Study of new cytochrome P450 monooxygenase model is of great importance to realize marked rate enhancement,high substrate specificity,and distinct reaction selectivity under mild oxidation conditions. In general,the active site of natural monooxygenases is regarded as a hydrophobic cavity or cleft created by folding of the polypeptide chain. To mimic the active site,macrocyclic compounds such as cyclodextrins ^[1],crown ethers ^{[2, 3]},cyclophanes ^[4] and calixarenes ^[5],each having an inclusion cavity as a basic skeleton of potent artificial monooxygenase, were usually employed. Our previous studies revealed that the oxa-crown ether substituted hydroxamic cobalt complexes as monooxygenase model showed much more enhanced O₂-binding and catalytic oxidation activity than the uncrowned analogs ^{[6, 7]}. This inspired us to expand the models to the N-pivot lariat ether type hydroxamic cobalt complexes due to their structural flexibility. However,to the best of our knowledge,no aza crowned hydroxamic metal complexes have been reported yet. A possible reason may be the synthetic difficulty of the key mediate,aza crowned acyl chloride. Giacomelli ^[8] reported a novel one-flash method without the use of acyl chloride to synthesize hydroxamic acid ligands,which was used herein to the preparation of the dihydroxamic acids functionalized N-pivot lariat ether ligands L¹H₂-L⁴H₂.

The synthetic route is shown in Scheme 1. The crowned dicarboxylic acids 1a-1d were prepared by our previously disclosed procedure ^[9]. 1a-1d were treated with cyanuric chloride (TCT) (0.6 equiv.),N-methylmorpholine (NMM) (2 equiv.),and dimethylamino pyridine (DMAP) as a catalyst (0.2 equiv.) in CH₂Cl₂,followed by hydroxylamine hydrochloride (2.1 equiv.) to obtain ligands L¹H₂-L⁴H₂. The cobalt complexes were conveniently prepared by treating the ligands L¹H₂-L⁴H₂ with a stoichiometric amount of Co(OAc)2 in ethanol under N2 atmosphere under reflux.

Scheme 1

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Scheme 1. Synthetic route of the cobalt complexes with aza-crowned dihydroxamic acid.

The oxygenation constants and thermodynamic parameters of CoL¹-CoL⁴ (Table 1) were determined by a reported method ^[10] (diglyme as solvent,0.99 mol L^-1 of pyridine as axial ligand (B), 5 × 10^-3 mol L^-1 of complexes,9.8 × 10⁴ Pa partial pressure of oxygen and specific temperatures).

Table 1

Table 1 Oxygenation constants and thermodynamic parameters (ΔH° and ΔS°).

Table 1 Oxygenation constants and thermodynamic parameters (ΔH° and ΔS°).

The oxidation of p-xylene to p-toluic acid (PTA) catalyzed by CoL¹-CoL⁴ were conducted in a normal gas-liquid apparatus. Air was bubbled into the mixture of p-xylene (40 mL) and CoL (1 × 10^-3 mol L^-1) with a 2.0Λ_min^-1 flow rate at 110 ℃. The reaction mixture (0.1 mL) was sampled by pipette periodically before the precipitates appeared (in 5 h),and diluted to 15 mL with ethanol. The accumulative concentration of PTA was determined by the standard acid-base titration. The selective oxidation for PTA was determined by HPLC. The catalytic oxidation performances of CoL¹-CoL⁴ were shown in Table 2.

The new compounds were characterized as follows. L¹H₂: Yield: 87.9%,m.p. 162-163 ℃,¹H NMR (CDCl₃): δ 10.32 (s, 2H,OH,D₂O exchangeable),4.50 (s,4H,COOCH₂),3.72 (s,4H, NCH₂CON),3.59 (s,4H,COCH₂N),3.11 (s,4H,NCH₂CH₂N); IR (KBr, cm^-1): υ_max 3226,3109,1732,1628,1425,1122,965; MS (m/z): 348 (M⁺); Anal. calcd. for C₁₂H₂₀N₄O₈: C 41.38,H 5.79,N 16.06; found: C 41.49,H 5.72,N 16.25.

L²H₂: Yield: 90.2%,m.p. 147-148 ℃,¹H NMR (CDCl₃): δ 10.30 (s, 2H,OH,D₂O exchangeable),4.39 (m,4H,COOCH₂),3.95 (s,4H, NCH₂CON),3.66-3.78 (s,8H,COCH₂N,COOCH₂CH₂O),3.25 (s,4H, NCH₂CH₂N); IR (KBr,cm^-1): υ_max 3226,3105,1730,1628,1427, 1122,962; MS (m/z): 392 (M⁺); Anal. calcd. for C₁₄H₂₄N₄O₉: C 42.86,H 6.17,N 14.28; found: C 42.55,H 6.11,N 14.36.

L³H₂: Yield: 86.3%,m.p. 129-130 ℃,¹H NMR (CDCl₃): δ 10.30 (s,2H,OH,D₂O exchangeable),4.37 (t,4H,COOCH₂),3.92 (s,4H, NCH₂CON),3.64-3.77 (s,8H,COCH₂N,COOCH₂CH₂O),3.60 (s,4H, OCH₂CH₂O),3.25 (s,4H,NCH₂CH₂N); IR (KBr,cm^-1): υ_max 3222, 3106,1732,1630,1425,1120,961; MS (m/z): 436 (M⁺); Anal. calcd. for C₁₆H₂₈N₄O₁₀: C 44.03,H 6.47,N 12.84; found: C 44.15,H 6.37,N 12.97.

L⁴H₂: Yield: 85.1%,m.p. 113-114 ℃,¹H NMR (CDCl₃): δ 10.28 (s,2H,OH,D₂O exchangeable),4.35 (t,4H,COOCH₂),3.91 (s,4H, NCH₂CON),3.65-3.77 (s,8H,COCH₂N,COOCH₂CH₂O),3.61 (s,8H, OCH₂CH₂O),3.25 (s,4H,NCH₂CH₂N); IR (KBr,cm^-1): υ_max 3225, 3105,1730,1630,1422,1122,960; MS (m/z): 480 (M⁺); Anal. calcd. for C₁₈H₃₂N₄O₁₁: C 45.00,H 6.71,N 11.66; found: C 45.21,H 6.77,N 11.80.

CoL¹: Yield: 70.6%,m.p. 261 ℃ (dec.),IR (KBr,cm^-1): υ_max 3112, 1732,1595,1420,1122,982; Anal. calcd. for C₁₂H₁₈N₄O₈Co: C 35.57,H 4.48,N 13.83,Co 14.54; found: C 35.39,H 4.39,N 14.03,Co 14.70. Λ_m (S cm² mol^-1): 2.56. CoL²: Yield: m.p. 248 ℃ (dec.),IR (KBr,cm^-1): υ_max 3109,1733, 1601,1421,1122,978; Anal. calcd. for C₁₄H₂₂N₄O₉Co: C 37.43,H 4.94,N 12.47,Co 13.12; found: C 37.31,H 5.02,N 12.58,Co 13.56. Λ_m (S cm² mol^-1): 5.71.

CoL³: Yield: m.p. 227 ℃ (dec.),IR (KBr,cm^-1): υ_max 3110,1733, 1605,1422,1120,978; Anal. calcd. for C₁₆H₂₆N₄O₁₀Co: C 38.95,H 5.31,N 11.36,Co 11.95; found: C 38.77,H 5.46,N 11.19,Co 12.18. Λ_m (S cm² mol^-1): 7.26.

CoL⁴: Yield: 64.1%,m.p. 221 ℃ (dec.),IR (KBr,cm^-1): υ_max 3107, 1731,1607,1420,1122,979; Anal. calcd. for C₁₈H₃₀N₄O₁₁Co: C 40.23,H 5.63,N 10.43,Co 10.97; found: C 40.15,H 5.47,N 10.64,Co 11.21. Λ_m (S cm² mol^-1): 4.85.

The oxygenation constants in Table 1 were of significant difference. The order of the O-binding activity is: CoL³ > CoL² > CoL⁴ > CoL¹,which should be attributed to the structural diversity. Since the only difference among the cobalt complexes was the size of the crown ether ring (or the number of the ethyleneoxy linkers), it could be deduced that the macrocyclic effect of crown ring, which possesses a special configuration,would favor oxygen molecule to approach the active center of the Co(II) complexes and form the Co-O₂ bond through its hydrophobic outer ethylene groups and orderly arranged inner aza oxa atoms. However,CoL⁴, which possesses the largest crown ring,did not show the highest O₂-binding activity. The reason may that the large crown ring of CoL⁴ would be distorted and create steric hindrance around the active center,which is disadvantageous for the binding of O₂ ^[11]. Moreover,the ΔH° seems to contribute to the formation of O₂-Co(II) bond. The Co(II) complexes with smallerΔH° show larger oxygenation constants. The relevance might be used to judge the O₂-binding activity of CoL.

As shown in Table 2,The oxidation of p-xylene catalyzed by CoL¹-CoL⁴ experienced a certain induction period (0.3-0.4 h), which indicated there may be a connection between the dioxygen affinity and induction period and the coordination of molecular oxygen to the central cobalt ions is necessary to the initiation of the catalytic oxidation reaction. Meanwhile,same as the order of the O₂-binding activity of CoL¹-CoL⁴,CoL³ showed the highest catalytic oxidation activity and selectivity followed by CoL²,and then CoL⁴ and CoL¹. This result indicated that on one hand,a proper size of crown ether ring could offer a favorable microenvironment or even some kind of substrate specificity to significantly enhance the catalytic oxidation performance of the cobalt complexes. On the other hand,the steric hindrance of the crown ether ring would shield the active center,which is not advantageous to the formation of the active oxygen affinity species and the inclusion to the substrate. It also seemed to indicate that the crown ring configuration played an important role in the modulation of the catalytic oxidation,which would be researched in our future structural studies of the cobalt complexes.

Table 2

Table 2 The catalytic oxidation performances of CoL.

Table 2 The catalytic oxidation performances of CoL.

In this paper,a novel type of aza crowned hydroxamic acids cobalt(II) complexes as a biomimetic oxygen carrier were synthesized and characterized. The O₂-binding and catalytic activity of the complexes indicated that the size and configuration of the aza crown ring play an important role in the modulation of the oxygen-activating performance.

This work was supported by Chongqing Education Commission (No. KJ1400632).