Robert W. Hay Victoria University of Wellington Wellington, N e w Zeolond
Some Reactions of Coordinated Ligands Containing Oxygen and Nitrogen Donors
Coordination chemists have been mainly concerned with the influence of the ligand on the metal ion, but in the last few years there has been a growing awareness of the changes the metal ion can bring about in the ligand (14). This aspect of coordination chemistry can he applied widely in many diverse fields, such as biochemistry and organic synthesis. The purpose of this paper is to discuss some reactions of this type.
The hydrolysis of histidine methyl ester (11) has been studied in detail by Kelly (6)
Effects of Charge
One obvious property of a metal ion is its ability to bring about polarization of the ligand. Effects of this type bear a formal resemblance to the well known acidcatalyzed reactions of organic chemistry. It is probably fair to say that for every proton catalyzed reaction that occurs, an analogous metal-ion catalyzed process exists, provided that secondary donor groups are present in the ligand to allow chelate ring formation to take place. The best known acid-catalyzed reaction of organic chemistry occurs in the hydrolysis of a carboxylic ester by the AAc2mechanism (I). R4-OR'+
II
H+
e
R 4 4 R '
+8H
0
+OH2
R 4 4 R ' /I
+ HiO e R - CI 4 K ' I
=
OH l H R 4 4 R ' I
I .
R ~ Z =R ~4+ - R'OH I
+
\
OH
OH
I
Metal ions do not cat,alyze the hydrolysis of simple carboxylic esters, but in amino acid esters such as glycine ethyl ester where chelate ring formation is possible, metal ions have a pronounced catalytic effect
(4).
I n this case, the catalytically active metal complexes have been isolated (6) and infrared studies have shown that coordination occurs via the imidazole nitrogen atom and the a-amino group and not the methoxycarbonyl group. The rate constants for the hydrolysis of the various chelates are listed in Table 1. The reactivity of the chelates is CUE%^+ > NiE2*+> CuEA+ > NiEA>>E. Several conclusions can be drawn from this series, concerning the factors influencing the catalysis of the hydrolysis of the ester. Coordination by the methoxy carbonyl group is not a necessary requirement. The reactivity of a species depends to a large extent on the overall positive charge. I n similar chelates such as CUE?+ and NiE22+,the copper chelate is more reactive. The formation constants of the copper chelates are cousiderahly greater (log KIKI = 23.12) than those of the nickel chelates (log KlK2 = 17.36), and the reactivity would seem to depend on the degree of interaction between the metal ion and the ester. The increase in the rate of hydrolysis is readily understood if it is remembered that the nucleophilic species is a negatively charged hydroxide ion. The introduction of a positive charge in the vicinity of the ester grouping effectively increases the concentration of hydroxyl ions Table 1.
Rate Constants for the Hvdrolvsis of Metal Complexes of Histidine ~ e t h h~e l r
--
10-% (liter
Reaction
++ + +
CUE?+ OHCuEA+ OHNiW+ OH-NiEAf OHEm +OH--A'
"E
=
mole-1 min-1) ~~~~~~
CuEAt CuAl NiEA+ NiAz
1.94 0.233 0.71 0.099 0.0047
histidine methyl ester; A = histidine. Volume 42, Number 8, August 1965
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41 3
Table 2.
Com~lex log K m 10*k(aee-1) log Ku* (oxalate)
Rate Constants and Stability Constants of Transition Metal Oxaloacetates
.
C d,I I I Mn(II) , . Co(III . . Z d.I I I. Ni(1II . . CufII) . . 2.6 0.24
2.8 0.65
3.1 2.4
3.2 3.1
3.5 2.3
4.9 6.6
3.0
3.9
4.7
4.9
5.3
6.3
in the neighborhood of the ester molecule and so increases the probability of effective collisions. Another reaction of a similar type is found in the decarboxylation of certain @-keto acids in solution. 0-keto acids decompose spontaneously in aqueous solution to liberate carbon dioxide (7).
ion catalyzed decarhoxylation of acetone dicarboxylic acid where the catalytic effect of various metal ions closely follows the thermodynamic stability of the corresponding malonate complexes (10). The decarboxylation of certain carboxylic acids such as nitroacetic acid is inhibited by the presence of metal ions (11).
Inhibition is probably due to the formation of chelates of the aci-nitro tautomer in which the labile carboxyl group is bound in the chelate ring (V).
In certain @-ketoacids such as oxaloacetic acid, HOeC. CO. CH2.C02H, chelate ring formation is possible and the reaction is markedly catalyzed by transition metal ions (8). Stiles and Finkbeiner (18) have made use of this effect to synthesize a-nitro acids (a useful route to a-amino acids), and @-keto acids. Treatment of nitromethane with magnesium methoxide and carbon dioxide in dimethylformamide gives nitroacetic acid in 63y0 yield
m).
The effect of various transition metal ions on the reaction has been studied in detail (9). Table 2 lists values of the rate constants and the stability constants of the metal oxaloacetates. A linear free energy relationship might he expected to exist between the logarithms of the appropriate rate constants and of the stability constants, as the stability constants give a measure of the strength of the metal-ligaud bonding. This correlation is not observed but the rate constants do parallel the stability constants of the corresponding oxalates (Fig. 1). This result has been interpreted as indicating the importance of the transition state in the reaction (111) which closely resembles the oxalate structure (IV)
f/J CH:IO->~
0
+
MgOCHs
II
-+
CHa0-C-0
- +MgOCHJ
The reaction is of considerable interest because it bears a formal resemblance to enzymatic carhoxylation systems which require metal ions such as manganese(I1) and magnesium(I1) as co-catalysts. The interaction of met,al ions with peptides is of considerable biological importance. Copper(I1) ions react with glycylglycine a t low pH t,o give the complex 0'11).
A!si~nilar effecthas been noted in the transition metal-
Figwe 1. Variation of rate conrtants k with stability constants -1-oxaloocetoter, 0 oxdates.
414 / Journal of Chemical Education
KMA fon
Around pH 4, ionization of the peptide nitrogen atom occurs to give complexes such as (VIII) (IS). Unless a peptide hydrogen atom is lost by ionization, coordination via a peptide nitrogen atom results in the loss of
the resonance energy of an amide group. The hydrolysis of peptides depends upon the reactivity of the carbonyl group a t the peptide bond. Carhonyl reactivity is almost absent in peptides due to resonance of the type
+
R-CH-NH,
I
c%H
O=CH OH
Me
and amides are very weak hases. Coordination of the peptide nitrogen atom to a metal ion will induce carbony1 activity toward nucleophilic attack, but if the electron withdrawal effect leads to ionization of the peptide hydrogen atom the resulting complex, as first pointed out by Rahin (Id), would be expected to be inactive. The pH-rate profde for the copper(I1) catalyzed hydrolysis of glycylglycine has maximum a t pH 4.2 (16). There is no catalysis below pH 3.5 because little complex formation occurs between the metal ion and the peptide. Above pH 4.2 inactive complexes are produced by ionization of the peptide nitrogen atom. The hydrolysis of many Schiff bases are catalyzed by transition metal ions by the general scheme (IX) (16, 17).
0Applications to Organic Synthesis
As in the hydrolysis of a-amino acid esters, secondary ligand groups are necessary for catalysis of this type to be effective. Schiff bases formed between pyridoxal and a-amino acids form complexes with metal ions such as copper(I1) and iron(II1) which undergo reactions such as transamination and racemization; these are catalyzed in biological systems by pyridoxal phosphate proteins (18, 19). Transamination for example can occur by the reactions in (X) (see top of next column). Many phosphate esters are readily hydrolyzed in the presence of metal ions. Phosphate esters are normally difficult to hydrolyze under alkaline conditions because of the larger number of negative charges on the oxygen atoms around the phosphorus atom, which effectively hinder the attack of an anionic nucleophile such as a hydroxide ion. Metal ions, for example magnesium(I1) and manganese(II), effectively neutralize these charges and so catalyze the reaction. The hydrolysis of acyl phosphates such as acetyl phosphate is catalyzed by metal ions around pH 8, where the phosphate group is completely ionized, indicating the chelate (XI) as the reactive intermediate (20).
A number of remarkable examples of the synthesis of macrocyclic ring systems via transition metal complexes have been described. Tris(ethylenediamine)nickel(II) perchlorate condenses readily with acetone under very mild conditions to give the tetra Schiff base (XII). I n the presence of the third molecule of ethylene diamine, the Schiff base undergoes a base catalyzed aldoltype condensation to give the macrocyclic tetramine (XIII), which can be reduced with NaBH4 or nickel/ aluminum alloy. Treatment with sodium cyanide liberates the free amine (XIV) (21).
XIV
XI11 Volume 42, Number 8, August 1965
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41 5
Busch (&?) has coined the term "template synthesis"
to describe reactions of this type, i.e., a synthesis in which the coordination sphere of a metal ion or metal chelate compound acts as a "template" and induces ligand molecules to orient themselves in a manner suitable for condensation and complex formation. The ability of simple metal ions to influence a reaction path is by no means new ($3) as evidenced by the well known synthesis of benzimidazoles ($4), phthalocyanines (%), and biguanides (26), where the products are isolated as metal salts or complexes. The novelty of ligand reactions lies in the fact that, rather than a simple metal ion directing the reaction path, the steric arrangement of the ligands about a preformed coordination complex influences the nature of the products. A number of other examples will illustrate these points. Reaction between p-mercaptoethylamine and adiketones by normal methods gives thiazolidines as the major product, with only small amounts of a-diimines (!27), but if the planar nickel(I1) complex of pmercaptoethylamine is reacted with or-diketones (B),new tetradentate ligands, coordinated through two imine linkages, are formed in yields in excess of 70'%.
When the reactants are brought together by coordinating them to the same metal ion, the unusual proximity of potentially reactive sites promotes a reaction that would otherwise take place far less readily if a t all. Ingraham has suggested that an important function of metal ions in enzymatic reactions may be to aid in such a gathering process (51). Coordination can also lead to the isolation of compounds which are otherwise impossible to prepare. Cyclobutadiene has four a-electrons, a system which is predicted to be energetically unstable, and Willstater for example attempted for years to prepare the compound without success. The highly unstable nature of cyclobutadiene may be inferred from reactions which should logically lead to cyclobutadiene, but which instead give dimeric products. Thus, tetramethyldichlorocyclobutene (XVII) can be dechlorinated with lithium amalgam in ether, but the hydrocarbon isolated is a dimer of tetramethylcyclobutadiene (XVIII). In the presence of nickel carbonyl, however, the same reaction leads to the red-violet diamagnetic nickel complex of tetramethylcyclobutadiene (XIX) (32), the structure of which has been confirmed by X-ray analysis (33). As first predicted by Longuet-Higgins and Orgel in 1956, stabilization of the four T-electron system is possible by a-bonding to nickel (54).
Treatment of bis(dimethylglyoxime)nicl~el(II) with BFa or BPh3 in non-hydroxylic solvents produces the cyclic complexes (XV, R = F or Ph), (88, $9).
XVIII XIX
Conclusion
Another remarkable reaction is the cyclic tetramerization of o-amino benzaldehyde in the presence of copper(11) or nickel(I1) ions to give the macrocyclic Schiff base (XVI) (50). I n the absence of metal ions the ligand rapidly polymerizes.
416
/
Journal o f Chemical Mucafion
I n recent years the "one subject" approach to chemistry has become more and more evident as the traditional barriers between the established branches of chemistry become less clearly defined. An attempt has been made to show how coordination chemistry can be of importance in fields such as physical organic chemistry, organic synthesis, and biochemistry. Literature Cited (1) "Reactions of Coordinated Ligands and Homogeneous Catalysis," in "Advances in Chemistry Series," No. 37, Edited by R. F. Gould, American Chemical Society, Washington, D. C., 1963. (2) HAY,R. W., Rev. Pure Appl. C h . , 13, 157 (1963). (3) JONES,M. M., AND CONNOR, W. A,, Ind. Eng. Chem., 55, 15 (1963). (4) KROLL, H., J . d m . C h . Sac., 74, 2036 (1952). T. R.,PhD Thesis, University of Glasgow, 1962. (5) KELLY, (6) HAY,R. W., AND PORTER, L., unpubl'i~hedresults. (7) BROWN, B. R., Quart. Rev., 5, 131 (1952). (8) HAY,R. W., AND GELLES,E., J. Chem. Soe., 3673 (1958). A,, J. Chem. Soc., 3684, 3689 (9) GELLES,E., AND SALAMA, (1958). J. E., J. Chem. Soc., 2331 (1952). (10) PRUE, K. J., Acta Chem. Sand., 3 , 6 7 6 (1949). (11) PEDERSEN,
STILES,M.,
AND
FINKBEINER, H. L., J. Am. Chem. Sot., 85,
616 (1963).
KIM, M. K.,
AND
MARTELL,A. E., Biochemistr~,3, 1169
(1964).
RABIN,B. R., Bioehem. Soc. Synp. (Cambridge, Engl.), No. 15, 21 (1958).
HAY.R. W.. AND GRANT. I. G.. Aust. J . Chem., in press. ErnEkIoRN, G. L.,AND B ~ A R , JC., . J. Am. C'hem.~Soe.,75, 2905 (1953).
EICHHORN, G. L., AND TRACTENBERG, I. M., J. Am. Chem. Soc.. 76. 5183 (1954). . . SNELL,E. E., Vitamins and H m n e s , 16, 77 (1958). METZLER, D. E., IKAWA, M., AND SNELL,E. E., J. Am. Chem Soc., 76, 648 (1954). KOSHLAND, D. E., J. Am. Chem. Sac., 74, 2286 (1952). CURTIS,N. F., J. Chem. Soc., 2644 (1964). Bnscn, D. H., AND THOMPSON, M. C., J. Am. Chem. Sac.,
. .
84, 1762 (1962). 8
MARTELL, A. E., AND CALVIN,M., "Chemistry of the Metd
(24) (25) (26) (27) (28)
Chelate Compounds," Prentiee Hall, Englewood Cliffs, N. J., 1952, p. 421. WEIDENHAGEN, R., Ber., 75, 1936 (1942). MOSER,F. H., AND THOMAS, A. L., "Phdoloeyanine Complexes," American Chemical Society Monograph 157. RAY,P., Chem. Rev., 6 1 , 313 (1961). COOK,A. H.,AND HEILBRON, I. M., "The Chemistry of Penicillin," Princeton Univ. Press, 1949, p. 921-72. UMLAND,F., AND THIERIU,D., Angm. them., 74, 388
(1962). (29) SCHRAUZER, G. N., Be?., 95, 1438 (1962). (30) MELSON, G. A., AND BUSCH,D. H., Pme. Chem. Sac., 223 (1963). (31) INGRAHAM, L. L., AND GREEN,D. E., Science, 128, 310 IlQ5RI >-,. (32) CRIEGEE,R., AND SCHRODER, G., Angew. Chem., 71, 70 (1959). J. D. ET AL.,Helv. Chim. Acta, 45, 647 11962). (33) DUNITZ, (34) LONGUET-HIGGINS, H. C., AND ORGEI,,L. E., J . Chem. Sac., 1969 (1956).
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1965
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