In Search of Wasserman's Catenane

Abstract

We repeat the earliest claimed [2]catenane synthesis, reported by Wasserman over 60 years ago, in order to ascertain whether or not a nontemplate, statistical synthesis by acyloin macrocyclization does indeed form mechanically interlocked rings. The lack of direct experimental evidence for Wasserman's catenane has led to it being described as a "prophetic compound", a technical term used in patents for claimed molecules that have not yet been synthesized. Contemporary synthetic methods were used to reconstruct Wasserman's deuterium-labeled macrocycle and other building blocks on the 10-100 g reaction scale necessary to generate, in principle, ∼1 mg of catenane. Modern spectrometric and spectroscopic tools and chemical techniques (including tandem mass spectrometry, deuterium nuclear magnetic resonance (NMR) spectroscopy, and fluorescent tag labeling) were brought to bear in an effort to detect, isolate, and prove the structure of a putative [2]catenane consisting of a 34-membered cyclic hydrocarbon mechanically linked with a 34-membered cyclic α-hydroxyketone.

Scheme 1. Wasserman’s Claimed 1960 Synthesis of [2]Catenane 1 by Statistical Threading and Macrocyclization of Alkyl Diester 2 through Deuterium-Labeled Cyclohydrocarbon 3 via Acyloin Condensation

The experimental evidence for the interlocked structure in 1960 was that following removal of 3 from the product mixture from the acyloin condensation by chromatography, oxidation (to cleave the acyloin group) released detectable quantities of 3. It was argued that the newly released 3 could only arise from it having been interlocked with 4 in a catenane (i.e., 1).^,

Scheme 2. Synthesis of Diester 2

(a) Synthesis of dialdehyde 6, (b) synthesis of phosphonium bromide 7, and (c) Wittig olefination of 6 + 7 and hydrogenation of the resulting alkene to form 2. bipy = 2,2′-bipyridine; TEMPO = (2,2,6,6-tetramethyl-piperidin-1-yl)oxidanyl; NMI = N-methylimidazole; KHMDS = potassium bis(trimethylsilyl)amide; TES-H = triethylsilane.

Scheme 3. Synthesis of Cyclic Acyloin 4 and Deuterated Cycloalkane/-alkene (D_0-6)-3/(D_0-4)-10

X-ray crystal structures of (D_0-6)-3 (the alkene group of 10 present in the crystal manifests itself as disorder distributed around the macrocycle) and 4, depicted in van der Waals radius space-filling representations.

Figure 1

(a) IR spectrum of a crystal of (D_0–6)-3/(D_0–4)-10 and (b) ²H NMR spectrum (77 MHz, CHCl₃, 298 K) of (D_0–6)-3/(D_0–4)-10. Signal shaded gray corresponds to trace CDCl₃.

Figure 2

(a) (i) Synthesis of [2]catenane 1/11 by statistical threading. (ii) Oxidation of catenane-containing mixture with alkaline H₂O₂. (b) Photograph of TLC analysis (silica, petroleum ether; cerium ammonium molybdate stain) of the oxidative cleavage reaction on the polar fraction obtained from step (i). Left-hand lane: polar fraction from the catenane-forming reaction (i.e., products from step (i)); 2nd-from-left lane: co-spot of before and after oxidative cleavage; 2nd-from-right lane: oxidation reaction (i.e., step (ii)) after 24 h; right-hand lane: pristine 3/10. (c) ²H NMR spectrum (77 MHz, CHCl₃, 298 K) of fast-eluting product from step (ii), i.e., 3/10 (0.07% yield, based on starting material 2).

Figure 3

APCI(+)-MS/MS tandem mass spectrometry of key molecular ions present in the polar fraction eluted from Figure 2, step (i) after removal of excess 3/10 by column chromatography. (a) MS/MS of m/z 489, corresponding to the acyloin macrocycle [4-H₂O]H⁺, using 20 eV collision energy. The fragment at m/z 471 corresponds to [4-2H₂O]H⁺. (b) MS/MS of m/z 970, corresponding to catenane [1/11-H₂O]H⁺, using 20 eV collision energy. Inset: Signals in blue arise from fragments of (D_0–6)-3 and (D_0–4)-10; signals in black arise from fragments of 4.

Figure 4

(a) Derivatization of the catenane-forming reaction mixture (after removal of excess 3/10) with dansyl chloride, enabling the isolation of 12, a derivative of Wasserman’s catenane. (b) DOSY spectrum (600 MHz, CDCl₃, 298 K) of 12a/12b. (c) Partial ¹H NMR stackplot (600 MHz, CDCl₃, 298 K) of (top) deuterium-labeled 3/10; (middle) dansyl-derivatized catenane 12a/12b; (bottom) dansyl-derivatized acyloin. Upper-case letters (deuterium-labeled macrocycle) and lower-case letters (acyloin) correspond to the lettering shown in (a). Signal in gray corresponds to CHCl₃. (d) ²H NMR spectrum (77 MHz, CHCl₃, 298 K) of 12a/12b. Signal in gray corresponds to CDCl₃. (e) HRMS (APCI+) mass spectrum of 12b.