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US-20260125394-A1 - METHOD OF PREPARATION OF CHIMERIC HEMICUCURBIT[N]URILS, DERIVATIVES, AND USES THEREOF

US20260125394A1US 20260125394 A1US20260125394 A1US 20260125394A1US-20260125394-A1

Abstract

A solvent free method for producing chimeric hemicucurbit[n]urils. The method comprises a first step of contacting, under mechanical agitation, at least two different cyclic urea derivatives and a compound that can form methylene bridges in the presence of an acid and templating anions and a second step of aging the products for at least about 30 minutes. The method has a very low process mass intensity (PMI) of 4, making it very attractive from a green chemistry perspective. New chimeric hemicucurbit[n]urils incorporating D-biotin are also described.

Inventors

  • Riina AAV
  • Elina SUUT-TUULE
  • Tatsiana JARG
  • Tatsiana NIKONOVICH
  • Dzmitry KANANOVICH
  • Lukaš USTRNUL

Assignees

  • TALLINN UNIVERSITY OF TECHNOLOGY

Dates

Publication Date
20260507
Application Date
20251226
Priority Date
20230626

Claims (16)

  1. 1 . A method of preparing of at least one chimeric hemicucurbit[n]uril, the method comprising: contacting, under mechanical agitation, two different cyclic urea derivatives and a compound that can form methylene bridges in the presence of at least one acid, at least one templating anion, and at least one solvent; and aging the products obtained at the step of contacting for at least about 30 minutes, wherein n is 6 or 8, wherein an amount of liquid per amount of solid in the reaction media is initially <1 μL/mg, and wherein one of the cyclic urea derivatives is (S,S)-N,N′-cyclohexa-1,2-diylurea or (R,R)-N,N′-cyclohexa-1,2-dylurea and the other cyclic urea derivative is D-biotin.
  2. 2 . The method according to claim 1 , wherein n is 8.
  3. 3 . The method according to claim 1 , wherein n is 6.
  4. 4 . The method according to claim 1 , wherein the at least one templating anion is selected from the group consisting of Cl − , Br − , I − , BF 4 − , IO 4 − , ClO 4 − , ReO 4 − , PF 6 − , SbF 6 − , SO 4 2− , BO 3 2− , NO 3 − , PO 3 3− , PO 4 2− , and RCO 2 − , R being selected from the group consisting of hydrogen atom, —OH, —COOH, —NH 2 , —NO 2 , —NHNH 2 , nitrile, alkyl, fluoro-alkyl, bromo-alkyl, chloro-alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, alkoxy, hydrocarbylthio, hydrocarbylamino, dihydrocarbylamino, carboxyl, aryl and heteroaryl, or a combination thereof, preferably PF 6 .
  5. 5 . The method according to claim 1 , wherein the at least one acid has a pK<1, and is preferably selected from the group consisting in HCl, HBr, HI, H 2 SO 4 , H 3 BO 3 , HNO 3 , H 3 PO 3 , H 3 PO 4 , HReO 4 , HClO 4 , HPF 6 , HSbF 6 , HBF 4 , HIO 4 , RCOOH, R being selected from or RCOOH, R being selected from the group consisting in hydrogen atom, —OH, —COOH, —NH 2 , —NO 2 , —NHNH 2 , nitrile, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, alkoxy, hydrocarbylthio, hydrocarbylamino, dihydrocarbylamino, carboxyl, aryl and heteroaryl, or a combination thereof, preferably HPF 6 .
  6. 6 . The method according to claim 1 , wherein the step of contacting further takes place in the presence of a salt and said salt is preferably selected from the list consisting in the combination of any templating anion according to claim 4 with a cation, and a combination thereof.
  7. 7 . The method according to claim 6 , wherein said salt is selected from the list consisting of AgPF 6 , [Cu(CH 3 CN) 4 ] PF 6 , KPF 6 , and/or a combination thereof, or wherein said salt is KPF 6 .
  8. 8 . The method according to claim 1 , wherein the aging step lasts at least about 1 h, at least about 1 h 30, or between about 2 h and about 24 h, or between about 2 h 30 and about 16 h, or between about 3 h and about 12 h.
  9. 9 . A chimeric hemicucurbit[n]uril obtained by the method according to claim 1 .
  10. 10 . The chimeric hemicucurbit[n]uril comprising two different cyclic urea monomers, wherein n is 6 or 8 and wherein one of the cyclic urea derivative is (S,S)-N,N′-cyclohexa-1,2-diylurea or (R,R)-N,N′-cyclohexa-1,2-dylurea and the other cyclic urea derivative is D-biotin, said chimeric hemicucurbit[n]uril being thus according to one of the following formula, the different monomers present in the cycle of said formula being in any order: wherein x+y=6; wherein x+y=6; wherein x+y=8; wherein x+y=8.
  11. 11 . The chimeric hemicucurbit[n]uril according to claim 10 , wherein said chimeric hemicucurbit[n]uril is according to one of the following formula, the different monomers present in the cycle of said formula being in any order.
  12. 12 . The chimeric hemicucurbit[n]uril according to claim 11 , wherein said chimeric hemicucurbit[n]uril is according to one of the following formula, the different monomers present in the cycle of said formula being in any order:
  13. 13 . The chimeric hemicucurbit[n]uril according to claim 11 , wherein n equals 8 and said chimeric hemicucurbit[n]uril is according to one of the following formula, the different monomers present in the cycle of said formula being in any order: wherein x+y=8; wherein x+y=8;
  14. 14 . The chimeric hemicucurbit[n]uril according to claim 13 , wherein said chimeric hemicucurbit[n]uril is according to one of the following formula, the different monomers present in the cycle of said formula being in any order:
  15. 15 . The chimeric hemicucurbit[n]uril according to claim 14 , wherein the chimeric hemicucurbit[n]uril is the (−)-((S,S,R)(R,R) 7 )-mono-biotinylated cyclohexanohemicucurbit[8]uril (XIV) or the (+)-((S,S,R)(S,S) 7 )-mono-biotinylated cyclohexanohemicucurbit[8]uril (XV) according to the following formula:
  16. 16 . The chimeric hemicucurbit[n]uril according to claim 10 , wherein the chimeric hemicucurbit[n]uril binds anions, cations or organic molecules.

Description

This nonprovisional application is a continuation of International Application No. PCT/IB2024/056236, which was filed on Jun. 26, 2024, and which claims priority to European Patent Application No. 23181344.5, which was filed in Germany on Jun. 26, 2023, and which are both herein incorporated by reference. FIELD OF THE INVENTION The present invention relates to the field of chemical sciences and more particularly to mechanochemistry. In particular, the invention relates to a solvent free method for producing chimeric hemicucurbit[n]urils. DESCRIPTION OF THE BACKGROUND ART Hemicucurbiturils are macrocycles usually composed of N,N′-(1,2-ethanediyl)-urea derivatives as monomers hinged together by methylene bridges via the nitrogen atoms of the N,N′-(1,2-ethanediyl)-urea monomers. They are well-known for their anion-binding capability and their solubility in non-polar solvents. They are usually synthesized in solution via an acid mediated, anion templated condensation reaction between the desired N,N′-(1,2-ethanediyl)-urea monomer and formaldehyde. However, this classic method of production of hemicucurbiturils is far from ideal. Indeed, the products selectivity toward different homologues is limited, process demands harsh conditions like prolonged heating in concentrated of strong acid and the method has a high process-mass intensity, making it not environmentally friendly. It would thus be desirable to promote a different approach of hemicucurbiturils synthesis. Mechanochemistry has recently emerged as a versatile, environmentally-friendly alternative to conventional chemical reactivity in solution. Besides offering a cleaner, safer way to conduct chemical transformations, mechanochemistry is also a route to discover new reactions and access materials or molecules that have been difficult to obtain. Indeed, at extreme concentrations in the solid state, when non-covalent interactions are stronger, the formation of products that are less favorable in solution becomes possible (Kwon, T. et al. J. Am. Chem. Soc. 2022, 144 (28), 12595-12601; Dračínský M. et al., Chemical Communications 2021, 57 (17), 2132-2135). Despite recent advances in understanding the kinetics and thermodynamics of mechanochemical reactions, the factors directing the formation of complex molecular structures under mechanochemical conditions remain largely unexplored. The self-assembly of molecular species is based on the formation of non-covalent interactions and can lead to complex supramolecular aggregates. Molecular interactions also mediate the formation of covalent bonds and are essential for covalent self-assembly. Control over supramolecular self-assembly may be highly sensitive to small changes in external stimuli, resulting in the amplification of various products (Schnitzer, T. et al, Angewandte Chemie 2022, 134 (41)). Solvent-free mechanochemistry has recently been used to assemble monomers in a one-pot reaction (Kaabel, S. et al., Angewandte Chemie International Edition 2019, 58 (19), 6230-6234). The size of the macrocycle is typically determined by external factors, such as anion templation (Kaabel, S. et al., Israel Journal of Chemistry 2018, 58 (3-4), 296-313). However, only some hemicucurbiturils macrocycles have been synthesized in the solid state via mechanochemistry (Kaabel, S. et al., Angewandte Chemie International Edition 2019, 58 (19), 6230-6234). Besides their synthesis method, another limitation to a wider use of hemicucurbiturils, is their range of action. Indeed, they are capable of forming complexes only with a limited range of anions, which binding strength is determined by the shape and size of the hemicucurbituril cavity (Andersen, N. et al., Israel Journal of Chemistry 2018, 58 (3-4), 435-448). It would thus be particularly interesting to develop new hemicucurbiturils having a wider range of interaction with anions or being capable to form complexes with different anionic guests. An interesting option to develop new hemicucurbiturils with such properties is to build macrocycles comprising different monomers. Recently, few teams have managed to synthetize oligomeric hemicucurbiturils incorporating non-uniform monomers (Zeng, Q. et al, Org. Chem. 2021, 17 (1), 2840-2847; Wang, L. et al., Tetrahedron Letters 2022, 101, 153918 Maršálek, K.; et al. Org. Lett. 2020, 22 (4), 1633-1637; De Simone et al. J. Org. Chem. 2022, 87 (15), 9829-9838). It has however been done in solution, utilizing multiple-step synthesis of particularly high process-mass intensity. There is thus still a need to develop a new method of preparation of chimeric hemicucurbiturils in a simple, cost effective, environmentally friendly and efficient way. The present invention meets these and other needs. SUMMARY OF THE INVENTION The inventors have successfully achieved a liquid assisted mechanochemically-activated, solid-state condensation reaction of (R,R)- or (S,S)-N,N′-cyclohexa-1,2-diylurea (CU), D-biotin, and formaldehyde. This is the first soli