (0.3) 4.3 (0.1) 4.6 (0.1) 4.4 (0.1) 3.8 (0.1) 2.7 (0.1) 2.9 (0.1) 3.3 (0.1) 3.7 (0.1) 3.6 (0.1) 3.1 (0.1) 3.7 (0.1) 8.0 (0.1) 4.2 (0.0) 7.8 (0.1) 6.5 (0.2) 11.0 (0.3) 9.8 (0.3) 14.3 (0.5) 10.1 (0.3) 10.7 (0.3)

Crystallographic Study. A colorless crystal with dimensions 0.3 X 0.3 0.1 mm3 of l l b and a blue crystal with dimensions 0.2 X 0.2 X 1.0 mm3 of 17a were used for data collection at room temperature. The lattice parameters and intensity data were measured on a Philips PW1 100 automatic four-circle diffractometer by using graphite-monochromated Cu K a radiation. Crystal data and data collection parameters are displayed in Table I. The structure was solved by the direct method for l l b and the heavy-atom method for 17a and refined by the blockdiagonal-matrix least-squares method to R values of 0.06 1 and 0.066, respectively. The molecular structures are illustrated in Figures 2 and 3 by ORTEP drawings with 30% probability thermal ellipsoids. The atomic positional parameters are given together with their standard deviations in Tables 11and 111. Selected interatomic distances, short intramolecular hydrogen-bonded distances, and bond angles are presented in Tables IV-'I. Phenol-Pendant Macrocyclic Tetraamines: 1la-c. The phenol-pendant 13-, 14-, and 15-membered macrocyclic monmxo tetraamines 10a-c were synthesized by refluxing coumarin (9) and the linear tetraamines X

Inorganic Chemistry, Vol. 26, No. 18, 1987 2977

New-Dimensional Cyclam Table IV. Bond Distances (A) for l l b , 17a(C104).H20, and 17b with Estimated Standard Deviations in Parentheses

Table VI. Bond Angles (deg) for l l b , 17a(CI04)-H20,and 17b with Estimated Standard Deviations in Parentheses ~

N(1)-C(2) N ( 1)-C( 14) C(2)-C(3) C(3)-N(4) N(4)-C(5) C(5)-C(6) C(5)-C( 15) C(6)-C(7) C(7)-N(8) N(8)-C(9) C(9)-C( 10) C(1O)-N(11) N(ll)-C(l2) C(12)-C(13) C ( 13)-C( 14) C ( 15)-C ( 16) C(15)-C(20) C ( 16)-C( 17) C( 16)-O(21) C( l7)-C( 18) C( l8)-C( 19) C ( 19)-C(20) M-N(1) M-N(4) M-N(8) M-N( 11) M-O(21) M-O( 1CI)

free ligand lla

Cu" complex 17a(ClO4).H20

Ni" complex" 17b

1.460 (4) 1.471 (4) 1.524 (5) 1.474 (3) 1.480 (4) 1.541 (4) 1.520 (4) 1.529 (5) 1.465 (4) 1.467 (4) 1.519 (5) 1.470 (4) 1.462 (4) 1.527 (5) 1.523 (5) 1.403 (4) 1.385 (4) 1.390 (5) 1.367 (3) 1.380 (5) 1.385 (5) 1.387 (5)

1.482 (7) 1.493 (8) 1.507 (8) 1.485 (7) 1.488 (7) 1.548 (8) 1.528 (7) 1.518 (8) 1.471 (8) 1.473 (10) 1.254 (15) 1.479 (13) 1.460 (8) 1.515 (10) 1.513 (8) 1.426 (7) 1.385 (7) 1.420 (8) 1.301 (6) 1.363 (8) 1.381 (8) 1.386 (8) 2.035 (4) 2.003 (4) 2.037 (5) 2.018 (5) 2.145 (4) 3.135 (6)

1.487 (8) 1.473 (10) 1.524 (11) 1.495 (11) 1.491 (9) 1.540 (11) 1.536 (11) 1.508 (9) 1.485 ( I O ) 1.471 (9) 1.521 (12) 1.502 (12) 1.480 (10) 1.526 (14) 1.515 (11) 1.387 (9) 1.392 (10) 1.434 (12) 1.339 (9) 1.371 (13) 1.373 (12) 1.393 (12) 2.072 (6) 2.051 (5) 2.085 (6) 2.078 (5) 2.015 (5) 2.402 (7)

"Here and in the following tables for 17b data, crystal data and final fractional coordinates are found in the supplementary material of ref 11. Table V. Short Intermolecular Bond Distances (A) for l l b and 17a(C104).H20 with Estimated Standard Deviations in Parentheses" free ligand llb N(l).-HN(4) N(l)**.HN(ll) N(8)-HN(4) N(I)-*HN( 11) N(4).-H0(21)

2.614 2.212 2.269 2.493 2.163

CUI' complex 17a(CIO,).H,O (26) (26) (24) (28) (34)

0(21)-.HO(W) O(W)-HN(ll) O(lCI)**.HN(4) 0(2CI)-*H'O(W)* 0(2'CI)-H'O(W)*

"Atoms marked with an asterisk are at x, y at x, y, z .

1.964 2.344 2.472 2.252 2.301

(68) (88) (56) (86) (83)

+ 1, z ; other atoms are

2a-q respectively, in MeOH. Reduction of the monmxo derivatives with B2H6 afforded lla-c. Typically, the synthetic procedure of l l b is as follows. Refluxing 9 (10.0 g, 68 mmol) and 1,9-diamin0-3,7-diazanonane (2b) (10.9 g, 68 mmol) in 1.5 L of dry MeOH for 2 weeks affords 7-(2-hydroxyphenyl)- 1,4,8,11-tetraazatetradecan-5-one(lob) as its trihydrochloride salt in 20% yield (5.7 g, 13.7 mmol), after purification by silica gel column chromatography (eluant CH2C12-MeOH-28% aqueous NH,, 100:5:1) and recrystallization from EtOH-HCI: mp 185 OC dec. IR (KBr): vCo = 1640 cm-I. Reduction of 10b3HCI (5.7 g) with freshly distilled B2H6 in T H F yielded 5-(2-hydroxyphenyl)-1,4,8,11-tetraazatetradecane ( l l b 2.0 g, 6.8 mmol) as colorless crystals in 50% yield. The product was purified by recrystallization from CH,CN. ' H N M R (CDCI,): 6 0-1.5 (m, 1 H), 1.5-2.1 (m, 4 H), 2.3-3.2 (m, 18 H), 3.7-4.0 (dd, 1 H), 6.6-7.2 (m, 4 H). "C N M R (CDCI,): 6 157.8, 127.9, 127.8, 126.6, 118.6, 116.4, 66.7, 51.2, 50.9, 50.1, 49.6, 49.3, 49.2, 47.3, 36.3, 29.3. The other physical data for all of the new compounds are listed in Table VII. Phenyl- and 2-Methoxyphenyl-Pendant Cyclam: 7e,f. Refluxing cinnamic acid ester derivatives 5 and the linear tetraamine 2b in dry MeOH afforded the monoxo derivatives 6. The cyclam derivatives 7 were synthesized by reduction of 6 with B2H6. Typically, the synthetic procedure of 7e is as follows. Refluxing the cinnamic acid ethyl ester 5e (10.0 g, 57 mmol) and 2b (9.1 g, 57 mmol) in 1.5 L of dry MeOH for 3 weeks (6e) as colorless afforded 7-phenyl-l,4,8,1l-tetraazatetradecan-5-one crystals in 30% yield (5.0 g, 17.2 mmol). The product was purified by recrystallization from CH3CN. IR (KBr): vco = 1640 cm-'. 'H NMR (CDC1,): S 1.1-2.4 (m, 3 H), 1.6-1.9 (m, 2 H), 2.4-3.0 (m, 12 H), 3.2-3.5 (m. 2 H), 3.7-4.0 (dd, 1 H), 7.0-7.3 (m, 5 H), 8.4-8.7 (m, 1 H). Reduction of 6e (5.0 g) with freshly distilled B2H6 in T H F yields the

free ligand llb C(2)-N(l)-C(14) C(3)-C(2)-N( 1) N(4)-C(3)-C(2) C(5)-N(4)-C(3) C(6)-C(5)-N(4) C(6)-C(5)-C(15) C(7)-C(6)-C(5) N(8)-C(7)-C(6) C(9)-N(8)-C(7) C( 10)-C(9)-N(8) N ( l l)-C(lO)-C(9) C( 12)-N( 11)-C( IO) C(l3)-C(l2)-N(ll) C(14)-C(13)-C(I2) N ( l)-C(14)-C( 13) C( 16)-C( 15)-C(5) C( 16)-C( 15)-C(20) C(5)-C( 15)-C(20) C(17)-C(16)-C(15) C( 17)-C( 16)-O(21) C ( 15)-C( 16)-0(21) C ( 18)-C( 17)-C( 16) C(20)-C( 19)-C( 18) N ( 1)-M-N(4) N(1)-M-N(l1) N (4)-M-N (8) N(8)-M-N(11) N(4)-M-0(21) N(8)-M-0(2 1) 0(21)-M-O( 1C1) M-O(21)-C( 16)

112.6 (2) 110.5 (2) 110.0 (2) 114.0 (2) 110.6 (2) 110.3 (2) 115.9 (3) 111.3 (3) 113.2 (2) 109.8 (3) 109.2 (3) 113.2 (2) 111.0 (3) 114.4 (3) 111.8 (2) 121.6 (2) 117.8 (3) 120.6 (2) 120.8 (3) 118.9 (3) 120.2 (3) 119.6 (3) 118.9 (3)

~~~

Cu" complex Nil1 complex 17a(C104).H20 17b 114.0 (4) 114.1 (6) 108.7 (4j 108.9 (6) 107.9 (4) 107.6 (6) 114.6 (4) 114.5 (5) 108.6 (4) 109.6 (6) 112.9 (4) 112.2 (6) 116.6 (5) 116.7 (6) 111.7 (5) 113.4 (6) 113.9 (5) 114.6 (6) 120.7 (9) 110.1 (7) 119.6 (10) 107.2 (7) 110.7 (6) 111.2 (6) 112.2 (5) 111.6 (7) 114.8 (5) 114.5 (7) 112.4 (5) 111.8 (7) 123.8 (4) 123.6 (6) 120.6 (7) 119.7 (5) 116.5 (4) 115.5 (6) 117.2 (7) 116.2 (5) 117.2 (6) 120.1 (5) 125.6 (7) 123.7 (5) 122.4 (5) 120.9 (8) 118.1 (5) 118.8 (8) 86.0 (2) 85.6 (2) 93.3 (2) 92.7 (2) 94.3 (2) 96.6 (2) 85.5 (2) 84.9 (2) 88.8 (2) 87.5 (2) 94.1 (2) 98.0 (2) 177.6 (2) 156.7 (2) 126.9 (4) 127.4 (3)

Table VII. Various Properties and Yields for New Macrocylic Polyamines macrocyclic oolvamine

mo. "C

M* peak,

6e 6f 7e 7f lla llb llc

155-1 57 151-152 266 dec 112-1 14 72-74 142-143 256 dec

13 15

215 dec 234 dec

m/e (M,) 290 320 276 306 278 292

(290.42) (320.44) (276.43)' (306.46) (278.40) (292.43)

anal. (C, H. N)"

yield, %

Cl6H26N40 30b C17H2BN402 25b CI6HzBN4-4HCI 50' CI7H3oN4O 60' CI5H2,N4O.H2O 50' Cl6H28N4O 20,b 50' C17H30N40*4HCI* 1 61' H20 C16H27NSOyHC104 19,b 50' C16H25N6O5*HC104. 36,d 67' O.5H2O

Compounds gave satisfactory analyses ( f 0 . 4 % ) , Cyclization yield. Reduction yield. Dinitration yield. e Deprotection yield. fFree form as colorless powder (by neutralization with 28% aqueous NH3). cyclam derivative 7e as its tetrahydrochloride salt in 50% yield (2.4 g, 8.6 mmol). The product was purified by recrystallization from EtOHHCI. 'H N M R (CDCI,, as free form): 6 1.6-2.0 (m, 4 H), 2.2-3.0 (m, 18 H), 3.6-3.8 (dd, 1 H), 7.0-7.3 (m, 5 H). 7-(2-Methoxyphenyl)1,4,8,11-tetraazacyclotetradecan-5-one(6f): IR (KBr) uc0 = 1640 cm-I; IH N M R (CDCI,) 6 1.1-2.4 (m, 3 H), 1.6-1.9 (m, 2 H), 2.4-3.0 (m, 12 H), 3.2-3.6 (m, 2 H), 3.8 (s, 3 H), 3.9-4.1 (dd, 1 H), 6.6-7.1 (m, 4 H ) , 8.8-9.1 (m, 1 H). 5-(2-Methoxyphenyl)-1,4,8,1l-tetraazacyclotetradecane ( 7 0 : IH N M R (CDCI3) 8 1.5-2.0 (m, 4 H), 2.0-3.0 (m, 18 H ) , 3.75 (s, 3 H), 3.9-4.1 (dd, 1 H), 6.6-7.1 (m, 4 H). 5- (2-Hydroxy-5-nitropheny1)-1,4,8,1l-tetraazatetradecane(13). Refluxing 6-nitrocoumarin (12; 5.0 g, 26.2 mmol) and 2b (4.2 g, 26.2 mmol) in 500 mL of dry MeOH for 3 days afforded 7-(2-hydroxy-5-nitroas its trihydrochloride salt phenyl)- 1,4,8,1l-tetraazacyclotetradecan-5-one in 19% yield (2.3 g, 5.0 mmol), after purification by silica gel column chromatography (eluant CH2CI2-MeOH-28% aqueous NH,, 1000:80:0.5) and recrystallization from EtOH-HCI: mp 195 OC dec. IR (KBr): vco = 1630 cm-I. ' H NMR (CDCI, and CD,OD, as free form): 6 2.0-2.3 (m, 2 H), 2.4-3.5 (m. 12 H), 3.7-4.0 (m, 1 H), 4.5-4.8 (dd, 2 H), 7.0-7.2 (d, 1 H), 8.0-8.4 (m, 2 H). Reduction of the monoamide compound (1 .O g, 2.85 mmol) with freshly distilled B2H, in T H F yielded the cyclam derivative 13 in 50% yield (480 mg, 1.42 mmol) as yellow

2918 Inorganic Chemistry, Vol. 26, No. 18, 1987 crystals of the monoperchlorate salt, recrystallized from water adjusted at pH 7 in the presence of excess sodium perchlorate. 'H N M R ( D 2 0 , NaOD): S 1.5-2.9 (m,2 H),2.1-2.9 (m,14 H), 4.0-4.2 (dd, 1 H), 6.3-6.4(d, 1 H), 7.7-8.0 (m, 2 H).

Kimura et al. attempt was made to synthesize 6d by substituting 2b for spermine (2d) but almost no cyclization reaction occurred.

5-(3,5-Dinitro-2-hydroxyphenyl)-1,4,8,1l-tetraazacyclotetradecane (15). llb in 35 mL of trifluoroacetic anhydride was stirred at room temperature for 5 h, and then the solvent was evaporated in vacuo. The oily residue was dissolved in dichloromethane and the solution washed with water, dried, and evaporated in vacuo. Addition of diethyl ether afforded 1,4,8,1l-tetrakis(trifluoroacetyl)-5-(2-hydroxyphenyl)1,4,8,1I-tetraazacyclotetradecane(14)in 94% yield (1.14g, 1.7 mmol): mp 184-187 OC. IR (KBr): uCo = 1685 cm-I. 'H N M R (CDCI,, (CD,),SO): 6 1.7-2.4(m. 4 H), 2.7-4.4 (m, 15 H), 6.6-6.9(d, 2 H), 6.9-7.2(d, 2 H). A mixture of 70% nitric acid (4.7mL) with 14 (760 mg, 1.12 mmol) in 2.8 mL of 98% sulfuric acid was stirred at room temperature for 3 h and then poured into crushed ice and water to precipitate yellow crystals, which were collected by filtration. Recrystallization from methanol and diethyl ether afforded 1,4,8,1l-tetrakis(trifluoroacetyl)-5-(3,5-dinitro-2-hydroxyphenyl)-l,4,8,1 l-tetracyclotetradecane in 36% yield (310 mg, 0.4mmol): mp 222-224 OC. IR (KBr): vc0 = 1685 cm-'. ' H N M R (CDCI,, CD,OD): 6 1.6-2.4(m, 4 H), 2.9-4.0(m.14 H), 4.0-4.2 (m, 1 H), 8.7-9.0 (m,2 H). The dinitro derivative (310 mg, 0.40mmol) was treated with 1 M NaOH solution (2.4mL) in 10 mL of methanol, at room temperature for 20 h. The solvent was evaporated in vacuo, and 1 M perchloric acid was added (3.3 mL) to precipitate yellow crystals, which were collected by filtration. Recrystallization from water adjusted at pH 7 by 1 M N a O H solution afforded 15 (1 30 mg, 0.27mmol) in 67% yield. 'H N M R (D20,NaOD): S 1.6-2.0 (m, 4 H), 2.3-3.0(m, 14 H), 4.0-4.3(dd, 1 H), 7.9(d, 1 H), 8.5 (d, 1 H).

Preparation of the Copper(I1) Complex with llb: [Cu"(llb-H-,)]The phenol-pendant cyclam llb (146 mg, C104.H20(17a(C104).H20). 0.5 mmol) and CuS0,.5H20 (1 25 mg, 0.5 mmol) were dissolved in 50 mL of 0.5 M NaCIO4 aqueous solution at ca. 50 OC, and the mixture was adjusted to pH 8 with 0.1 M NaOH solution. The resulting blue solution was filtered, and the filtrate stood for 2 weeks at room temperature. Blue crystals of 17a were obtained in ca. 50% yield (120mg). Anal. Calcd for C1,H27N40CuC104~H20: C , 40.68;H, 6.19;N,11.86.Found: C, 40.42;H, 6.18;N , 11.76.

Results and Discussion Synthesis. Earlier, we reported the synthesis of the 14-membered monooxo tetraamine 3b by condensation of ethyl acrylate (1) with 1,9-diamin0-3,7-diazanonane (zb)." We have applied U"

N-\

r N

a We have further extended this one-pot cyclization method to preparation of the phenol-side-armed macrocyclic N, compound 10. The treatment of coumarin (9) with 2a-c in refluxing dry

lOa,b,c

-%NH0 B2H6

nNVN~ 1 1 a,b,c

MeOH gave the corresponding 13- (loa), 14- (lob), and 15membered (1Oc) monooxo N, compounds, respectively. Obviously, the annelation involves the reactions of the two terminal amines for the initial Michael type addition followed by an intramolecular lactamization. However, the annelation with spermine (2d) failed. The reduction of the lactam function was successful with diborane in tetrahydrofuran, leading to 11. The p-nitrophenol-pendant cyclam 13 was synthesized from 6-nitrocoumarin (12). The 2,4-dinitrophenol-pendantcyclam 15 was derived from nitration of the phenol-pendant tetrakis(trifluoroacety1)cyclam 14 in HN03-H2S04, followed by alkaline removal of the trifluoroacetyl groups.

u,.

1 2a: n.2 ,m=2 b: n=2,m=3 c; n:3,m=2 d; n=3.m=4 (spermine)

13

2b

3a,b,c

n

YN '7 I

I

t

N' H U H

\N

4a.b.c

llb H2 HZ a ~ = Hk O ~ R Se; X=H f ; X=MeO

+

CN H '1~

MeOH, A

~

~

26

H 6e. f

B2H6

14:R.CF3CO

15

The present new synthetic method is also applicable to preparation of macrocyclic t r i a m i n e ~and ' ~ pentaamine~.'~The pyridyl-pendant cyclam was prepared in a similar treatment of 3-(2-pyridyl)acrylic acid methyl ester with 2b.20 Since cyclic spermine and spermidine alkaloids often possess biological activities,*' our macrocyclic polyamines may serve as good candidates for new drug design. Ligand Properties. In CHC13 solution, the motion of the phenolic group of l l b is restricted with its OH group strongly hydrogen bonded with the nearest nitrogen N(4) of the macrocycle (see X-ray structure of Figure 2). The 'H NMR spectrum in

7e.f

this annelation procedure to the synthesis of the phenyl-side-armed N4 compounds 6 and 7 starting from phenyl-substituted cu,p-unsaturated ester 5 and 2b. Since 6e happened to be a homologue an of macrocyclic spermine alkaloids such as verbascenine @),I8 (17) Kimura, E.; Koike, T.; Machida, R.; Nagai, R.; Kodama, M. Inorg. Chem. 1984, 23, 4181-4188.

(18) (a) Seifert, K.; Johne, S.; Hesse, M. Helv. Chim. Acta 1982, 65, 2540-2547. (b) Guggisberg, A,; Hesse, M. The Alkaloids; Brossi, A,, Ed.; Academic: New York, 1983;Vol. XXII, pp 85-188. (19) Kimura, E., unpublished results. (20) Kimura, E.; Koike, T.; Nada, H.; Iitaka, Y . J . Chem. SOC.,Chem. Commun. 1986, 1322-1323. (21) Smith, T.A,; Negrel, J.; Bird, C. R. Advances in Polyamine Research; Bachrach, U., Kaye, A., Chayen, R., Eds.; Raven: New York, 1983; Vol. 4,pp 347-370.

Inorganic Chemistry, Vol. 26, No. 18. 1987 2919

New-Dimensional Cyclam

P

Table VIII. pK, Valuesa and UV Data at I = 0.1 M (NaCIO,) and 25 "C UV abs max, nm (e) PK, phenol phenolate ligand phenol amines form form lla 8.71 11.54 272 (2300) 292 (3800) 10.31 [pH 4.01 [pH 11.11 llb

8.86