A C-H Activation Route Toward Inherently Chiral Calix[4]arenes

Visagie, Kevin Johan (2019-12)

Thesis(MSc)--Stellenbosch University, 2019.

Thesis

ENGLISH ABSTRACT:The unique three-dimensional structure of the calixarene molecule allows it to possess, what is known as, inherent chirality. The compound, therefore, has potential application in various host-guest chemistry interactions. Our group is interested in developing new methods of synthesizing meta-functionalized inherently chiral calix[4]arenes. Recently, it has been demonstrated that ortho-halogenated N-aryl methyl carbamates may be selectively synthesized in acidic conditions through a Pd(OAc)2 assisted C-H activation. However, our research showed that when brominating a methyl (4-methoxyphenyl)carbamate without the inclusion of the catalyst, the regioselectivity of the reaction was not compromised. With this in mind, we investigated the role of the Pd(OAc)2 and the carbamate directing group when synthesizing meta-brominated inherently chiral calix[4]arenes. On a mono-substituted carbamate calix[4]arene system, we found that meta-brominated inherently chiral calix[4]arenes could be synthesized in high yields (85–90%), either through electrophilic aromatic substitution or C-H activation. After establishing the reaction conditions, we attempted to asymmetrically brominate the calix[4]arene by making use of a chiral 1(S)- (+)-menthyl carbamate directing group. For the reactions that included the catalyst, slightly higher yields were obtained compared to the reactions that did not. It was also found through alpha-D experiments that the Pd(OAc)2 assisted reactions resulted in a higher specific rotation. Unfortunately, no further evidence of diastereoselectivity could be obtained as the respective 1H NMR spectra showed no obvious differences and attempting to separate the diastereomers using HPLC proved unsuccessful. We also demonstrate for the first time that meta-functionalized inherently chiral calix[4]arenes of C4 symmetry can be synthesized through direct modification. This was achieved by making use of a methyl N-aryl carbamate directing group in an acid catalyzed electrophilic aromatic substitution. Purification was burdened with issues of isolating co-forming achiral stereoisomers, however, the desired inherently chiral calix[4]arene was finally isolated in yields as high as 40%.

AFRIKAANSE OPSOMMING: Die unieke drie-dimensionele struktuur van die calixarene molekule stel dit in staat om te besit, wat bekend staan as inherente chiraliteit. Die molekule het dus potensiële toepassing in verskeie gasheer-gas chemiese interaksies. Ons groep is geïnteresseerd om nuwe metodes vir die sintetisering van meta-gefunksionaliseerde inherente chiral calix[4]arene te ontwikkel. Onlangs is dit gedemonstreer dat orto-gehalogeneerde N-arielmatielkarbamate selektief gesintetiseer kan word in suur toestande deur ‘n Pd(OAc)2 assistente C-H aktivering. Ons navorsing het egter getoon dat by die brominering van 'n metiel (4-metoksifeniel)karbamaat sonder die insluiting van die katalisator die regioselektiwiteit van die reaksie nie gekompromiseer is nie. Met hierdie in gedagte het ons die rol van die Pd(OAc)2 en die karbamaat-regerende groep in die sintese van meta-gebroomde inherente chiral calix[4]arene ondersoek. Op 'n mono-gesubstitueerde karbamaat calix[4]arene stelsel het ons bevind dat metagebroomde inherente chirale calix[4]arene gesintetiseer kan word in hoë opbrengste (85-90%), óf deur elektrofiliese aromatiese substitusie of C-H aktivering. Nadat ons die reaksietoestande gevestig het, het ons probeer om die calix[4]arene asimmetries te bromineer deur gebruik te maak van 'n chirale 1(S)-(+)-mentielkarbamaat-regerende groep. Vir die reaksies wat die katalisator ingesluit het, is effens hoër opbrengste behaal in vergelyking met die reaksies wat dit nie gedoen het nie. Daar is ook deur alfa-D eksperimente gevind dat die Pd(OAc)2 assistente reaksies tot 'n hoër spesifieke rotasie gelei het. Ongelukkig kan geen verdere bewys van diastereoselektiwiteit verkry word nie, aangesien die onderskeie 1H NMR spektra geen duidelike verskille toon nie en pogings om die diastereomere met behulp van HPLC te skei, was onsuksesvol. Ons demonstreer ook vir die eerste keer dat meta-funksionaliseerde inherente chirale calix[4]arene van C4-simmetrie deur direkte modifikasie gesintetiseer kan word. Dit is behaal deur gebruik te maak van 'n metiel N-arylkarbamaat-regiegroep in 'n suur gekataliseerde elektrofiliese aromatiese substitusie. Suiwering is belas met die probleme van die isolering van ko-vormende achirale stereoisomere, maar die verlangde inherente chirale calix[4]arene is uiteindelik geïsoleer in opbrengste so hoog as 40%.

Please refer to this item in SUNScholar by using the following persistent URL: http://hdl.handle.net/10019.1/107001
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