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1H, 13C and 15N NMR study of the solution structure of meta-bridged bis(benzo-15-crown-5 ether)s
Journal of
MOLECULAR STRUCTURE ELSEVIER
Journal of Molecular Structure 356 (1995) 15-24
1H, 13C and 15N NMR study of the solution structure of meta-bridged bis(benzo- 15-crown-5 ether)s I. S t a r k e a, A . K o c h % E. K l e i n p e t e r ~'*, H . - J . H o l d t b alnstitut fi~r Organische Chemie und Strukturanalytik, UniversitiJt Potsdam, Am Neuen Palais 10, D-14469 Potsdam, Germany bChemische Institute, Universiti~t Rostock, Buchbinder Str. 9, D-18055 Rostock, Germany
Received 6 February 1995;acceptedin final form 13 April 1995
Abstract
The IH and 13CNMR spectra of the three isomers of the bis(benzo-15-crown-5 ether) studied and their complexes with K + and Na + cations were recorded and assigned by H,H-COSY and HMQC 2D-NMR experiments. The three isomers with respect to the amide C( = O)-NH bonds could be assigned by 15N NMR spectroscopy and heteronuclear coupling constants. Relevant conclusions about the isomerism were deduced from the 1Jt5_N,l_H coupling constants of the various NH amide groups and the 1Jl3_C,1 H coupling constants of C3H and C~H2-C(= O)- groups, respectively. From 2DROESY NMR experiments, further stereochemical information about the preferred conformation of the free and complexed bis(benzo-15-crown-5 ether) was obtained. The conformational study is accompanied and corroborated by molecular dynamics and quantum chemical calculations. In the case of the K + complex, a "sandwich"-like complex could be determined. This structure clearly proved to be already preorganized in the non-complexed host molecule. For the corresponding Na + complex, the "usual" 2:1 host-guest complex was detected.
I. Introduction
The complexational behaviour of bis(benzocrown ether)s with alkali metals and other cations has been widely studied [1-6]. Compounds of this type consist of two crown ether units in the same molecule and provide the formation of "sandwich"-like complexes with cations of radii larger than the cavity size of the single crown ether unit [7-10]. The complex stability and the complexation thermodynamics of bis(benzo-15crown-5-ether)s, having acylhydrazide fragments as the linking chain, with different cations were investigated by spectrophotometric titrations * Corresponding author.
[ 11-13]. The stability of these complexes proved to depend strongly on the length of the linking chain. Within the homologous series of the methylenebridged carbonylhydrazones 1 ( n = 0 - 8 ) , the potassium complex of the propylene-bridged compound 1 (n = 3, Fig. 1) shows the highest stability constant compared with the other methylenebridged bis(benzo-15-crown-5 ether) complexes with K+; the formation of a stable sandwich complex was concluded [11]. Owing to the two amide C ( = O ) - N H fragments present, the bis(benzo-15crown-5 ether)s 1 can exist as three isomers. To study this isomerism and the conformational behaviour of this interesting kind of compound by means of N M R spectroscopy [14] is the major objective of the present paper. In addition, the
0022-2860/95/$09.50 © 1995 Elsevier Science B.V. All rights reserved S S D I 0022-2860(95)0891 1-X
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L Starke et al./Journal of Molecular Structure 356 (1995) 15-24
o O O= A B C n = 3 [ CH2-CH2-CH2 ]
Fig. 1. Polymethylene-bridgedcarbonylhydrazoneof4'-formylbis(benzo-15-crown-5 ether)s;studiedcompound 1 (n = 3). question of "usual" or "sandwich"-like complexation of K + and Na + cations to the compounds 1 was answered. First of all, the propylene-bridged bis(benzo-15-crown-5 ether) 1 (n -- 3) was studied, because it is outstanding in its affinity to complex with potassium cations. The investigation of analogous compounds is in progress.
2. Experimental The synthesis of compound 1 (n = 3) has been described by Holdt et al. [15]. The 1H and 13C NMR spectra were recorded at 300.13 and 75.47 MHz, respectively (BRUKER ARX 300), in DMSO-d6 solution (5 mm probe tubes, ambient temperature, deuterated solvents as internal lock). laC: 30° pulse, 2 s repetition time, 200 scans, 32K data points, 18 750 Hz spectral width and 0.57 Hz per point digital resolution, full proton broadband decoupling; 1H: 30° pulse, 2s repetition time, 128 scans, 32K data points, 7500 Hz spectral width and 0.23 Hz per point digital resolution. Chemical shifts are referenced to TMS (internal). The 15N NMR spectra were recorded at 30.42 MHz and at 60.81 Hz (on a UNITY 600 VARIAN NMR spectrometer) in natural abundance (solvent DMSO-d6, 10 mm probe tubes, spectra recorded at ambient temperature): 45 ° pulse, 4 s repetition time, 32K data points, 9259.26 Hz spectral width and 0.28 Hz per point digital resolution. The alkali salts used in the complexation study were dried over P4O10. The ill, 13C and 15N NMR spectra were assigned by the 2D-, H,H-COSY and reversed H, C-correlation and H,N-correlation experiments [16, 17]. The standard Bruker software was applied for these experiments; typical settings are as follows. HMQC: sweep width in F1 is 18 kHz
and in F2 6.9 kHz, 8K data points in F2, 512 experiments in F2 (8 scans), relaxation delay 0.2 s, pulse width (1H, 90°), 11.0/zs, (laC) 9.5 #s, zero filling, filter function sine-bell in both dimensions; for the lSN measurement the sweep width in F1 is 1 kHz and in F2 7 kHz, pulse width P1 (90 °, 15N) 10.2 #s, 8K data points in F 2 and 128 experiments in F1. For the 2D-ROESY NMR measurements, the samples were degassed at least three times and sealed under argon. The 2D-ROESY NMR spectra were recorded in the phase-sensitive mode [18, 19] with zero filling in F1. Also in this case, the standard Bruker software was employed, with sweep width in F 1 and in F 2 7 kHz, 1K data points in Fl and 2K data points in F2, relaxation delay 2 s, mixing time 200 ms, filter functions sine-bell in both dimensions. The molecular dynamics calculations (SIMULATED ANNEALING) were carried out with the TRIPOS force field starting at 1000 K and later cooling down to 200 K for 1000 fs. The default setup used a constant N, V, T ensemble based on Berendsen's method [20]. Quantum mechanical calculation was processed with the PM3 method from MOPAC 6.0 using the Silicon Graphics IRIS INDIGO XS 4000 [21,22] (keywords: XYZ MMOK GNORM = 0.01 SCFCRT = 0.0000001).
3. Results and discussion 3.1.1H,
13Cand
15N NMR spectra
The proton NMR spectra are very characteristic for the structure of the studied compound (see Table l(a)). The resonance ranges are sufficiently dispersed, the multiplets for the crown ether fragments (H-10-H-13) are shifted to higher field with respect to the aromatic ring current effect; the H, H coupling constants as extracted from the AA'BB' subspectra indicate gauche O - C H a - C H 2 - O fragments, readily inverting on the NMR time scale at ambient temperature. The vicinal H, H coupling constants between the different aromatic protons are unequivocal for the substitution pattern present (see Table 2(a)). In DMSO-d6, the 1H, 13C and 15N NMR spectra
17
L Starke et al./Journal of Molecular Structure 356 (1995) 15-24 Table 1 (a) 1H chemical shifts 8 (ppm) of 1 (n = 3) in DMSO-d6/(TMS) Isomer
NH
H-3
H-5
H-8
H-9
H-10
H-11
H-12
H-13 a
CH 2 groups b
E/E E/Z
11.27 11.24 11.15 11.11
8.04 8.02 7.87 7.84
7.26 7.26 7.23 7.23
6.98 6.98 6.92 6.92
7.14 7.14 7.12 7.12
4.07
3.77
3.62
3.34
A, B, C A, B, C
2.23, 1.88, 2.23 2.65, 1.88, 2.26
A, B, C
2.68, 1.88, 2.68
Z/Z
(b) 13C chemical shifts ~5(ppm) of 1 (n = 3) in DMSO-d6/(TMS ) Isomer
C-I
C-3
C-4
C-5
C-6
C-7
C-8
C-9
C-10
C-I 1
C-12
C13 a
E/E E/Z
146.0 145.9 142.6 142.5
127.2 127.2 127.2 127.2
110.7 110.6 110.0 110.0
148.6 148.6 148.5 148.5
150.2 150.2 150.0 150.0
113.0 112.9 112.8 112.8
121.7 121.7 120.8 120.7
68.3
68.7
69.6
70.4
Z/Z
168.0 173.8 168.2 173.9
Isomer
CH2 b
E/Z E/Z Z/Z
A, B, C A, B, C A, B, C
33.5, 21.0, 33.5 31.5, 20.3, 33.3 31.3, 19.7, 31.3
a H-10-H-13 and C-10-C-13, respectively, of the various isomers could not be differentiated due to signal overlapping. b Methylene groups of the linking chain.
Table 2 (a) Homonuclear coupling constants JH, ri (Hz) within the aromatic moiety and in the linking chain of I (n = 3) Isomer E/E E/Z Z/Z
3j (H, H) H-8-H-9 H-8-H-9 H-8-H-9 H-8-H-9
8.31 8.31 8.32 8.32
H-5-H-9 H-5-H-9 H-5-H-9 H-5-H-9
4j (H, H)
3j (H, H)
1.44 1.44 1.43 1.43
B-CH 2 7.17, B-CH2 7.17, A-CH 2 7.35, A-CH2 7.33,
7.27 7.20 7.35 7.36
(b) Heteronuclear coupling constants IJc, H (Hz) for the C 3 - H and a-CH 2 groups in the linking chain Isomer E/E E/Z Z/Z
i j (C, H) 3-CH 3-CH 3-CH 3-CH
163.7 164.8 163.7 165.0
i j (C, H) A-CH 2 B-CH 2
129.2 130.0
(c) Heteronuclear coupling constants l Jr~,n (Hz) of N z - H in the isomers of 1 (n = 3) Isomer
Ij(N, H)
E/E E/Z Z/Z
94 94, 92 92
18
L Starke et al./Journal of Molecular Structure 356 (1995) 15-24
prove that compound 1 (n = 3) exists as a mixture of three isomers with reference to the E/Z isomerism of the amide C ( = O ) - N H - bond (E/E, E/Z and Z/Z, respectively). Adequately well-separated signals for the NH, H-3, H-5, H-8 and H-9 protons in the IH N M R spectrum, and for the carbonyl carbon, C-3, C-5, C-8, C-9, and for the linking CH 2 groups in the 13C N M R spectrum were obtained (Table 1). Both the 1H and the 13C N M R spectra could be detected without any line broadening; at ambient temperature, the interconversion of the present isomers is slow on the N M R time scale. The chemical shifts of the linking methylene groups in the range of 1.8-3.0 ppm also document the presence of three isomers; the vicinal coupling constants 3j (H, H) indicate staggered conformations along this fragment (Table 2(a)). The assignment of the various isomers of the bis(benzo-15-crown-5 ether) 1 (n = 3) could be determined via the heteronuclear coupling constants IJls_N,l_H and lJl3_C,1.H. First, the N, H connectivities were detected by inverse 2D-N, H shift correlation experiments and then the 1J15_N,1.n coupling constants were measured. In peptides, the corresponding coupling constants are usually larger in E amide fragments compared to the values in the corresponding Z analogues [23,24]. In 1 (n = 3) the size of the relevant coupling constants 1JIS_N,I.H (Table 2(c)) amount to 94.0 Hz in the E/E isomer and 92.0 Hz in the Z/Z analogue. In the E/Z isomer, the values of 1J15_N,1.H were 92.0 and 94.0 Hz, proving the presence of the two - C ( = O ) - N H - configurations in the same isomer. The 1J13_C,l_H coupling constants of C-3 in the hydrazone moiety and o~-CH2 of the linking chain in the various isomers of 1 (n = 3) support the latter assignments. In the case of the c~-CH2 carbon atoms, lJ13_c,1.H coupling constants of 130.0 Hz were measured in the E configuration (B-CH2, see Fig. 1), in the Z isomer only 129.2 Hz (for A-CH2, see Fig. 1) was obtained [25,26]. As further proof of the present E/Z isomerism, along with the amide fragments of 1 (n = 3) we considered (i) the lowfield position of C=O of the E isomers (173.8-173.9 ppm) with respect to the Z analogue (168.0-168.2 ppm) [27] and (ii) the ROE between NH and C(c0H protons in the E isomer (no ROE obtained for the Z analogue). For hydrazones, a clear correlation between the
magnitude of the 1J13_c,1.H coupling constant at C3 and the configuration of the sp 2 nitrogen atom is found; the C - H bond, positioned trans to the lone pair at the nitrogen, exhibits the smaller 1Jl3.C,l_n coupling constant [28]. The size of the corresponding coupling constants in 1 (n = 3), J13-C,I-H = 163.7-165.0 Hz, along all the P h - C H = N - N H fragments clearly proves the anti arrangement of the nitrogen lone pair and the C - H bond at C-3 in this compound (see Fig. 4(a)). For the corresponding syn configuration, values of about 185 Hz for the same coupling c o n s t a n t IJl3.C,1.H at C-3 were expected [28]. The NH protons are characteristically shifted to lower field (6 > 11.0 ppm). However, from the dependence of the 1H chemical shift of the NH protons on different concentrations and various temperatures, intramolecular hydrogen bonding could not take place. However, the concentration and temperature dependence of the NH protons can be interpreted by the presence of intermolecular hydrogen bonding to the solvent or other molecules of 1 (n = 3) in solution [29,30]. The integration of these NH signals (assigned to the corresponding isomers, vide supra) and those of the corresponding H-3 protons readily allowed us to quantify the percentage ratio of the present isomers: Z/Z : Z/E : E / E = 27.7 : 51 : 21.3. The barrier to E/Z isomerization of the amide bond in peptides is usually expected at about 18 kcal mol-1; thus, the corresponding restricted rotation should be slow on the N M R time scale at 313 K [31]. Also in hydrazones, as for example in formylthiophene n-acetyl hydrazone, the restricted rotation about the partial C, N double bond at ambient temperature is slow on the N M R time scale, but the two isomers could be detected both in solution and in the solid state [32,33]. For the present compound 1 (n = 3) the occurrence of all possible isomers was also found experimentally, and this result was corroborated by quantum chemical calculations, which are given later in this paper. 3.2. Complexation o f the bis(benzo-15-crown-5 ether) 1 (n = 3) with K + and Na + cations
The complexation of crown ether molecules and alkali cations can be readily studied by N M R
L Starke et al./Journal of Molecular Structure 356 (1995) 15-24 c h e m i c a l shifts
19
c h e m i c a l shifts
high field
shifts
low field shifts
I
e
8.(3~
H-3
~ ~r'~*'~j*
e.s
H-3
7.75
I *
~
H-5
*
~*
H-9
*
~
H-8
7
.
2
~
~
-'*
-~
-~ H-5
*
~,
• H-9
*
~
* H-8
6.5--
I 0,5:1
I 1:1
f 1.5:1
I
I
2:1
3:1
J[Na,:( .... ] 4:1
i
I
I
i
I
0.5:1
1:I
1.5:1
2:1
3:1
I [~F4l:(cro~) 4:1
Fig. 2. Study of the complexation of 1 (n = 3) with Na + cations of Nal.
Fig. 3. Study o f the complexation of 1 (n = 3) with K + cations of KBF4.
spectroscopy. In particular, the upfield or downfield shift of the resonances of protons involved in the studied crown ethers can be usefully correlated with the present complexational behaviour [14,34, 35]. If in the case of bis(crown ether)s the "usual" 1:2 ligand:cation complexes are formed, the 1H resonances will be shifted downfield with respect to their resonances in the free non-complexed bis-(crown ether). In the case of the formation of 1 : 1 "sandwich" complexes, however, the corresponding proton resonances are shifted upfield with complexation of the alkali cations proceeding with the present bis(crown ether) molecules [14,35]. With the complexation of the title compound 1 (n = 3) to Na ÷ cations, the 1H N M R resonances of the protons involved are shifted to lower field (see Fig. 2); typical 2 : 1 complexation can be concluded. The same information comes from the shapes of the 61_H VS. [NaI]:[1] curves (see Fig. 2). The sodium cation is clearly suitable for the cavity size of the benzo-15-crown-5 moieties of 1 (n = 3).
If, however, 1 (n = 3) is complexed to the potassium cations of KBF4, the proton resonances are shifted upfield (see Fig. 3). For this reason and from the shapes of the corresponding ~5]_ri vs. [KBF4]:[1] curves (see Fig. 3), "sandwich"-like 1:1 complexation of the present bis(benzo-15 crown-5 ether) to K + cations proved to be the case. The ratio of the Z/Z, E/Z and E/E isomers of 1 (n = 3) is only slightly changed during the complexation: Z/Z: E/Z: E / E = 31.5:47.2:21.35. All the results obtained experimentally are in total agreement with the stability constants of the K + complexes of the bis(benzo-15-crown-5 ether)s as determined by spectrophotometric titration [1 l]. The stability of the 1:1 "sandwich" complexes with K + is higher than that of the "usual" 2:1 complexes; the reason for this result is twofold: (i) the cavity size of the crown ether units of 1 (n = 3) is too small to host the K + cations and, avoiding this, the "sandwich" 1:1 complex is formed for which the cavity size is less important or (ii) the
20
L Starke et al./Journal of Molecular Structure 356 (1995) 15-24
"bis(benzo crown ether) effect", in which the crown ether moieties are positioned parallel to each other, is completely dominating the solution structure estimated for the K + complex of 1 (n = 3). In the case of the smaller sodium cation, at least, the "bis(benzo crown ether) effect" is only of negligible importance. 3.3. Spatial ROESY distance measurements
Further stereochemical information about the spatial connectivity of the protons involved in the bis(benzo-15 crown-5 ether) molecule can be obtained from the 2D ROESY N M R spectra [19]. For the three isomers of the free non-complexed 1 (n = 3) the following structurally relevant ROE cross-peaks were obtained: (i) Nuclear Overhauser effects in the rotating coordinate system between the N H protons and the protons H-3 prove the anti position of the nitrogen lone pair and H-3 within the P h - C 3 H = N - N H fragment to be correct (see Fig. 4(a)). (ii) From the intensities of the ROE cross-peaks between the proton H-3 of the linking chain and (¢)
H
I
H
I
\tone peiron ntnel~
(b)
/,
~ E/E isomere
-8
5
H8
"'x
H8 Z/E isomefe
Fig. 4. (a) Anti arrangement of the imine nitrogen lone pair relative to C3H and NH in the NH-N=CH-Ph fragment of all isomers of 1 (n = 3). (b) ROE connectivitieswithin all isomers of the free bis(benzo-15-crown-5ether) 1 (n = 3) and the E/ E and E/Z isomers of its K+ complex.
the aromatic protons H-5 and H-9, it can be concluded that the phenyl ring is twisted from the common plane of resonance and that the proton H-3 is positioned closer to H-5 than to H-9 (Fig. 4(b)). (iii) Between the methylene protons H-10 and H-10 t and the aromatic protons H-5 and H-8, respectively, ROE cross-peaks were detected, in agreement with the graduated upfield shifts of these protons and with the anisotropy effect of the aromatic moieties of the studied molecule (see Table l(b)). (iv) With the 1 : 1 "sandwich"-like complexation of 1 (n = 3) to K + cations, the ROE cross-peaks between the protons H-3 and H-9 in the E/E isomer and the one between H-3 and H-5 in the E/Z isomer at the E-positioned amide bond side are disappearing (see Fig. 4(b)); in the Z/Z isomer and at the Z side arm of the E/Z isomer, the corresponding ROE cross-peaks are still present. Also the ROEs between the N H protons and the H-3 protons do not change significantly with the complexation of the three isomers. Thus, it may be concluded that the phenyl rings together with the whole crown ether moieties must be twisted from the plane with the H-3 proton in the E/E and the E/Z isomer, respectively (Fig. 5), clearly, in order to complex the K + cation in the bis(benzo-15-crown-5 ether) "sandwich" complex most effectively. (v) In addition, the ROE cross-peaks between the aromatic protons H-5 and the protons H-10 of the crown ether moieties proved to no longer exist in the K + complexed state of the three isomers of I (n = 3). Only between the protons H-8 to H10' could relevant cross-peaks be detected. Consequently, the polyether segments of the crown ether moieties must also change their spatial positions in order to better complex the K + ion. The ROE cross-peaks obtained for the free and the K + complexed bis(benzo- 15-crown-5 ether) 1 (n = 3) were used as constraints in molecular modelling studies (vide infra); as a result of these studies, one of the obtained lowest energy conformations of the E/Z isomer of 1 (n = 3) is given in Fig. 5(a) for the noncomplexed state and in Fig. 5(b) for the K + complexed state. The twisting of the one crown ether moiety during the K + complexation, as just concluded, is remarkably well corroborated.
I. Starke et al./Journal o f Molecular Structure 356 (1995) 15-24
21
v
free crown
(a)
complex with K
(b)
Fig. 5. Complexation behaviour of the title compound 1 (n = 3): (a) one of the lowest energy conformations of the free E/Z isomer (sketch and calculated structure); (b) one of the lowest energy conformations of the E/Z isomer complexedto the K+ cations of KBF4 (sketch and calculated structure). For the N a + complex of 1 ( n - - 3 ) , the same ROEs as for the free bis(benzo-15 crown-5 ether) were obtained from the corresponding 2 D - R O E S Y N M R experiment; only minor structural variations of the molecule along with the "usual" complexation of 1 (n = 3) to N a + cations can be concluded. 3.4. Dynamic simulation with N O E distances as constraints and quantum mechanical calculations The distances between the protons H - 3 - N H and H - 3 - H - 5 and H - 3 - H - 9 , respectively, as qualitatively (strong ROE, medium ROE, weak ROE) obtained for the nuclear Overhauser effects in the rotating frame of the 2 D - R O E S Y N M R experi-
ment of the three isomers of 1 (n = 3) were used as constraints for the simulated annealing program with the T R I P O S force field in the SVBVLsoftware [36]. The simulated annealing program is applying a high temperature to surpass any torsional barriers within the molecule; the energy is then removed by lowering the temperature to obtain reasonable structures for the studied molecule. These dynamic calculations were carried out within a temperature range of 200 to 1000 K with 100 cycles for each isomer with the dielectric constant 46.7 for the solvent D M S O - d 6 used. About 20 different conformations for 1 (n = 3) which resulted from this molecular dynamics simulation were selected and used as the starting
22
L Starke et aL /Journal o f Molecular Structure 356 (1995) 15-24
Table 3 Results of the molecular dynamics simulation and the MOPAC/PM3calculations of the "sandwich"-like structure and the extended conformation of the free and the K+ complexedcompound 1 (n = 3)
Conformation with constraints of the free isomer Z/Z Conformation with constraints of the K+ complex Conformation with constraints of the free isomer Z/E Conformation with constraints of the K + complex Conformation with constraints of the free isomer E/E Conformation with constraints of the K+ complex a
Energy of "Sandwich" like-structure (kcal mol-l)
Energy of "Extended" structure (kcal mol-1)
Molecular dynamics
MOPAC/PM3 a
Moleculardynamics
MOPAC/PM3 a
17.48
-321.41
32.70
-318.02
8.53
-321.86
32.51
-321.51
21.77
-321.55
37.23
-311.93
15.80
-321.41
43.50
-315.18
25.37
-316.19
34.70
-314.13
19.47
-314.13
46.90
-313.54
Starting conformations result from the molecular mechanic calculations with constraints.
geometries for T R I P O S force field minimizations. These calculations were carried out with and without the distance constraints as obtained from the ROEs (vide supra). The outcome of these calculations proved higher conformational energies and also different geometries for the isomers of 1 (n = 3) when taking the distance constraints into account. The results proved the E/Z isomer to be the most stable isomer (Table 3). The calculations were carried out generally for two forms; one for an "extended" structure and one for the "sandwich"-like preorganized structure of the three isomers of I (n = 3). In both cases, the E/Z isomers proved to be most stable. The dynamic calculation illustrates clearly that the "sandwich"-like arrangement of the benzo-15-crown-5 ether moieties near to each other is much more stable than any other "extended" structure of the molecule. Any attempt to find intramolecular hydrogen bonding between the amide - C ( = O ) - N H fragments for the stabilization of any preferred conformer [10] failed; this result is also in coincidence with the experimental results (vide supra). All the minimized conformations of the three isomers of the title compound were also used as
starting geometries for MOPAc/PM3 calculations. Surprisingly, the PM3 minimized conformations based on T R I P O S force field calculations with distance constraints were energetically more stable than the former. The T R I P O S force field without constraints proved unsatisfactory for these isomers of 1 (n = 3). The configuration of the amide bonds in 1 (n = 3) was of special interest and was further studied by theoretical calculations. Along with the molecular dynamics simulations (vide supra) using the T R I P O S force field, the transition states between the various E and the Z isomers were observed. Because of the special amide bond isomerism problem, the rotational barrier of the amide bond was also examined carefully by means of the PM3 method [21]. Three models were used to analyse both the barrier to rotation about the partial, C, N double bond and the stability of the E/E, E/Z and Z / Z isomers: (i) only the following fragment of compound 1 (n = 3): (CH 3 - C H 2 - C H 2 - C O - N H - N = C H - P h ) ; (ii) the most stable conformation of the Z/Z isomer of the whole compound 1 (n = 3); (rio the model tetrapeptide Gly 1-Gly2-Glya-Gly4.
L Starke et al./Journal of Molecular Structure 356 (1995) 15-24
The calculations were carried out using the PM3 Hamiltonian and the AM1 Hamiltonian as credible methods to handle the amide bonds of interest. The saddle algorithm [22] leads to transition states between the E and the Z isomers. The energy obtained for the saddle point of the E/Z isomerization with the first model was 9.8 kcal mol-l but was only 9.4 kcal mo1-1 for the Z/E isomerization. This outcome supports, from the theoretical point of view, the experimentally obtained result that 1 (n = 3) prefers the Z configuration of the - C ( = O ) - N H - moiety of the R - C O - N H - N = C H - P h fragment. The theoretical outcome obtained for model (ii) also supports the experimental findings; the barrier to rotation of one of the two partial C,N double bonds when being E/Z isomerized was calculated to be 11.2 kcal mo1-1. For model (iii), the barrier to rotation for the amide bond isomerization between the GIy2 and Gly3 moieties of the tetrapeptide was calculated to be about 17.1 kcal mol-1, coincident with the experiment [31]. At the same time and as expected, the E isomer was found to be the more stable one. The results of the AM 1 calculation are similar to those obtained by the PM3 method. From the model calculations (i)-(iii), it can be concluded that steric and electronic conditions of the amide moieties in the bis(benzo-15-crown-5 ether) 1 (n = 3) studied and usual peptides are very different. For both groups of compounds the experimentally determined configuration sequences could be reproduced. As major reasons for the reversed behaviour in the case of the bis(benzo-15-crown-5 ether) the following structural differences may be responsible: (i) Steric destabilization of a - C H - N H protons in the Z isomer of usual peptides is not present in 1 (n = 3), and (ii) the fragment C H = N - N H - C = O is well conjugated in both the E and the Z isomer of 1 (n = 3) because the imine nitrogen is positioned adjacent to the - N H - C = O - amide moiety.
4. Conclusions The studied bis(benzo-15-crown-5
ether)
1
23
(n = 3) exists as a mixture of three isomers which build up "sandwich"-like complexes with K + cations but form only "usual" 2:1 host-guest complexes with Na + cations. The E/Z isomer with respect to the two amide - C ( = O ) - N H - fragments present is the most stable diastereomer both in the free and in the complexed state; the Z/Z isomers follows and finally the E/E isomer is the one of highest energy in DMSOd6. The comparison of the preferred conformations found in the free and in the complexed state allows the following conclusions to be made about the complexational behaviour of compound 1 (n = 3). According to the molecular dynamic simulation, taking the ROE distances as constraints into account, it can be concluded that the isomers of the non-complexed bis(benzo-15-crown-5 ether) already exist in a preferred preorganised "sandwich"-like structure in solution. With the complexation of the bis(benzo- 15-crown5 ether) to K +, (i) the anti configuration of the C 3 H - N = lone pair of the P h - C H = N - N H - fragments in the various isomers is maintained, (ii) the planes of the phenyl rings of the crown ether moieties are twisted from the plane of the - C H = N - N H fragment, and (iii) the crown ether moieties change their positions with respect to the phenyl ring protons H-5 and H-8.
Acknowledgement The kind support by G. Hgssner (T U Miinchen) in recording the 600 MHz NMR spectra is gratefully acknowledged.
References [1] K. Kimura, T. Maeda and T. Shono, Talanta, 26 (1979) 945. [2] K.H. Wong and H.L. Ng, J. Coord. Chem., 11 (1981) 49. [3] M. Bourgoin, K.H. Wong, J.Y. Hui and J. Smid, J. Am. Chem. Soc., 97 (1975) 3462. [4] T. Ikeda, A. Abe, K. Kikukawa and T. Matsuda, Chem. Lett., (1983) 369. [5] L. T6ke, I. Bitter, B. Agai, Z. Hell, E. Lindner, K. Toth, M. Horvath, S. Harfouch, E. Pungor, Liebigs Ann. Chem., (1988) 549.
24
L Starke et al./Journal of Molecular Structure 356 (1995) 15-24
[6] E. Lindner, K. Toth, M. Horvath, E. Pungor, B. Agai, I. Bitter, L. T6ke and Z. Hell, Fresenius Z. Anal. Chem., 322 (1985) 157. [7] K. Kikukawa, G.X. He, A. Abe, T. Goto, R. Arata, T. Ikeda, F. Wada and T. Matsuda, J. Chem. Soc., Perkin Trans 2, (1987) 135. [8] S. Shinkai, T. Ogawa, Y. Kusano, O. Manabe, K. Kikukawa, T. Goto and T. Matsuda, J. Am. Chem. Soc., 104 (1982) 1960. [9] P.D. Beer, Z. Chen, A. Grieve and J. Haggitt, J. Chem. Soc., Chem. Commun., (1994) 2413. [10] N.G. Lukyanenko, N.Y. Nazarova, V.U. Vetrogon, H.-J. Holdt, J. Aurich and G. Kuntosch, Inorg. Chim. Acta, 155 (1989) 35. [11] C. Griittner and H.-J. Holdt, J. Inclus. Phenom., 16 (1993) 219. [12] T.M. Handyside, J.C. Lockhardt, M.B. McDonnell and P.V. Suba Rao, J. Chem. Soc., Dalton Trans., (1982) 2331. [13] Y. Inoue and G.W. Gokel, Cation Binding by Macrocycles, Marcel Dekker, New York, 1990, pp. 1-110. [14] S. Stoss, E. Kleinpeter and H.-J. Holdt, Magn. Reson. Chem., 29 (1991) 999. [15] H.-J. Holdt, J. Aurich, J. Teller and G. Kuntosch, German Patent DD 257 070 A1, 1988. [16] A. Bax, J. Am. Chem. Soc., 108 (1986) 2093. [17] H. Kessler, C. Griesinger and K. Wagner, J. Am. Chem. Soc., 109 (1987) 6927. [18] T.E. Bull, J. Magn. Reson., 80 (1988) 470.
[19] H. Kessler, M. Gehrke and C. Griesinger, Angew. Chem., 100 (1988) 507. [20] H.J.C. Berendsen, J.M.P. Postma, W.F. van Gunsteren, A. Dinola and J.R. Haak, J. Chem. Phys., 81 (1984) 3684. [21] J.J.P. Stewart, MOPAC6.0, QCPE 455, 1991. [22] M.J.S. Dewar, E.F. Healy and J.J. Stewart, J. Chem. Soc., Faraday Trans., 3 (1984) 277. [23] H. Kessler, W. Hehlein and R. Schuck, J. Am. Chem. Soc., 104 (1984) 4534. [24] H. Kessler, Liebigs Ann. Chem., 6 (1985) 1145. [25] V.F. Bystrov, Prog. NMR Spectrosc., 10 (1976) 41. [26] V.M.S. Gil and W. Philipsborn, Magn. Reson. Chem., 27 (1989) 40922. [27] D.E. Dorman and F.A. Bovey, J. Org. Chem., 38 (1973) 1719. [28] R.R. Fraser and M. Bresse, Can. J. Chem., 61 (1983) 576. [29] H. Kessler, Angew. Chem., 94 (1982) 509. [30] Y.A. Bara, A. Friedrich, H. Kessler and M. Molter, Chem. Ber., 111 (1978) 1046. [31] H.R. Loosli, H. Kessler, H. Oschkinat, H.P. Weber, T.J. Petcher and A. Widmer, Helv. Chim. Acta, 68 (1985) 682. [32] P. Domiano, G. Predieri, M. Lanfranchi, P. Tarasconi and G. PaUa, J. Chem. Soc., Perkin Trans. 2, (1986) 521. [33] L.P. Battaglia, A. Bonamartini Corradi, G. Pelosi and P. Tarasconi, J. Cryst. Spectrosc. Res., 19 (1989) 93. [34] E. Kleinpeter, S. Stoss, M. G/ibler and W. Schroth, Magn. Reson. Chem., 27 (1989) 676. [35] J.C. Lockhart, J. Chem. Soc., Dalton Trans., (1978) 611. [36] SYBYL6.1, Tripos Associates Inc., St. Louis, MO, 1994.
MOLECULAR STRUCTURE ELSEVIER
Journal of Molecular Structure 356 (1995) 15-24
1H, 13C and 15N NMR study of the solution structure of meta-bridged bis(benzo- 15-crown-5 ether)s I. S t a r k e a, A . K o c h % E. K l e i n p e t e r ~'*, H . - J . H o l d t b alnstitut fi~r Organische Chemie und Strukturanalytik, UniversitiJt Potsdam, Am Neuen Palais 10, D-14469 Potsdam, Germany bChemische Institute, Universiti~t Rostock, Buchbinder Str. 9, D-18055 Rostock, Germany
Received 6 February 1995;acceptedin final form 13 April 1995
Abstract
The IH and 13CNMR spectra of the three isomers of the bis(benzo-15-crown-5 ether) studied and their complexes with K + and Na + cations were recorded and assigned by H,H-COSY and HMQC 2D-NMR experiments. The three isomers with respect to the amide C( = O)-NH bonds could be assigned by 15N NMR spectroscopy and heteronuclear coupling constants. Relevant conclusions about the isomerism were deduced from the 1Jt5_N,l_H coupling constants of the various NH amide groups and the 1Jl3_C,1 H coupling constants of C3H and C~H2-C(= O)- groups, respectively. From 2DROESY NMR experiments, further stereochemical information about the preferred conformation of the free and complexed bis(benzo-15-crown-5 ether) was obtained. The conformational study is accompanied and corroborated by molecular dynamics and quantum chemical calculations. In the case of the K + complex, a "sandwich"-like complex could be determined. This structure clearly proved to be already preorganized in the non-complexed host molecule. For the corresponding Na + complex, the "usual" 2:1 host-guest complex was detected.
I. Introduction
The complexational behaviour of bis(benzocrown ether)s with alkali metals and other cations has been widely studied [1-6]. Compounds of this type consist of two crown ether units in the same molecule and provide the formation of "sandwich"-like complexes with cations of radii larger than the cavity size of the single crown ether unit [7-10]. The complex stability and the complexation thermodynamics of bis(benzo-15crown-5-ether)s, having acylhydrazide fragments as the linking chain, with different cations were investigated by spectrophotometric titrations * Corresponding author.
[ 11-13]. The stability of these complexes proved to depend strongly on the length of the linking chain. Within the homologous series of the methylenebridged carbonylhydrazones 1 ( n = 0 - 8 ) , the potassium complex of the propylene-bridged compound 1 (n = 3, Fig. 1) shows the highest stability constant compared with the other methylenebridged bis(benzo-15-crown-5 ether) complexes with K+; the formation of a stable sandwich complex was concluded [11]. Owing to the two amide C ( = O ) - N H fragments present, the bis(benzo-15crown-5 ether)s 1 can exist as three isomers. To study this isomerism and the conformational behaviour of this interesting kind of compound by means of N M R spectroscopy [14] is the major objective of the present paper. In addition, the
0022-2860/95/$09.50 © 1995 Elsevier Science B.V. All rights reserved S S D I 0022-2860(95)0891 1-X
16
L Starke et al./Journal of Molecular Structure 356 (1995) 15-24
o O O= A B C n = 3 [ CH2-CH2-CH2 ]
Fig. 1. Polymethylene-bridgedcarbonylhydrazoneof4'-formylbis(benzo-15-crown-5 ether)s;studiedcompound 1 (n = 3). question of "usual" or "sandwich"-like complexation of K + and Na + cations to the compounds 1 was answered. First of all, the propylene-bridged bis(benzo-15-crown-5 ether) 1 (n -- 3) was studied, because it is outstanding in its affinity to complex with potassium cations. The investigation of analogous compounds is in progress.
2. Experimental The synthesis of compound 1 (n = 3) has been described by Holdt et al. [15]. The 1H and 13C NMR spectra were recorded at 300.13 and 75.47 MHz, respectively (BRUKER ARX 300), in DMSO-d6 solution (5 mm probe tubes, ambient temperature, deuterated solvents as internal lock). laC: 30° pulse, 2 s repetition time, 200 scans, 32K data points, 18 750 Hz spectral width and 0.57 Hz per point digital resolution, full proton broadband decoupling; 1H: 30° pulse, 2s repetition time, 128 scans, 32K data points, 7500 Hz spectral width and 0.23 Hz per point digital resolution. Chemical shifts are referenced to TMS (internal). The 15N NMR spectra were recorded at 30.42 MHz and at 60.81 Hz (on a UNITY 600 VARIAN NMR spectrometer) in natural abundance (solvent DMSO-d6, 10 mm probe tubes, spectra recorded at ambient temperature): 45 ° pulse, 4 s repetition time, 32K data points, 9259.26 Hz spectral width and 0.28 Hz per point digital resolution. The alkali salts used in the complexation study were dried over P4O10. The ill, 13C and 15N NMR spectra were assigned by the 2D-, H,H-COSY and reversed H, C-correlation and H,N-correlation experiments [16, 17]. The standard Bruker software was applied for these experiments; typical settings are as follows. HMQC: sweep width in F1 is 18 kHz
and in F2 6.9 kHz, 8K data points in F2, 512 experiments in F2 (8 scans), relaxation delay 0.2 s, pulse width (1H, 90°), 11.0/zs, (laC) 9.5 #s, zero filling, filter function sine-bell in both dimensions; for the lSN measurement the sweep width in F1 is 1 kHz and in F2 7 kHz, pulse width P1 (90 °, 15N) 10.2 #s, 8K data points in F 2 and 128 experiments in F1. For the 2D-ROESY NMR measurements, the samples were degassed at least three times and sealed under argon. The 2D-ROESY NMR spectra were recorded in the phase-sensitive mode [18, 19] with zero filling in F1. Also in this case, the standard Bruker software was employed, with sweep width in F 1 and in F 2 7 kHz, 1K data points in Fl and 2K data points in F2, relaxation delay 2 s, mixing time 200 ms, filter functions sine-bell in both dimensions. The molecular dynamics calculations (SIMULATED ANNEALING) were carried out with the TRIPOS force field starting at 1000 K and later cooling down to 200 K for 1000 fs. The default setup used a constant N, V, T ensemble based on Berendsen's method [20]. Quantum mechanical calculation was processed with the PM3 method from MOPAC 6.0 using the Silicon Graphics IRIS INDIGO XS 4000 [21,22] (keywords: XYZ MMOK GNORM = 0.01 SCFCRT = 0.0000001).
3. Results and discussion 3.1.1H,
13Cand
15N NMR spectra
The proton NMR spectra are very characteristic for the structure of the studied compound (see Table l(a)). The resonance ranges are sufficiently dispersed, the multiplets for the crown ether fragments (H-10-H-13) are shifted to higher field with respect to the aromatic ring current effect; the H, H coupling constants as extracted from the AA'BB' subspectra indicate gauche O - C H a - C H 2 - O fragments, readily inverting on the NMR time scale at ambient temperature. The vicinal H, H coupling constants between the different aromatic protons are unequivocal for the substitution pattern present (see Table 2(a)). In DMSO-d6, the 1H, 13C and 15N NMR spectra
17
L Starke et al./Journal of Molecular Structure 356 (1995) 15-24 Table 1 (a) 1H chemical shifts 8 (ppm) of 1 (n = 3) in DMSO-d6/(TMS) Isomer
NH
H-3
H-5
H-8
H-9
H-10
H-11
H-12
H-13 a
CH 2 groups b
E/E E/Z
11.27 11.24 11.15 11.11
8.04 8.02 7.87 7.84
7.26 7.26 7.23 7.23
6.98 6.98 6.92 6.92
7.14 7.14 7.12 7.12
4.07
3.77
3.62
3.34
A, B, C A, B, C
2.23, 1.88, 2.23 2.65, 1.88, 2.26
A, B, C
2.68, 1.88, 2.68
Z/Z
(b) 13C chemical shifts ~5(ppm) of 1 (n = 3) in DMSO-d6/(TMS ) Isomer
C-I
C-3
C-4
C-5
C-6
C-7
C-8
C-9
C-10
C-I 1
C-12
C13 a
E/E E/Z
146.0 145.9 142.6 142.5
127.2 127.2 127.2 127.2
110.7 110.6 110.0 110.0
148.6 148.6 148.5 148.5
150.2 150.2 150.0 150.0
113.0 112.9 112.8 112.8
121.7 121.7 120.8 120.7
68.3
68.7
69.6
70.4
Z/Z
168.0 173.8 168.2 173.9
Isomer
CH2 b
E/Z E/Z Z/Z
A, B, C A, B, C A, B, C
33.5, 21.0, 33.5 31.5, 20.3, 33.3 31.3, 19.7, 31.3
a H-10-H-13 and C-10-C-13, respectively, of the various isomers could not be differentiated due to signal overlapping. b Methylene groups of the linking chain.
Table 2 (a) Homonuclear coupling constants JH, ri (Hz) within the aromatic moiety and in the linking chain of I (n = 3) Isomer E/E E/Z Z/Z
3j (H, H) H-8-H-9 H-8-H-9 H-8-H-9 H-8-H-9
8.31 8.31 8.32 8.32
H-5-H-9 H-5-H-9 H-5-H-9 H-5-H-9
4j (H, H)
3j (H, H)
1.44 1.44 1.43 1.43
B-CH 2 7.17, B-CH2 7.17, A-CH 2 7.35, A-CH2 7.33,
7.27 7.20 7.35 7.36
(b) Heteronuclear coupling constants IJc, H (Hz) for the C 3 - H and a-CH 2 groups in the linking chain Isomer E/E E/Z Z/Z
i j (C, H) 3-CH 3-CH 3-CH 3-CH
163.7 164.8 163.7 165.0
i j (C, H) A-CH 2 B-CH 2
129.2 130.0
(c) Heteronuclear coupling constants l Jr~,n (Hz) of N z - H in the isomers of 1 (n = 3) Isomer
Ij(N, H)
E/E E/Z Z/Z
94 94, 92 92
18
L Starke et al./Journal of Molecular Structure 356 (1995) 15-24
prove that compound 1 (n = 3) exists as a mixture of three isomers with reference to the E/Z isomerism of the amide C ( = O ) - N H - bond (E/E, E/Z and Z/Z, respectively). Adequately well-separated signals for the NH, H-3, H-5, H-8 and H-9 protons in the IH N M R spectrum, and for the carbonyl carbon, C-3, C-5, C-8, C-9, and for the linking CH 2 groups in the 13C N M R spectrum were obtained (Table 1). Both the 1H and the 13C N M R spectra could be detected without any line broadening; at ambient temperature, the interconversion of the present isomers is slow on the N M R time scale. The chemical shifts of the linking methylene groups in the range of 1.8-3.0 ppm also document the presence of three isomers; the vicinal coupling constants 3j (H, H) indicate staggered conformations along this fragment (Table 2(a)). The assignment of the various isomers of the bis(benzo-15-crown-5 ether) 1 (n = 3) could be determined via the heteronuclear coupling constants IJls_N,l_H and lJl3_C,1.H. First, the N, H connectivities were detected by inverse 2D-N, H shift correlation experiments and then the 1J15_N,1.n coupling constants were measured. In peptides, the corresponding coupling constants are usually larger in E amide fragments compared to the values in the corresponding Z analogues [23,24]. In 1 (n = 3) the size of the relevant coupling constants 1JIS_N,I.H (Table 2(c)) amount to 94.0 Hz in the E/E isomer and 92.0 Hz in the Z/Z analogue. In the E/Z isomer, the values of 1J15_N,1.H were 92.0 and 94.0 Hz, proving the presence of the two - C ( = O ) - N H - configurations in the same isomer. The 1J13_C,l_H coupling constants of C-3 in the hydrazone moiety and o~-CH2 of the linking chain in the various isomers of 1 (n = 3) support the latter assignments. In the case of the c~-CH2 carbon atoms, lJ13_c,1.H coupling constants of 130.0 Hz were measured in the E configuration (B-CH2, see Fig. 1), in the Z isomer only 129.2 Hz (for A-CH2, see Fig. 1) was obtained [25,26]. As further proof of the present E/Z isomerism, along with the amide fragments of 1 (n = 3) we considered (i) the lowfield position of C=O of the E isomers (173.8-173.9 ppm) with respect to the Z analogue (168.0-168.2 ppm) [27] and (ii) the ROE between NH and C(c0H protons in the E isomer (no ROE obtained for the Z analogue). For hydrazones, a clear correlation between the
magnitude of the 1J13_c,1.H coupling constant at C3 and the configuration of the sp 2 nitrogen atom is found; the C - H bond, positioned trans to the lone pair at the nitrogen, exhibits the smaller 1Jl3.C,l_n coupling constant [28]. The size of the corresponding coupling constants in 1 (n = 3), J13-C,I-H = 163.7-165.0 Hz, along all the P h - C H = N - N H fragments clearly proves the anti arrangement of the nitrogen lone pair and the C - H bond at C-3 in this compound (see Fig. 4(a)). For the corresponding syn configuration, values of about 185 Hz for the same coupling c o n s t a n t IJl3.C,1.H at C-3 were expected [28]. The NH protons are characteristically shifted to lower field (6 > 11.0 ppm). However, from the dependence of the 1H chemical shift of the NH protons on different concentrations and various temperatures, intramolecular hydrogen bonding could not take place. However, the concentration and temperature dependence of the NH protons can be interpreted by the presence of intermolecular hydrogen bonding to the solvent or other molecules of 1 (n = 3) in solution [29,30]. The integration of these NH signals (assigned to the corresponding isomers, vide supra) and those of the corresponding H-3 protons readily allowed us to quantify the percentage ratio of the present isomers: Z/Z : Z/E : E / E = 27.7 : 51 : 21.3. The barrier to E/Z isomerization of the amide bond in peptides is usually expected at about 18 kcal mol-1; thus, the corresponding restricted rotation should be slow on the N M R time scale at 313 K [31]. Also in hydrazones, as for example in formylthiophene n-acetyl hydrazone, the restricted rotation about the partial C, N double bond at ambient temperature is slow on the N M R time scale, but the two isomers could be detected both in solution and in the solid state [32,33]. For the present compound 1 (n = 3) the occurrence of all possible isomers was also found experimentally, and this result was corroborated by quantum chemical calculations, which are given later in this paper. 3.2. Complexation o f the bis(benzo-15-crown-5 ether) 1 (n = 3) with K + and Na + cations
The complexation of crown ether molecules and alkali cations can be readily studied by N M R
L Starke et al./Journal of Molecular Structure 356 (1995) 15-24 c h e m i c a l shifts
19
c h e m i c a l shifts
high field
shifts
low field shifts
I
e
8.(3~
H-3
~ ~r'~*'~j*
e.s
H-3
7.75
I *
~
H-5
*
~*
H-9
*
~
H-8
7
.
2
~
~
-'*
-~
-~ H-5
*
~,
• H-9
*
~
* H-8
6.5--
I 0,5:1
I 1:1
f 1.5:1
I
I
2:1
3:1
J[Na,:( .... ] 4:1
i
I
I
i
I
0.5:1
1:I
1.5:1
2:1
3:1
I [~F4l:(cro~) 4:1
Fig. 2. Study of the complexation of 1 (n = 3) with Na + cations of Nal.
Fig. 3. Study o f the complexation of 1 (n = 3) with K + cations of KBF4.
spectroscopy. In particular, the upfield or downfield shift of the resonances of protons involved in the studied crown ethers can be usefully correlated with the present complexational behaviour [14,34, 35]. If in the case of bis(crown ether)s the "usual" 1:2 ligand:cation complexes are formed, the 1H resonances will be shifted downfield with respect to their resonances in the free non-complexed bis-(crown ether). In the case of the formation of 1 : 1 "sandwich" complexes, however, the corresponding proton resonances are shifted upfield with complexation of the alkali cations proceeding with the present bis(crown ether) molecules [14,35]. With the complexation of the title compound 1 (n = 3) to Na ÷ cations, the 1H N M R resonances of the protons involved are shifted to lower field (see Fig. 2); typical 2 : 1 complexation can be concluded. The same information comes from the shapes of the 61_H VS. [NaI]:[1] curves (see Fig. 2). The sodium cation is clearly suitable for the cavity size of the benzo-15-crown-5 moieties of 1 (n = 3).
If, however, 1 (n = 3) is complexed to the potassium cations of KBF4, the proton resonances are shifted upfield (see Fig. 3). For this reason and from the shapes of the corresponding ~5]_ri vs. [KBF4]:[1] curves (see Fig. 3), "sandwich"-like 1:1 complexation of the present bis(benzo-15 crown-5 ether) to K + cations proved to be the case. The ratio of the Z/Z, E/Z and E/E isomers of 1 (n = 3) is only slightly changed during the complexation: Z/Z: E/Z: E / E = 31.5:47.2:21.35. All the results obtained experimentally are in total agreement with the stability constants of the K + complexes of the bis(benzo-15-crown-5 ether)s as determined by spectrophotometric titration [1 l]. The stability of the 1:1 "sandwich" complexes with K + is higher than that of the "usual" 2:1 complexes; the reason for this result is twofold: (i) the cavity size of the crown ether units of 1 (n = 3) is too small to host the K + cations and, avoiding this, the "sandwich" 1:1 complex is formed for which the cavity size is less important or (ii) the
20
L Starke et al./Journal of Molecular Structure 356 (1995) 15-24
"bis(benzo crown ether) effect", in which the crown ether moieties are positioned parallel to each other, is completely dominating the solution structure estimated for the K + complex of 1 (n = 3). In the case of the smaller sodium cation, at least, the "bis(benzo crown ether) effect" is only of negligible importance. 3.3. Spatial ROESY distance measurements
Further stereochemical information about the spatial connectivity of the protons involved in the bis(benzo-15 crown-5 ether) molecule can be obtained from the 2D ROESY N M R spectra [19]. For the three isomers of the free non-complexed 1 (n = 3) the following structurally relevant ROE cross-peaks were obtained: (i) Nuclear Overhauser effects in the rotating coordinate system between the N H protons and the protons H-3 prove the anti position of the nitrogen lone pair and H-3 within the P h - C 3 H = N - N H fragment to be correct (see Fig. 4(a)). (ii) From the intensities of the ROE cross-peaks between the proton H-3 of the linking chain and (¢)
H
I
H
I
\tone peiron ntnel~
(b)
/,
~ E/E isomere
-8
5
H8
"'x
H8 Z/E isomefe
Fig. 4. (a) Anti arrangement of the imine nitrogen lone pair relative to C3H and NH in the NH-N=CH-Ph fragment of all isomers of 1 (n = 3). (b) ROE connectivitieswithin all isomers of the free bis(benzo-15-crown-5ether) 1 (n = 3) and the E/ E and E/Z isomers of its K+ complex.
the aromatic protons H-5 and H-9, it can be concluded that the phenyl ring is twisted from the common plane of resonance and that the proton H-3 is positioned closer to H-5 than to H-9 (Fig. 4(b)). (iii) Between the methylene protons H-10 and H-10 t and the aromatic protons H-5 and H-8, respectively, ROE cross-peaks were detected, in agreement with the graduated upfield shifts of these protons and with the anisotropy effect of the aromatic moieties of the studied molecule (see Table l(b)). (iv) With the 1 : 1 "sandwich"-like complexation of 1 (n = 3) to K + cations, the ROE cross-peaks between the protons H-3 and H-9 in the E/E isomer and the one between H-3 and H-5 in the E/Z isomer at the E-positioned amide bond side are disappearing (see Fig. 4(b)); in the Z/Z isomer and at the Z side arm of the E/Z isomer, the corresponding ROE cross-peaks are still present. Also the ROEs between the N H protons and the H-3 protons do not change significantly with the complexation of the three isomers. Thus, it may be concluded that the phenyl rings together with the whole crown ether moieties must be twisted from the plane with the H-3 proton in the E/E and the E/Z isomer, respectively (Fig. 5), clearly, in order to complex the K + cation in the bis(benzo-15-crown-5 ether) "sandwich" complex most effectively. (v) In addition, the ROE cross-peaks between the aromatic protons H-5 and the protons H-10 of the crown ether moieties proved to no longer exist in the K + complexed state of the three isomers of I (n = 3). Only between the protons H-8 to H10' could relevant cross-peaks be detected. Consequently, the polyether segments of the crown ether moieties must also change their spatial positions in order to better complex the K + ion. The ROE cross-peaks obtained for the free and the K + complexed bis(benzo- 15-crown-5 ether) 1 (n = 3) were used as constraints in molecular modelling studies (vide infra); as a result of these studies, one of the obtained lowest energy conformations of the E/Z isomer of 1 (n = 3) is given in Fig. 5(a) for the noncomplexed state and in Fig. 5(b) for the K + complexed state. The twisting of the one crown ether moiety during the K + complexation, as just concluded, is remarkably well corroborated.
I. Starke et al./Journal o f Molecular Structure 356 (1995) 15-24
21
v
free crown
(a)
complex with K
(b)
Fig. 5. Complexation behaviour of the title compound 1 (n = 3): (a) one of the lowest energy conformations of the free E/Z isomer (sketch and calculated structure); (b) one of the lowest energy conformations of the E/Z isomer complexedto the K+ cations of KBF4 (sketch and calculated structure). For the N a + complex of 1 ( n - - 3 ) , the same ROEs as for the free bis(benzo-15 crown-5 ether) were obtained from the corresponding 2 D - R O E S Y N M R experiment; only minor structural variations of the molecule along with the "usual" complexation of 1 (n = 3) to N a + cations can be concluded. 3.4. Dynamic simulation with N O E distances as constraints and quantum mechanical calculations The distances between the protons H - 3 - N H and H - 3 - H - 5 and H - 3 - H - 9 , respectively, as qualitatively (strong ROE, medium ROE, weak ROE) obtained for the nuclear Overhauser effects in the rotating frame of the 2 D - R O E S Y N M R experi-
ment of the three isomers of 1 (n = 3) were used as constraints for the simulated annealing program with the T R I P O S force field in the SVBVLsoftware [36]. The simulated annealing program is applying a high temperature to surpass any torsional barriers within the molecule; the energy is then removed by lowering the temperature to obtain reasonable structures for the studied molecule. These dynamic calculations were carried out within a temperature range of 200 to 1000 K with 100 cycles for each isomer with the dielectric constant 46.7 for the solvent D M S O - d 6 used. About 20 different conformations for 1 (n = 3) which resulted from this molecular dynamics simulation were selected and used as the starting
22
L Starke et aL /Journal o f Molecular Structure 356 (1995) 15-24
Table 3 Results of the molecular dynamics simulation and the MOPAC/PM3calculations of the "sandwich"-like structure and the extended conformation of the free and the K+ complexedcompound 1 (n = 3)
Conformation with constraints of the free isomer Z/Z Conformation with constraints of the K+ complex Conformation with constraints of the free isomer Z/E Conformation with constraints of the K + complex Conformation with constraints of the free isomer E/E Conformation with constraints of the K+ complex a
Energy of "Sandwich" like-structure (kcal mol-l)
Energy of "Extended" structure (kcal mol-1)
Molecular dynamics
MOPAC/PM3 a
Moleculardynamics
MOPAC/PM3 a
17.48
-321.41
32.70
-318.02
8.53
-321.86
32.51
-321.51
21.77
-321.55
37.23
-311.93
15.80
-321.41
43.50
-315.18
25.37
-316.19
34.70
-314.13
19.47
-314.13
46.90
-313.54
Starting conformations result from the molecular mechanic calculations with constraints.
geometries for T R I P O S force field minimizations. These calculations were carried out with and without the distance constraints as obtained from the ROEs (vide supra). The outcome of these calculations proved higher conformational energies and also different geometries for the isomers of 1 (n = 3) when taking the distance constraints into account. The results proved the E/Z isomer to be the most stable isomer (Table 3). The calculations were carried out generally for two forms; one for an "extended" structure and one for the "sandwich"-like preorganized structure of the three isomers of I (n = 3). In both cases, the E/Z isomers proved to be most stable. The dynamic calculation illustrates clearly that the "sandwich"-like arrangement of the benzo-15-crown-5 ether moieties near to each other is much more stable than any other "extended" structure of the molecule. Any attempt to find intramolecular hydrogen bonding between the amide - C ( = O ) - N H fragments for the stabilization of any preferred conformer [10] failed; this result is also in coincidence with the experimental results (vide supra). All the minimized conformations of the three isomers of the title compound were also used as
starting geometries for MOPAc/PM3 calculations. Surprisingly, the PM3 minimized conformations based on T R I P O S force field calculations with distance constraints were energetically more stable than the former. The T R I P O S force field without constraints proved unsatisfactory for these isomers of 1 (n = 3). The configuration of the amide bonds in 1 (n = 3) was of special interest and was further studied by theoretical calculations. Along with the molecular dynamics simulations (vide supra) using the T R I P O S force field, the transition states between the various E and the Z isomers were observed. Because of the special amide bond isomerism problem, the rotational barrier of the amide bond was also examined carefully by means of the PM3 method [21]. Three models were used to analyse both the barrier to rotation about the partial, C, N double bond and the stability of the E/E, E/Z and Z / Z isomers: (i) only the following fragment of compound 1 (n = 3): (CH 3 - C H 2 - C H 2 - C O - N H - N = C H - P h ) ; (ii) the most stable conformation of the Z/Z isomer of the whole compound 1 (n = 3); (rio the model tetrapeptide Gly 1-Gly2-Glya-Gly4.
L Starke et al./Journal of Molecular Structure 356 (1995) 15-24
The calculations were carried out using the PM3 Hamiltonian and the AM1 Hamiltonian as credible methods to handle the amide bonds of interest. The saddle algorithm [22] leads to transition states between the E and the Z isomers. The energy obtained for the saddle point of the E/Z isomerization with the first model was 9.8 kcal mol-l but was only 9.4 kcal mo1-1 for the Z/E isomerization. This outcome supports, from the theoretical point of view, the experimentally obtained result that 1 (n = 3) prefers the Z configuration of the - C ( = O ) - N H - moiety of the R - C O - N H - N = C H - P h fragment. The theoretical outcome obtained for model (ii) also supports the experimental findings; the barrier to rotation of one of the two partial C,N double bonds when being E/Z isomerized was calculated to be 11.2 kcal mo1-1. For model (iii), the barrier to rotation for the amide bond isomerization between the GIy2 and Gly3 moieties of the tetrapeptide was calculated to be about 17.1 kcal mol-1, coincident with the experiment [31]. At the same time and as expected, the E isomer was found to be the more stable one. The results of the AM 1 calculation are similar to those obtained by the PM3 method. From the model calculations (i)-(iii), it can be concluded that steric and electronic conditions of the amide moieties in the bis(benzo-15-crown-5 ether) 1 (n = 3) studied and usual peptides are very different. For both groups of compounds the experimentally determined configuration sequences could be reproduced. As major reasons for the reversed behaviour in the case of the bis(benzo-15-crown-5 ether) the following structural differences may be responsible: (i) Steric destabilization of a - C H - N H protons in the Z isomer of usual peptides is not present in 1 (n = 3), and (ii) the fragment C H = N - N H - C = O is well conjugated in both the E and the Z isomer of 1 (n = 3) because the imine nitrogen is positioned adjacent to the - N H - C = O - amide moiety.
4. Conclusions The studied bis(benzo-15-crown-5
ether)
1
23
(n = 3) exists as a mixture of three isomers which build up "sandwich"-like complexes with K + cations but form only "usual" 2:1 host-guest complexes with Na + cations. The E/Z isomer with respect to the two amide - C ( = O ) - N H - fragments present is the most stable diastereomer both in the free and in the complexed state; the Z/Z isomers follows and finally the E/E isomer is the one of highest energy in DMSOd6. The comparison of the preferred conformations found in the free and in the complexed state allows the following conclusions to be made about the complexational behaviour of compound 1 (n = 3). According to the molecular dynamic simulation, taking the ROE distances as constraints into account, it can be concluded that the isomers of the non-complexed bis(benzo-15-crown-5 ether) already exist in a preferred preorganised "sandwich"-like structure in solution. With the complexation of the bis(benzo- 15-crown5 ether) to K +, (i) the anti configuration of the C 3 H - N = lone pair of the P h - C H = N - N H - fragments in the various isomers is maintained, (ii) the planes of the phenyl rings of the crown ether moieties are twisted from the plane of the - C H = N - N H fragment, and (iii) the crown ether moieties change their positions with respect to the phenyl ring protons H-5 and H-8.
Acknowledgement The kind support by G. Hgssner (T U Miinchen) in recording the 600 MHz NMR spectra is gratefully acknowledged.
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