To elucidate intrinsic recognition of carboxamides by zinc(II) in carbonic anhydrase (CA) (as inhibitors) and carboxypeptidase A (CPA) (as substrates), a new series of Zn2+-carboxamide-appended cyclen complexes have been synthesized and characterized (cyclen = 1,4,7,10-tetraazacyclododecane). Two types of Zn2+-carboxamide interactions have been found. In the first case represented by a zinc(II) complex of carbamoylmethyl-1,4,7,10-tetraazacyclodoclecane (L-1), the amide oxygen binds to zinc(II) at slightly acidic pH (to form ZnL1), and the deprotonated amide N- binds to zinc(II) at alkaline pH (to form ZnH-L-1(1)) with pK(a) = 8.59 at 25 degreesC and I = 0.1 (NaNO3) as determined by potentiometric pH titrations, infrared spectral changes, and C-13 and H-1 NMR titrations. The X-ray crystal structure of ZnH-1L3 (where L-3 = N-(4-nitrophenyl)carbamoylmethyl cyclen, pK(a) = 7.01 for ZnL(3)reversible arrowZnH(-1)L(3)) proved that the zinc(II) binds to the amidate N-(Zn-N- distance of 1.974(3) Angstrom) along with the four nitrogen atoms of cyclen (average Zn-N distance 2.136 Angstrom). Crystal data: monoclinic, space group P2(1)/n (No. 14) with a = 10.838(1) Angstrom, b = 17.210(2) Angstrom, c = 12.113(2) Angstrom, b = 107.38(1)degrees, V = 2156.2(5) Angstrom(3), Z = 4, R = 0.042, and R-w = 0.038. These model studies provide the first chemical support that carboxamides are CA(-) inhibitors by occupying the active Zn2+ site both in acidic and alkaline pH to prevent the occurrence of the catalytically active Zn2+-OH- species. In the second case represented by a zinc(II) complex of 1-(N-acetyl)aminoethylcyclen, ZnL6, the pendant amide oxygen had little interaction with zinc(II) at acidic pH. At alkaline pH, the monodeprotonation yielded a zinc(II)-bound hydroxide species ZnL6(OH-) (pK(a) = 7.64) with the amide pendant remaining intact. The ZnL6(OH-) species showed the same nucleophilic activity as Zn2+-Cyclen-OH-. The second case may mimic the Zn2+-OH- mechanism of CPA, where the nucleophilic Zn2+-OH- species does not act as a base to deprotonate a proximate amide.