Highly selective acid-catalyzed olefin isomerization of limonene to terpinolene by kinetic suppression of overreactions in a confined space of porous metal-macrocycle frameworks

Abstract

Natural enzymes control the intrinsic reactivity of chemical reactions in the natural environment, giving only the necessary products. In recent years, challenging research on the reactivity control of terpenes with structural diversity using artificial host compounds that mimic such enzymatic reactions has been actively pursued. A typical example is the acid-catalyzed olefin isomerization of (+)-limonene, which generally gives a complex mixture due to over-isomerization to thermodynamically favored isomers. Herein we report a highly controlled conversion of (+)-limonene by kinetic suppression of over-isomerization in a confined space of a porous metal-macrocycle framework (MMF) equipped with a Brønsted acid catalyst. The terminal double bond of (+)-limonene migrated to one neighbor, preferentially producing terpinolene. This reaction selectivity was in stark contrast to the homogeneous acid-catalyzed reaction in bulk solution and to previously reported catalytic reactions. X-ray structural analysis and examination of the reaction with adsorption inhibitors suggest that the reactive substrates may bind non-covalently to specific positions in the confined space of the MMF, thereby inhibiting the over-isomerization reaction. The nanospaces of the MMF with substrate binding ability are expected to enable highly selective synthesis of a variety of terpene compounds.

Fig. 1. Acid-catalyzed (+)-limonene isomerization in bulk solution and in the MMF.

Fig. 2. Metal–macrocycle framework (MMF). (a) Self-assembly of asymmetrically twisted Pd^II-macrocycles into (b) a porous crystal MMF (sticks model) with five enantiomeric pairs of binding pockets (surface model). (c) Previously reported site-selective adsorption of (−)-α-pinene (6) (space-filling model) on the channel surface of the MMF. Blue, yellow, red, or black dashed circles indicate the ceiling-, side-, bottom-, or tubular-pockets of the MMF, respectively. MMF: Pd, yellow; Cl, green; N, blue; C, grey. 6: C, pink; H, white. Hydrogen atoms attached to the MMF were omitted for clarity. Green or blue surface represents exposed Cl or N–H groups of the MMF, respectively.

Fig. 3. Immobilization of 2-NBSA·H₂O in the MMF. (a) Schematic representation of the soaking and washing procedures. (b and c) Crystal structures after each step. MMF: sticks model or surface model; 2-NBSA and water: space-filling model. Hydrogen bonds are indicated by red dashed straight lines and adjacent values indicate distances (Å) between non-hydrogen atoms. Red dashed circles indicate the bottom pocket of the MMF. MMF: Pd, yellow; Cl, green; N, blue; C, grey. 2-NBSA and water molecules: O, red; C, blue; H, white. Hydrogen atoms attached to the MMF were omitted for clarity. Green or blue surface represents exposed Cl or N–H groups of the MMF, respectively.

Fig. 4. Isomerization of (+)-limonene (1) catalyzed by 2-NBSA@MMF or 2-NBSA·H₂O. (a) Reaction scheme, conditions, and the results of reactions. (b and c) Time-course analysis (left) and time-rate (TOF: turnover frequency) plots (right) of both reactions. (d) Plot of conversion vs. selectivity for each catalyst. ^a The selectivity for 2 is defined as [2]/([2]+[3]+[4]+[5]+[others]); ^b The yields of “others” = 100% – (the total yields of 2–5 and the ratio of unreacted 1). The vertical and horizontal error bars in (d) represent the standard errors of selectivity and conversion ratio at each reaction time, based on three replicates, respectively (Fig. S16†).

Fig. 5. Investigation of the inhibitory effects of additives on the isomerization reaction of 2 using 2-NBSA@MMF at 25 °C for 102 h.

Fig. 6. Crystallographic study of MMFs soaked in (a) a CHCl₃ solution containing 1 (1.0 M), (b) a CHCl₃ solution containing 2 (1.0 M), and (c) a CH₃CN solution containing 7 (1.0 M). MMF: stick model or surface model; 1 and 7: space-filling model; water and CHCl₃: stick model. Red dashed circles indicate the bottom pocket of the MMF. MMF: Pd, yellow; Cl, green; N, blue; C, grey. 1: C, yellow; H, white. 7: C, pink; H, white. Water and CHCl₃: O, red; H, white; C, grey; Cl, green. Hydrogen atoms attached to the MMF were omitted for clarity. Green and blue surface represents exposed Cl and N–H groups of the MMF, respectively.

Fig. 7. A possible mechanism that kinetically suppresses over-isomerization inside the MMF by sterically blocking the acid sites that are housed deep inside.

Fig. 8. Acid-catalyzed cyclization of 10 catalyzed by 2-NBSA@MMF or 2-NBSA·H₂O. (a) Reaction scheme, conditions, and the results of reactions. (b and c) Time-course analysis of both reactions. ^a The yields of “others” = 100% – (the total yields of 1, 2, and 5 and the ratio of unreacted 10).