Inorganic Organic Synthesis

Cyclam (1,4,8,11-tetraazacyclotetradecane) synthesis


Cyclam (1,4,8,11-tetraazacyclotetradecane) is an organic compound used widely as a macrocyclic ligand in coordination chemistry. It is a white solid with formula (NHCH2CH2NHCH2CH2CH2)2 and molar mass 200.33 g/mol. The compound is well-soluble in water, chloroform and it is insoluble in acetonitrile.  In its structure four nitrogen donor atoms are present. Almost planar arrangement of the donor atoms is highly desirable due to the ability of blocking all four equatorial position of a metal center. The structure of the ligand is depicted in scheme 1. Most of the metal complexes have trans-III configuration respectively to the cyclam ring [1].


Scheme 1 Structure of cyclam

A template synthesis proposed by Barefield is used to prepare the ligand in laboratory [2]. A reaction scheme is shown below. The ligand was first claimed by Van Alphen [3]. Stetter and Mayer synthetized the ligand with 24% yield [4]. A critical step is the addition of nickel salt into bapen solution. When glyoxal is added first to the amine no reaction occurs. When nickel ion is not added at all, reaction does not occur as well. Cyanide is used to free the ligand from the nickel complex (according to stability constants of two complexes [Ni(cyclam)]2+ and K2[Ni(CN)4]) [2]. Glyoxal must be used in its active – monomeric form.



Bis(3-aminopropylamino)-1,2-ethane (10 g, 10.5 mL, 57 mmol) was dissolved in 250 mL of distilled water. Under constant stirring Nickel(II) chloride hexahydrate (13.65 g, 57 mmol) was added to the solution. The solution turned purple after addition due to the formation of [Ni(bapen)]2+. The resulting solution was then cooled down to 5 °C in an ice-bath. Monomeric glyoxal was formed by heating a suspension of glyoxale trimer dihydrate (6 g, 34 mmol) in 60 mL of distilled water to 65-70 °C for a few minutes. The hot solution of monomeric glyoxal was dropwise added to the solution of nickel salt over 20 minutes. The mixture was stirred for 4 hours yielding unsaturated macrocyclic ligand 1,4,8,11-tetraazacyclotetradeca-4,7-diene. 100 mL of 4.5M sodium hydroxide solution along with 10 g of Raney nickel and additional 5 grams of powdered aluminium  was slowly added to the mixture. The reaction mixture was stirred for 12 hours to reduce all molecules of unsaturated ligand. Unreacted Raney nickel and alumínium powder was filtered off. Potassium cyanide (25 g, 380 mmol) was added to the resulting solution. The suspension was refluxed for three hours and the solid was filtered off after cooling. The solution was extracted three times with 100 mL of chloroform. The extracts were combined together, dried over anhydrous sodium sulfate and the solvent was distilled off using RVE. The product was filtered off, washed by acetonitril and dried in an oven at 90 °C. Yield: 63,5 %.



[1] O. Hitoshi and S. Hiroyuki, J. Macromol. Scie.-Chem. 1990, Vol. A27, Iss. 9-11, p. 1305-1319
[2] K. Barefield, Inorganic chemistry. 1972, Vol. 11, No. 9, p. 2273-2274.
[3] J. Van Alphen, Red. Tim. Chim. Pays-Bas. 1936, Vol. 56, p.835.
[4] H.Stetterand and K. H. Mayer, Chem. Ber. 1961, Vol. 94, p.1410.