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Coordination complexes of beryllium(II) with various antihistaminic substances: Their stabilities and thermodynamic values
J. inorg,nucl.Chem., 1969.Vol. 3I, pp. 3809to 3816. PergamonPress. Printedin Great Britain
COORDINATION COMPLEXES OF BERYLLIUM(II) WITH VARIOUS ANTIHISTAMINIC SUBSTANCES: THEIR STABILITIES AND THERMODYNAMIC VALUES 1. D. C H A W L A * and A. C. A N D R E W S Department of Chemistry, Kansas State University, Manhattan, Kansas 66504 (First received 15 August 1968; in revised form 4 June 1969)
Ahstraet-Stepwise formation constants for the Be(ll) complexes with adrenaline, antistine, ephedrine, benadryl and pyribenzamine are reported at five different temperature. The Gibbs free energy, entropy and enthalpy values for these reactions are discussed in terms of coordination number of the metal ion, complexing ability and steric hinderance of ligands, and possible tetrahedral structures for these complexes. Results show that all the antihistamines form stable compounds with Be(ll), demonstrating thereby the validity of nitrogen-beryllium coordination bond. It is also observed that Be(ll)-antihistamine complex formation results in greater free energy change than is associated with the formation of Be(l l)-histamine complex. The data from this work substantiates the theory of competitive binding between histamine and antihistamine for the etectrophilic site of a metal ion. INTRODUCTION
previous paper[l] the coordination complexes of Be(II) with histamine and its associated compounds were reported in terms of their formation constants and associated thermodynamic functions. It was believed that a similar study of the Be(II) complexes with various antihistaminic molecules could provide valuable comparison in evaluating the importance of complex formation in the mechanism of histamine-antihistamine activity. Wells[2], in 1950, proposed a concept of competitive binding for the antihistaminic activity in which the antihistamine is in competition with the histamine for an electrophilic metal ion. Andrews, Lyons and O'Brien[3] have determined the stability constants and free energy of complex formations between Cu(II), Co(lI), and Ni(lI) with various antihistamines and their data also suggest the competitive nature of reactions between histamine and the antihistamine for the binding site of a metal ion under study. Recently Andrews and Romary[4], using the polarographic technique, have demonstrated from the thermodynamic data on Cd(I l)-antihistamine binding that the order of spontaneity of complex formation was benadryl > ephedrine > antistine > histamine. I N THE
*To whom all correspondence should be addressed. Present address: Department of Chemistry, Long Island University, Brooklyn, N.Y. 11201.
!. 2. 3. 4.
1. D. Chawla and A. C. Andrews,J. inorg. Nucl. Chem. To be published. J. A. Wells,A nn. N. Y. A cad. Sci. 50, 1202 (1950). A. C. Andrews, T. D. Lyons and T. D. O'Brien, J. chem. Soc. 1776 (1962). A. C. Andrews andJ. K. Romary,J. chem. Soc. 405 (1964). 3809
3810
I . D . C H A W L A and A. C. A N D R E W S EXPERIMENTAL
Procedure and materials. The potentiometric titration technique of Bjerrum[5] was used in this
work. The theoretical background and experimentation involved were discussed previously[l]. A Leeds and Northrup pH meter No. 7663-A1, capable of reproducing readings to within 0.02 pH units, was used with Leeds and Northrup electrodes No. 1199-44 for 0°C, and 15°C; and No. 1199-30 for 25°C, 35°C and 45°C titrations; all measured against a saturated calomel electrode. Enough of ligand was added to maintain a ligand to metal ion ratio greater than four to one. The ionic strength of the medium was kept at 0.12 (_+0.006) by the addition of KCI. The antihistamines obtained from industrial concerns were adrenaline, l-(3,4-dihydroxyphenyl)-2-methylaminoethanol; antistine, 2-(N-benzylanilinomethyl) imidazoline hydrochloride; benadryl, NN-dimethyl-2-diphenylmethoxyethylamine hydrochloride; ephedrine, 2-methylamino-l-phenyl-l-propanol; pyribenzamine, 2-[benzyl-(2-dimethylaminoethyl)amino] pyridine. The analysis and percentage purity of these compounds have been determined by Lyons et al.[3] and their values were relied upon in the preparation of standard solutions of these compounds. Solutions of beryllium chloride, potassium chloride and hydrochloric acid were standardized by their gravimetric precipitation as silver chloride. Carbonate free standard potassium hydroxide, used as a titrant, was prepared by passing the solution through an anion exchange column containing amberlite 1RA-400. The concentrations of beryllium chloride and the various antihistamines ranged from 1.74-2.12 x 10-3 molar and 7.18-9.03 × 10-a M, respectively. The complex formation occured between 4.0 and 7.5 pH, depending upon the ligand under study and the temperature of the reaction. The justifications for the absence of metal hydrolysis in these titrations are the same, as discussed in our previous paper [ 1]. RESULTS AND DISCUSSION
The stepwise complex formation by Be(I I) with bidentate ligands refer to the following generalized reactions: Be(H20)4 +2 + li ~ Be(li)(HzO)2 +2+ 2H~O for log K1 = p(li)Inl. 5 Be(Ii)(H20)2 +2 + li ~- Be(li)z +2 + 2H20 for log K2 =
p(li)s~j.5
For monodentate ligands the complex formation by the Be(lI) would follow reactions in which only one coordinated water molecule can be replaced by the incoming ligand. Hence, it is theoretically possible to obtain four successive equilibrium constants for the Be(ll) complexes with unidentate ligands. In actuality, however, only the first and the second stepwise reactions are observed in every case and values of their equilibrium constants determined in a manner discussed above. The evaluation of log K1 and log Ke for these reactions is undoubtedly valid only in the absence of simultaneous complex formation. As pointed out in our earlier paper[l], the shapes and character of the formation curves, plots of t~ vs. p(li)f, would indicate the nature of the reactions. From Figs. 1 to 5, it is clearly evident that the likelihood of simultaneous reaction can easily be ruled out in these systems. Except for Adrenaline, all other antihistamines yield fairly good formation curves where the values of log K1 and log K2 are well defined. The Be(II)adrenaline system exhibits successive equilibrium constants which are widely separated yet their formation curves are poor. It is estimated that the log Kn values are correct to within __+0.05. The stepwise formation constants, log Kn, for Be(II) complexes of various antihistamines at five different temperatures are given in Table 1 ; along with acid 5. J. Bjerrum, MetalAmine Formation inAqueous Solution. Haase, Copenhagen (1941).
pa,~
"
I
Fig. 1. Formation curves for Be(ll)-antistine system. • 0°C; [] [] 15°C; H 25°C; V V 35°C; 0 45°C.
8.o
©
50
I
60
\
I
7o
I
8-o
I
p( /i )f
9.0
I
to o
I
11,o
Fig. 2. Formation curves for Be(ll)-adrenaline system. 0°C; [] [] 15°C, ~ ~ 25°C V V 35°C: O 45°C.
O0
|
7.o
0.0
,I 6.0
0.5
I0
0.5
~
I-5
I-5
L~: I-0
2-0
2.0
A
Izo
O
%
O"
O
O
5O
p(lijr
6.0
I
\
40
Fig. 3. Formation curves for Be(ll)-benadryl system. H O°C; [ ] [] 15°C; ~ 25°C; V V 35°C; 0 0 45°C.
O0 I
"t.O
Fig.
0.0
0.5
0'5
1.5
I-0
1¢
2.0
I-0
1.5
2.0
4.
Formation 0°C; []
I
50
I
70 curves for Be(ll)-ephedrine system. [] 15°C; ~ 25°C; V ~7 35°C; O O 45°C.
p(~,&
I
60
t"n
7~
>
Coordination complexes of beryllium(l I)
3 813
-~'0
1.5
~:
1.0
0'5
0"0
I
4.0
5-0
pOiJ~
I
I
6.0
7.0
Fig. 5. Formation curves for Be(ll)-pyribenzamine system. H 0°C: [] [] 15oc; ~ 25°C: ~7 V 35°C; 0 0 45°C.
dissociation constants,-log K,,, of the ligands. The values for the overall stability constants, log K1K2, were calculated by the combination of the successive formation constants of each reaction (assuming thereby the validity of stepwise complex formation). It is evident from Table 1 that Be(ll) forms very strong complexes with all the antihistamines and their stabilities can be determined in aqueous media. The adrenaline-Be(II) complex exhibits a much greater stability than any other antihistamine-Be(II) complex. In fact this is expected because both of the coordinating sites on adrenaline have very high pK,, values. The highest ordered complex of Be(II) with each of these antihistamines was found to have a ligand to metal ion ratio of two. This means that in the case of monodentate ligands, such as benadryl, ephedrine and pyribenzamine, the remaining two coordination valences of Be(II) are still occupied by water molecules. The steric hinderance exerted by these bulky ligands seems to become the limiting factor in determining the highest order of their complexes with Be(II). Similar conclusions have been advanced by Andrews and Romary[4] in the case of Cd(II) complexes with benadryl and ephedrine. On the other hand, the bidentate ligands, adrenaline and antistine, also form 2 : 1 complexes with Be(II), indicating the possibility of
3814
I . D . C H A W L A and A. C. A N D R E W S
Table 1. Acid dissociation constants of ligands, stepwise formation constants and thermodynamic values of beryllium(ll) complexes with adrenaline, antistine, benadryl, ephedrine, pyribenzamine, and histamine at 0, 15, 25.35, and 45°C Ligand
Adrenaline
Antistine
Benadryl
Ephedrine
Pyribenzamine
Histamine
°C pK~, pK~,, logK1--AGI°--AH1° ~$1 ° logK~--AG2 ° --AH2° Z3S2° logK1Kz (kcai/mole) (e.u.) (kcal/mole) (e.u.) 0 15 25 35 45 0 15 25 35 45 0 15 25 35 45 0 15 25 35 45 0 15 25 35 45 15 25 35 45
10.90 10.35 10.00 9.30 8.55 11.09 10.48 10.12 9.85 9.45 9.65 9.33 9.12 8.90 8-64 10.42 9.89 9.58 9.25 8.90 9.45 9.05 8.80 8.55 8.27 10.20 9.88 9.52 9.20
9.55 10.78 12.99 9.06 10.08 13.29 8.75 9.65 13.17 25.0 8 " 4 0 8'75 12.34 8-00 8.30 12.09 2.45 7 . 7 1 9.29 2.42 7.55 9.96 2.40 7.44 10.15 5.7 2.35 7.20 10.16 2.15 7.14 10.40 6.43 7-75 6.40 8.44 6-30 8.60 16.3 5.90 8'32 5.55 8"08 6.96 8.39 6.80 8.97 6.57 8.97 1 2 . 6 6.19 8.73 5.90 8.59 5.83 7.29 5.76 7.60 5.56 7.59 9.9 5.28 7.45 5.05 7'35 6.30 7.90 10.42 6.12 7 - 1 2 9.72 28.4 5.86 6.50 9.17 5.65 5.84 .8.50
-40
15
--26
--13
-7
--62
7.47 6.90 6.31 5.60 5.20 6.48 6.31 6.20 6.08 6.01 5.16 5.09 5.04 4.95 4-90 5.67 5.55 5.47 5-11 4.81 4.63 4.59 4.55 4.53 4.51 5.60 5.35 5.06 4.82
9.00 9.10 8 . 6 1 23.8 -51 7.90 7.57 7.81 8.32 8.46 3.3 17 8.58 8.75 6.22 6.71 6.88 2.5 14 6.98 7-13 6.83 7.32 7.46 1 3 . 5 -21 7.21 7.00 5.79 6.05 6.21 !.0 17 6.39 6.57 7.39 7.30 1 0 - 9 - 1 2 7.14 7.02
18.25 16.98 15.96 14.35 13.50 14.19 13.86 13.64 13.28 13.15 11-59 11.49 11.34 10.85 10-45 12-63 12.35 12.04 11.30 t0.71 10.46 10.35 10.11 9.81 9.56 13.50 12.47 11.56 10.66
chelation in these reactions. However, the likelihood of the formation of an eight membered ring between the side chain amine and phenolic group of Adrenaline is not great, the reaction showing a very high negative entropy change (see Table 1). In the case of antistine-Be(l I) complexes there are exhibited favorable entropy changes which suggests the formation of a five-membered chelate through the side chain amine and the secondary amine nitrogen of the imidazoline ring of the antistine molecule. This would result in a considerable strain in the bidentate complexes of antistine with Be(II) or any other metal ion of small ionic radii. Smith [6], with the use of models demonstrated such steric hindrances for tetrahedral configurations of antistine complexes with metal ions. However, a situation similar to beryllium phthalocynin complex, where Be(II) is preforce surrounded by four nitrogen atoms in a plane[7], is possible in Be(If) complexes with biden6. 1. C. Smith, Ph.D Thesis, Kansas State Univ. 1961. 7. F. A. Cotton and G. Wilkinson, Advanced Inorganic Chemistry, p. 245. lnterscience, New York (1966).
Coordination complexes of beryllium(I I )
38 t 5
tate antistine. Nevertheless, this type of coordination by Be(II) would require the availability of planar orbitals which are precluded in the case of Be(lI). It can thus be safely stated that Be(I l) would only form tetrahedral complexes (with both monodentate and bidentate ligands), provided there are no limiting steric factors. In Table 1 are listed the values of the various thermodynamic functions calculated for the stepwise complex formation reactions of Be(ll) with antihistamines and histamine. The values for the Be(ll)-histamine complex are the same as reported in the previous paper (1) and are included here for comparison with other complexes of Be(II). It is estimated that the values for these functions are correct to within ___0.1 kcal/mole for AG O and A H °, and to within __+3.0 e.u. for AS°. Except for antistine, all the other antihistamines exhibit an unfavorable entropy change for their l : l complexes with Be(lI), indicating unfavorable conditions for chelation in these reactions. The positive values, of AS° for 2 : 1 complexes of benadryl, antistine, and pyribenzamine with Be(II) seem to arise from the very low values of enthalpy changes in these cases. In general, the influence of temperature on the stabilities of Be(ll)-antihistamine complexes is normal i.e. a decrease in the value of formation constant when temperature is raised of the reaction. However, the increase in the stability of some of these complexes at 0°C is not as marked as would be expected at that temperature. From Table 1 it can be observed that the AG1° for the bidentate histamineBe(ll) complex is less than the AG1° for the bidentate antihistamine (antistine and adrenaline) complex with Be(II). In the case of monodentate ligand's (ephedrine, benadryl, and pyribenzamine) complexes with Be(IlL it is necessary to compare the sum of their AG1° and A G 2 ° with the AG1 ° of the histamine-Be(II) complex. Again, it is found that the free energy change per bond formed for any antihistamine-Be(l I) compound is greater than the free energy change associated with the single bond formation of the histamine-Be(II) complex. Similar conclusions have been reported by other authors (3, 4, 6) and are summarized in Table 2. Hence, considering the theory of competitive binding between the histamine and the antihistamine for the electrophilic site of a metal ion[2], it is
Table 2. Free energies of histamine and various antihistamine complex formation at 25°C Ligand Histamine Antistine Adrenaline Benadryl Ephedrine Pyribenzamine
Be(ll)
Cu(li)
Co(il)
Ni(ll)
Cd(II)
9.72(a) 10.15(a) 13-17(a) 15.48(a) 16.43(a) 14.80(a)
13.0(b) 8-4(c) 14.6(c) 14.3(c) -12.0(c)
7.0(b) 5.4(c) 7.8(c) 8.9(c) -8.7(c)
9.4(b) 5.5(c) 8-5(c) 8.9(c) -9.5(c)
6.94(d) 7.20(d) -9.93(d) 8-85(d) --
(a) This work; (b) ref. [8]; (c) ref. [3]; (d) ref. [4].
8. B. L. Mickel and A. C. A n d r e w s . J . . 4 m . chem. Soc. 77. 5291 (1955).
3816
I . D . CHAWLA and A. C. ANDREWS
found that the antihistaminic activity decrease in order ephedrine > benadryl > pyribenzamine > adrenaline > antistine.
Acknowledgement-The authors wish to express their appreciation to the National Institutes of Health, Public Health Service, Bethesda, Maryland for the funds in grant number E-1354(C6). which supported this work.
COORDINATION COMPLEXES OF BERYLLIUM(II) WITH VARIOUS ANTIHISTAMINIC SUBSTANCES: THEIR STABILITIES AND THERMODYNAMIC VALUES 1. D. C H A W L A * and A. C. A N D R E W S Department of Chemistry, Kansas State University, Manhattan, Kansas 66504 (First received 15 August 1968; in revised form 4 June 1969)
Ahstraet-Stepwise formation constants for the Be(ll) complexes with adrenaline, antistine, ephedrine, benadryl and pyribenzamine are reported at five different temperature. The Gibbs free energy, entropy and enthalpy values for these reactions are discussed in terms of coordination number of the metal ion, complexing ability and steric hinderance of ligands, and possible tetrahedral structures for these complexes. Results show that all the antihistamines form stable compounds with Be(ll), demonstrating thereby the validity of nitrogen-beryllium coordination bond. It is also observed that Be(ll)-antihistamine complex formation results in greater free energy change than is associated with the formation of Be(l l)-histamine complex. The data from this work substantiates the theory of competitive binding between histamine and antihistamine for the etectrophilic site of a metal ion. INTRODUCTION
previous paper[l] the coordination complexes of Be(II) with histamine and its associated compounds were reported in terms of their formation constants and associated thermodynamic functions. It was believed that a similar study of the Be(II) complexes with various antihistaminic molecules could provide valuable comparison in evaluating the importance of complex formation in the mechanism of histamine-antihistamine activity. Wells[2], in 1950, proposed a concept of competitive binding for the antihistaminic activity in which the antihistamine is in competition with the histamine for an electrophilic metal ion. Andrews, Lyons and O'Brien[3] have determined the stability constants and free energy of complex formations between Cu(II), Co(lI), and Ni(lI) with various antihistamines and their data also suggest the competitive nature of reactions between histamine and the antihistamine for the binding site of a metal ion under study. Recently Andrews and Romary[4], using the polarographic technique, have demonstrated from the thermodynamic data on Cd(I l)-antihistamine binding that the order of spontaneity of complex formation was benadryl > ephedrine > antistine > histamine. I N THE
*To whom all correspondence should be addressed. Present address: Department of Chemistry, Long Island University, Brooklyn, N.Y. 11201.
!. 2. 3. 4.
1. D. Chawla and A. C. Andrews,J. inorg. Nucl. Chem. To be published. J. A. Wells,A nn. N. Y. A cad. Sci. 50, 1202 (1950). A. C. Andrews, T. D. Lyons and T. D. O'Brien, J. chem. Soc. 1776 (1962). A. C. Andrews andJ. K. Romary,J. chem. Soc. 405 (1964). 3809
3810
I . D . C H A W L A and A. C. A N D R E W S EXPERIMENTAL
Procedure and materials. The potentiometric titration technique of Bjerrum[5] was used in this
work. The theoretical background and experimentation involved were discussed previously[l]. A Leeds and Northrup pH meter No. 7663-A1, capable of reproducing readings to within 0.02 pH units, was used with Leeds and Northrup electrodes No. 1199-44 for 0°C, and 15°C; and No. 1199-30 for 25°C, 35°C and 45°C titrations; all measured against a saturated calomel electrode. Enough of ligand was added to maintain a ligand to metal ion ratio greater than four to one. The ionic strength of the medium was kept at 0.12 (_+0.006) by the addition of KCI. The antihistamines obtained from industrial concerns were adrenaline, l-(3,4-dihydroxyphenyl)-2-methylaminoethanol; antistine, 2-(N-benzylanilinomethyl) imidazoline hydrochloride; benadryl, NN-dimethyl-2-diphenylmethoxyethylamine hydrochloride; ephedrine, 2-methylamino-l-phenyl-l-propanol; pyribenzamine, 2-[benzyl-(2-dimethylaminoethyl)amino] pyridine. The analysis and percentage purity of these compounds have been determined by Lyons et al.[3] and their values were relied upon in the preparation of standard solutions of these compounds. Solutions of beryllium chloride, potassium chloride and hydrochloric acid were standardized by their gravimetric precipitation as silver chloride. Carbonate free standard potassium hydroxide, used as a titrant, was prepared by passing the solution through an anion exchange column containing amberlite 1RA-400. The concentrations of beryllium chloride and the various antihistamines ranged from 1.74-2.12 x 10-3 molar and 7.18-9.03 × 10-a M, respectively. The complex formation occured between 4.0 and 7.5 pH, depending upon the ligand under study and the temperature of the reaction. The justifications for the absence of metal hydrolysis in these titrations are the same, as discussed in our previous paper [ 1]. RESULTS AND DISCUSSION
The stepwise complex formation by Be(I I) with bidentate ligands refer to the following generalized reactions: Be(H20)4 +2 + li ~ Be(li)(HzO)2 +2+ 2H~O for log K1 = p(li)Inl. 5 Be(Ii)(H20)2 +2 + li ~- Be(li)z +2 + 2H20 for log K2 =
p(li)s~j.5
For monodentate ligands the complex formation by the Be(lI) would follow reactions in which only one coordinated water molecule can be replaced by the incoming ligand. Hence, it is theoretically possible to obtain four successive equilibrium constants for the Be(ll) complexes with unidentate ligands. In actuality, however, only the first and the second stepwise reactions are observed in every case and values of their equilibrium constants determined in a manner discussed above. The evaluation of log K1 and log Ke for these reactions is undoubtedly valid only in the absence of simultaneous complex formation. As pointed out in our earlier paper[l], the shapes and character of the formation curves, plots of t~ vs. p(li)f, would indicate the nature of the reactions. From Figs. 1 to 5, it is clearly evident that the likelihood of simultaneous reaction can easily be ruled out in these systems. Except for Adrenaline, all other antihistamines yield fairly good formation curves where the values of log K1 and log K2 are well defined. The Be(II)adrenaline system exhibits successive equilibrium constants which are widely separated yet their formation curves are poor. It is estimated that the log Kn values are correct to within __+0.05. The stepwise formation constants, log Kn, for Be(II) complexes of various antihistamines at five different temperatures are given in Table 1 ; along with acid 5. J. Bjerrum, MetalAmine Formation inAqueous Solution. Haase, Copenhagen (1941).
pa,~
"
I
Fig. 1. Formation curves for Be(ll)-antistine system. • 0°C; [] [] 15°C; H 25°C; V V 35°C; 0 45°C.
8.o
©
50
I
60
\
I
7o
I
8-o
I
p( /i )f
9.0
I
to o
I
11,o
Fig. 2. Formation curves for Be(ll)-adrenaline system. 0°C; [] [] 15°C, ~ ~ 25°C V V 35°C: O 45°C.
O0
|
7.o
0.0
,I 6.0
0.5
I0
0.5
~
I-5
I-5
L~: I-0
2-0
2.0
A
Izo
O
%
O"
O
O
5O
p(lijr
6.0
I
\
40
Fig. 3. Formation curves for Be(ll)-benadryl system. H O°C; [ ] [] 15°C; ~ 25°C; V V 35°C; 0 0 45°C.
O0 I
"t.O
Fig.
0.0
0.5
0'5
1.5
I-0
1¢
2.0
I-0
1.5
2.0
4.
Formation 0°C; []
I
50
I
70 curves for Be(ll)-ephedrine system. [] 15°C; ~ 25°C; V ~7 35°C; O O 45°C.
p(~,&
I
60
t"n
7~
>
Coordination complexes of beryllium(l I)
3 813
-~'0
1.5
~:
1.0
0'5
0"0
I
4.0
5-0
pOiJ~
I
I
6.0
7.0
Fig. 5. Formation curves for Be(ll)-pyribenzamine system. H 0°C: [] [] 15oc; ~ 25°C: ~7 V 35°C; 0 0 45°C.
dissociation constants,-log K,,, of the ligands. The values for the overall stability constants, log K1K2, were calculated by the combination of the successive formation constants of each reaction (assuming thereby the validity of stepwise complex formation). It is evident from Table 1 that Be(ll) forms very strong complexes with all the antihistamines and their stabilities can be determined in aqueous media. The adrenaline-Be(II) complex exhibits a much greater stability than any other antihistamine-Be(II) complex. In fact this is expected because both of the coordinating sites on adrenaline have very high pK,, values. The highest ordered complex of Be(II) with each of these antihistamines was found to have a ligand to metal ion ratio of two. This means that in the case of monodentate ligands, such as benadryl, ephedrine and pyribenzamine, the remaining two coordination valences of Be(II) are still occupied by water molecules. The steric hinderance exerted by these bulky ligands seems to become the limiting factor in determining the highest order of their complexes with Be(II). Similar conclusions have been advanced by Andrews and Romary[4] in the case of Cd(II) complexes with benadryl and ephedrine. On the other hand, the bidentate ligands, adrenaline and antistine, also form 2 : 1 complexes with Be(II), indicating the possibility of
3814
I . D . C H A W L A and A. C. A N D R E W S
Table 1. Acid dissociation constants of ligands, stepwise formation constants and thermodynamic values of beryllium(ll) complexes with adrenaline, antistine, benadryl, ephedrine, pyribenzamine, and histamine at 0, 15, 25.35, and 45°C Ligand
Adrenaline
Antistine
Benadryl
Ephedrine
Pyribenzamine
Histamine
°C pK~, pK~,, logK1--AGI°--AH1° ~$1 ° logK~--AG2 ° --AH2° Z3S2° logK1Kz (kcai/mole) (e.u.) (kcal/mole) (e.u.) 0 15 25 35 45 0 15 25 35 45 0 15 25 35 45 0 15 25 35 45 0 15 25 35 45 15 25 35 45
10.90 10.35 10.00 9.30 8.55 11.09 10.48 10.12 9.85 9.45 9.65 9.33 9.12 8.90 8-64 10.42 9.89 9.58 9.25 8.90 9.45 9.05 8.80 8.55 8.27 10.20 9.88 9.52 9.20
9.55 10.78 12.99 9.06 10.08 13.29 8.75 9.65 13.17 25.0 8 " 4 0 8'75 12.34 8-00 8.30 12.09 2.45 7 . 7 1 9.29 2.42 7.55 9.96 2.40 7.44 10.15 5.7 2.35 7.20 10.16 2.15 7.14 10.40 6.43 7-75 6.40 8.44 6-30 8.60 16.3 5.90 8'32 5.55 8"08 6.96 8.39 6.80 8.97 6.57 8.97 1 2 . 6 6.19 8.73 5.90 8.59 5.83 7.29 5.76 7.60 5.56 7.59 9.9 5.28 7.45 5.05 7'35 6.30 7.90 10.42 6.12 7 - 1 2 9.72 28.4 5.86 6.50 9.17 5.65 5.84 .8.50
-40
15
--26
--13
-7
--62
7.47 6.90 6.31 5.60 5.20 6.48 6.31 6.20 6.08 6.01 5.16 5.09 5.04 4.95 4-90 5.67 5.55 5.47 5-11 4.81 4.63 4.59 4.55 4.53 4.51 5.60 5.35 5.06 4.82
9.00 9.10 8 . 6 1 23.8 -51 7.90 7.57 7.81 8.32 8.46 3.3 17 8.58 8.75 6.22 6.71 6.88 2.5 14 6.98 7-13 6.83 7.32 7.46 1 3 . 5 -21 7.21 7.00 5.79 6.05 6.21 !.0 17 6.39 6.57 7.39 7.30 1 0 - 9 - 1 2 7.14 7.02
18.25 16.98 15.96 14.35 13.50 14.19 13.86 13.64 13.28 13.15 11-59 11.49 11.34 10.85 10-45 12-63 12.35 12.04 11.30 t0.71 10.46 10.35 10.11 9.81 9.56 13.50 12.47 11.56 10.66
chelation in these reactions. However, the likelihood of the formation of an eight membered ring between the side chain amine and phenolic group of Adrenaline is not great, the reaction showing a very high negative entropy change (see Table 1). In the case of antistine-Be(l I) complexes there are exhibited favorable entropy changes which suggests the formation of a five-membered chelate through the side chain amine and the secondary amine nitrogen of the imidazoline ring of the antistine molecule. This would result in a considerable strain in the bidentate complexes of antistine with Be(II) or any other metal ion of small ionic radii. Smith [6], with the use of models demonstrated such steric hindrances for tetrahedral configurations of antistine complexes with metal ions. However, a situation similar to beryllium phthalocynin complex, where Be(II) is preforce surrounded by four nitrogen atoms in a plane[7], is possible in Be(If) complexes with biden6. 1. C. Smith, Ph.D Thesis, Kansas State Univ. 1961. 7. F. A. Cotton and G. Wilkinson, Advanced Inorganic Chemistry, p. 245. lnterscience, New York (1966).
Coordination complexes of beryllium(I I )
38 t 5
tate antistine. Nevertheless, this type of coordination by Be(II) would require the availability of planar orbitals which are precluded in the case of Be(lI). It can thus be safely stated that Be(I l) would only form tetrahedral complexes (with both monodentate and bidentate ligands), provided there are no limiting steric factors. In Table 1 are listed the values of the various thermodynamic functions calculated for the stepwise complex formation reactions of Be(ll) with antihistamines and histamine. The values for the Be(ll)-histamine complex are the same as reported in the previous paper (1) and are included here for comparison with other complexes of Be(II). It is estimated that the values for these functions are correct to within ___0.1 kcal/mole for AG O and A H °, and to within __+3.0 e.u. for AS°. Except for antistine, all the other antihistamines exhibit an unfavorable entropy change for their l : l complexes with Be(lI), indicating unfavorable conditions for chelation in these reactions. The positive values, of AS° for 2 : 1 complexes of benadryl, antistine, and pyribenzamine with Be(II) seem to arise from the very low values of enthalpy changes in these cases. In general, the influence of temperature on the stabilities of Be(ll)-antihistamine complexes is normal i.e. a decrease in the value of formation constant when temperature is raised of the reaction. However, the increase in the stability of some of these complexes at 0°C is not as marked as would be expected at that temperature. From Table 1 it can be observed that the AG1° for the bidentate histamineBe(ll) complex is less than the AG1° for the bidentate antihistamine (antistine and adrenaline) complex with Be(II). In the case of monodentate ligand's (ephedrine, benadryl, and pyribenzamine) complexes with Be(IlL it is necessary to compare the sum of their AG1° and A G 2 ° with the AG1 ° of the histamine-Be(II) complex. Again, it is found that the free energy change per bond formed for any antihistamine-Be(l I) compound is greater than the free energy change associated with the single bond formation of the histamine-Be(II) complex. Similar conclusions have been reported by other authors (3, 4, 6) and are summarized in Table 2. Hence, considering the theory of competitive binding between the histamine and the antihistamine for the electrophilic site of a metal ion[2], it is
Table 2. Free energies of histamine and various antihistamine complex formation at 25°C Ligand Histamine Antistine Adrenaline Benadryl Ephedrine Pyribenzamine
Be(ll)
Cu(li)
Co(il)
Ni(ll)
Cd(II)
9.72(a) 10.15(a) 13-17(a) 15.48(a) 16.43(a) 14.80(a)
13.0(b) 8-4(c) 14.6(c) 14.3(c) -12.0(c)
7.0(b) 5.4(c) 7.8(c) 8.9(c) -8.7(c)
9.4(b) 5.5(c) 8-5(c) 8.9(c) -9.5(c)
6.94(d) 7.20(d) -9.93(d) 8-85(d) --
(a) This work; (b) ref. [8]; (c) ref. [3]; (d) ref. [4].
8. B. L. Mickel and A. C. A n d r e w s . J . . 4 m . chem. Soc. 77. 5291 (1955).
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I . D . CHAWLA and A. C. ANDREWS
found that the antihistaminic activity decrease in order ephedrine > benadryl > pyribenzamine > adrenaline > antistine.
Acknowledgement-The authors wish to express their appreciation to the National Institutes of Health, Public Health Service, Bethesda, Maryland for the funds in grant number E-1354(C6). which supported this work.