Determination of the interconversion energy barrier of three novel pentahelicene derivative enantiomers by dynamic high resolution liquid chromatography
Introduction
Helicenes are ortho-condensed polycyclic aromatic compounds in which benzene ortho fused rings or other aromatics are angularly annulated to give helically-shaped molecules which are governed by a conformational distortion of the π-system imposed by a strong steric strain.
As a consequence, the helicity renders them chiral and they have chiroptical properties. There is evidence for a simple relationship between the optical rotation of helicenes and their absolute configuration [1]. The remarkable similarity between the circular dichroism (CD) and optical rotatory dispersion (ORD) spectra of hepta-, octa- and nona-helicenes [2] with penta- and hexa-helicene, whose absolute configuration had been determined by chemical means [3] and by X-ray crystallography [4] lend support to the suggestion made earlier [5] that all dextrarotatory pentahelicenes may be assigned the P-helical configuration. Details on the non-stereoselective and stereoselective syntheses, chiral separations, as well as applications and properties of carbohelicenes can be found in three recently published reviews [6], [7], [8].
As a general trend in a homochiral series, the P series of carbohelicenes has a (+) dextrorotatory specific rotation and the M series has a (−) levorotatory specific rotation [6], [7].
Due to their intrinsic chirality spanned over a large polyaromatic template, preliminary results clearly established the efficiency of carbohelicenes to induce asymmetry and chirality in organic synthesis and in supramolecular chemistry. The chemistry of helicenes has attracted continuing attention because of their unique structural, spectral, and optical features. Additionally, they have some potential uses in several fields: materials science, nanoscience, chemical biology and supramolecular chemistry [8].
For many of these applications, the helicences are required to be enantiomerically enriched or pure, thus there is a need to develop robust synthetic, preparative, and analytical methods for the production and analysis of enantiomerically enriched helicenes.
Further, depending on the size and substitution of a helicene, different racemization energy barriers exist for different helicenes [2], [7]. As such, the development of methods to determine the stability of enantiomerically purified helicenes is critical. The most widely used analytical and semi-preparative technique for the separation of helicences is HPLC with the use of various chiral stationary phases (CSPs) [7]. The first HPLC separation of hexa- to tetradecahelicenes utilized (+)-2-(2,4,5,7-tetranitro-9-fluorenylidene-aminooxy) propionic acid (+)-TAPA coated on silica gel. Three other TAPA derivatives have also been studied under similar conditions by changing a substituent at the stereogenic center from a methyl to an ethyl group (TABA), to an isopropyl (TAIVA) or to a butyl group (TAHA) [7]. A list of the most frequently used CSPs for the HPLC separation of non-functionalized and functionalized carbohelicene enantiomers has been summarized [7].
Recently, a novel class of CSPs based on cyclofructans (CFs) has been developed. Aromatic derivatives of CFs have proven to be broadly selective, separating many classes of chiral compounds in the normal phase and polar organic modes [9], [10]. Additionally, an aliphatic derivative (isopropylcarbamate) of CF has not only proven to be broadly selective, but also class selective for primary amine containing chiral compounds [11], [12], [13]. An alkyl derivatized cyclofructan 6 chiral stationary phase (LARIHC CF6-P) performed well both in HPLC as well as in supercritical fluid chromatography (SFC) and most recently proved to be highly selective for the separation of biaryl atropisomers [14], [15].
Consequently, the LARIHC CF6-P CSP was utilized in this paper for its ability to separate enantiomers of three novel pentahelicene derivative enantiomers. Further, once separations of these pentahelicene derivative enantiomers were achieved on the CSP, dynamic HPLC (DHPLC) was used to determine their kinetic and thermodynamic interconversion parameters [16]. A quantum chemistry method was applied to estimate theoretical kinetic and thermodynamic interconversion parameters and to compare experimental data of this three novel pentahelicene derivative enantiomers.
Section snippets
Synthesis of pentahelicene derivatives
The three pentahelicene derivatives used in this study were synthesized in the same manner through the annulations of BINOL, similar to the procedure used by Xue and Scott [17]. In short, BINOL was converted into its corresponding triflate form [18], [19] and then transformed into the pentahelicene derivaties via catalytic intramolecular C-H arylation in the presence of Pd(OAc)2, xantphos [20] and Cs2CO3. Details of synthesis as well as X-ray crystal structures, NMR, CD and ORD spectra which
Results and discussion
The interconversion of the 2CF3, TNP and OME enantiomers was studied by separating racemates by HPLC on a LARIHC CF6-P column using a constant composition of normal phase solvent (99.9% of heptane + 0.1% of methanol) and varying either the flow rates or the isothermal column temperatures. Equations used for the calculation of rate constants and thermodynamic interconversion parameters are reviewed in Theoretical part of the Supplementary Data. The equation numbers cited in this section are
Conclusions
Dynamic HPLC with effective chiral stationary phases provide a particularly effective and efficient way to evaluate the interconversion energy barrier between helicene enantiomers. Further, this approach facilitated understanding the significant effect of peripheral substituents to the helicene “backbone” on their configurational stabilities. The thermodynamic parameters of the 3,5-bis(trifluoro-methyl)benzo[i]pentahelicene, naphtho[1,2-i]pentahelicene and 4-methoxybenzo-[i]pentahelicene are
Acknowledgements
PM and JK would like to thank the Scientific Grant Agency of the Ministry of Education of Slovak Republic and the Slovak Academy of Sciences VEGA 1/0573/14 and the Slovak Research and Development Agency under the contract No. APVV-15-0455. DWA would like to acknowledge the Welch Foundation (Y-0026) for partial funding of this work. LMS gratefully acknowledges the National Science Foundation (CHE-1360610) for their monetary support.
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