Expedient synthesis of amides: application of biomass-derived catalysts and multicompo-nent reactions

DEPARTAMENTO DE QUÍMICA

Expedient synthesis of amides: application of biomass-derived catalysts and multicompo- nent reactions

JOANA RITA SANCHES PEREIRA

Licenciada em Engenharia Química e Biológica

MESTRADO EM QUÍMICA BIOORGÂNICA Universidade NOVA de Lisboa

Outubro, 2022

Orientadora: Maria Manuel Marques,

Professora Catedrática, Universidade NOVA de Lisboa

Coorientadores: Ana Aguiar-Ricardo,

Professora Auxiliar, Universidade NOVA de Lisboa

Júri:

Presidente: Nome do(a) presidente,

Professor(a) Catedrático(a), FCT-NOVA

Arguentes: Nome de um dos arguentes,

Professor Associado, Outra Universidade

Orientador: Nome do orientador presente nas provas,

Professor Associado, FCT-NOVA

Membros: Mais um membro do júri,

Professora Catedrática, Outra Universidade

E ainda mais um membro do júri,

Professor Auxiliar, Ainda Outra Universidade

DEPARTAMENTO DE QUÍMICA

Expedient synthesis of amides: application of biomass-derived catalysts and multicompo- nent reactions

JOANA RITA SANCHES PEREIRA

Licenciada em Engenharia Química e Biológica

MESTRADO EM QUÍMICA BIOORGÂNICA Universidade NOVA de Lisboa

Outubro, 2022

Expedient synthesis of amides: application of biomass-derived catalysts and multicompo- nent reactions

Copyright © Joana Rita Sanches Pereira, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa.

A Faculdade de Ciências e Tecnologia e a Universidade NOVA de Lisboa têm o direito, per- pétuo e sem limites geográficos, de arquivar e publicar esta dissertação através de exemplares impressos reproduzidos em papel ou de forma digital, ou por qualquer outro meio conhecido ou que venha a ser inventado, e de a divulgar através de repositórios científicos e de admitir a sua cópia e distribuição com objetivos educacionais ou de investigação, não comerciais, desde que seja dado crédito ao autor e editor.

A GRADECIMENTOS

Agradecer primeiramente à minha orientadora Doutora Maria Manuel Barata Marques pela oportunidade de entrar neste maravilhoso projeto, pela excelente orientação, atenção, dis- ponibilidade, e pela partilha de conhecimentos ao longo deste último ano. Gostaria ainda de agradecer por todo o empenho, paciência, motivação, otimismo, e boa disposição contagiante ao longo de todo o percurso, independentemente dos obstáculos.

De seguida agradecer à minha co-orientadora Doutora Ana Aguiar-Ricardo pela orien- tação e acompanhamento ao longo deste último ano, que também foram muito importantes para que este projeto pudesse progredir. Também um especial agradecimento à Doutora An- dreia F. Peixoto por toda a ajuda, orientação e apoio ao longo deste ano que foram igualmente muito importantes. À Doutora Ana Teresa Lopes pela simpatia e pelo eficiente processamento dos espetros de RMN.

Um generoso obrigada a todos os meus colegas e professoras do laboratório 202 e 205 pela hospitalidade e boa disposição que também tornaram de certa forma este ano memorável.

Gostaria de agradecer particularmente ao João Macara por toda a ajuda, apoio e disponibili- dade que sempre demonstrou sem nenhuma hesitação. À Ana Sofia Santos pela partilha de saberes. Às minhas colegas de mestrado Catarina Caldeira, Rita Ferro e Diana Alves por todo o apoio e amizade que partilhamos ao longo deste ano. Um calorento obrigada à Gabriela Malta por todo o bom-humor e carinho que sempre demonstrou à sua maneira.

Por fim, quero agradecer de coração cheio à minha mãe e ao meu pai por todo o amor e suporte durante todo este percurso, e por tornarem tudo isto possível. Agradecer de igual forma ao João Matos por todo o apoio, paciência, e carinho partilhado, que também tornou possível a concretização desta tese.

R ^ESUMO

As amidas são um grupo funcional de extrema importância visto que estão presentes na estrutura de diver- sos compostos biologicamente relevantes. Em Química Medicinal, as amidas revelaram ser muito interessantes para o design de novos fármacos, sendo que um quarto dos fármacos aprovados e disponíveis no mercado contêm um grupo amida. Para além da sua relevância para os fármacos, as amidas são também importantes grupos funci- onais para a síntese de polímeros, devido à sua estabilidade e robustez. As poliamidas encontram-se naturalmente presentes na composição de várias biomoléculas, tais como as proteínas. Devido a esta similaridade, têm vindo a ser cada vez mais usadas em drug delivery.

Os métodos tradicionais para síntese de amidas envolvem o acoplamento entre um ácido carboxílico e uma amina, necessitando de reagentes ativadores do grupo carboxílico, gerando desperdício. A utilização de catalisa- dores tem contribuído para a maior sustentabilidade dos métodos de formação de amidas. Uma das metodologias desenvolvidas para síntese de amidas é a reação de Ritter, que envolve a reação de um álcool com um nitrilo, catalisada por um ácido. Grande parte dos exemplos da reação de Ritter descritos na literatura envolvem o uso de grandes quantidades de ácidos fortes, muitos deles associados a perigos ambientais, comprometendo a sustentabi- lidade da formação da ligação amida. Nos últimos anos, os nanocatalisadores têm emergido como uma alternativa verde para a catálise, dado que combina as vantagens dos catalisadores homogéneos e heterogéneos. Nesta tese de mestrado, a reação de Ritter foi realizada com diversos catalisadores derivados de fontes naturais, para formar a respetiva amida. Multi Wall Carbon Nano Tubes (MWCNT ) proporcionou os melhores rendimentos quando compa- rado com outros catalisadores testados. Adicionalmente, compostos derivados da biomassa, como por exemplo o álcool furfurílico (FA), foram também selecionados para este estudo, no entanto, foi observada a polimerização do FA. Com o objetivo de prevenir esta reação secundária, foram feitas algumas investigações com diferentes aditivos.

Apenas o Na²S²O⁴ (5%m/m), diminuiu substancialmente a formação do polímero, mas sem qualquer influência na formação da amida. De seguida, sintetizaram-se 10 amidas diferentes a partir de diversos álcoois e nitrilos, catali- sadas com o MWCNT com rendimentos entre os 13%-78%.

Com vista à preparação de poliamidas usando compostos vindos da biomassa, considerou-se ainda a reação de Ugi. Aplicando a reação de Ugi a derivados do furfuraldeído obteve-se uma amida, usando água como solvente, de forma quantitativa e que constitui um potencial monómero para posteriores estudos de polimerização.

Palavas chave: Amidas; Nanocatalisadores; Biomassa; Reação de Ritter; Reação de Ugi

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A ^BSTRACT

Amides are an extremely important functional group since they are present in several biological structures. In medicinal chemistry, amide is highly attractive for the design of new drugs, whereas a quarter of approved and available drugs in the market have an amide group. Besides drugs, amide bonds are also important functional groups in polymer synthesis, due to their stability and strength.

Polyamides are naturally present in composition of diverse biomolecules, such as proteins. Due to this similarity, they have been highly implemented in drug delivery.

Traditional methodologies to achieve amides involve combination between a carboxylic acid and an amine, requiring a pre-activation agent of carboxylic acid, lead to waste amounts. The use of catalysts has contributed to the sustainability of amide formation methods. One of the methodologies developed for amide synthesis is the Ritter reaction, which involves reaction of an alcohol with a nitrile catalysed by an acid. Several examples of Ritter reaction reported in literature employed the use of high quantities of strong acids most of them associated to environmental hazards compromise the sustainability of am- ide bond formation. Over the last years, nanocatalysts have been emerging as a green alternative in catalysis, since join the positive aspects of homogeneous and heterogeneous catalysts. In this master thesis, Ritter reaction was performed with several nanocatalysts derived from a natural source, to achieve the corresponding amide. MWCNT provide better yields when compared to other catalysts tested. Additionally, biomass-derived compounds, such as Furfuryl Alcohol (FA), were also employed for this study, however these compounds revealed an undesirable behavior, polymerization of FA. In order to prevent this side reaction, some investigation was performed by employing different additives.

Only Na²S²O⁴ (5%w/w) decreased substantially the polymer formation, but with no influence in amide formation. Next, amide synthesis from several alcohols and nitriles catalyzed by MWCNT was ex- plored, yielding 10 different products ranging from 13% to 78% yields.

To produce the polyamides by using biomass building blocks, Ugi reaction was considered. Ap- plying the Ugi reaction to furfural derivatives, an amide was quantitatively obtained, by employing water as solvent, as a potential monomer for further polymerization studies.

Keywords: Amides, Nanocatalysts, Biomass, Ritter reaction, Ugi reaction.

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I ^NDEX

AGRADECIMENTOS ... IX

RESUMO ... XIII

ABSTRACT ...XV

1 INTRODUCTION ... 39

1.1 Amides - relevant groups in medicinal and synthetic chemistry ... 39

1.1.1 Polyamides - interesting polymers in drug delivery ... 40

1.2 Amide Bond Synthesis ... 41

1.2.1 Classical methods for amide bond synthesis ... 41

1.2.1.1 Ritter Reaction ... 42

1.2.1.2 Ugi Reaction ... 44

1.2.2 Recent amidation approaches ... 46

1.2.2.1 Boron chemistry ... 46

1.2.2.2 Metal catalysts ... 47

1.2.2.3 Metal-free processes ... 48

1.2.3 Synthesis of Polyamides ... 48

1.3 Biomass Valorization ... 49

1.3.1 Lignin ... 50

1.3.2 Cellulose... 51

1.3.3 Hemicellulose ... 52

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1.4 Homogeneous, heterogeneous catalysis and nanocatalysis ... 54

1.4.1 Clays: K10, Halloysite (HNT) and Cloisite (CLOI) ... 55

1.4.2 Biochar (Bio) ... 56

1.4.3 Multi Wall Carbon Nano Tubes (MWCNT) ... 56

2 DISCUSSION AND RESULTS ... 59

2.1 Background and objetives ... 59

2.2 Nanocatalysis - A New Approach for Amide Synthesis from Ritter Reaction ... 61

2.2.1 Amide synthesis via 1-phenylethanol - Finding the optimal conditions ... 61

2.2.2 Screening of Different Nanocatalysts ... 62

2.2.3 Amide synthesis from biomass derived compounds ... 66

2.2.4 Experiments with furfuryl alcohol - Screening of additives ... 70

2.2.5 Beyond furfuryl alcohol - other biomass derived compounds ... 74

2.2.6 Extending the scope with MWCNT-CSP catalyst ... 77

2.3 Ugi reaction - one-pot reaction for the synthesis of polyamides polymers ... 81

2.4 Final Remarks ... 88

2.5 Future Work ... 91

3 EXPERIMENTAL SECTION ... 93

3.1 General Information ... 93

3.2 Synthesis of reagents and experiments ... 94

3.2.1 General procedure A for the synthesis of N-(1-phenylethyl)acetamide with different catalysts... 94

3.2.1.1 N-(1-phenylethyl)acetamide ... 94

3.2.1.2 Bis(1-phenylethyl)ether ... 95

3.2.2 General procedure B for the synthesis of N-(furan-2-ylmethyl)acetamide ... 95

3.2.2.1 N-(furan-2-ylmethyl)acetamide ... 95

3.2.3 Experiments with Furfuryl Alcohol ... 96

3.2.4 General procedure C for the synthesis of secondary alcohol of FA ... 96

3.2.4.1 1-(2-furyl)ethanol ... 97

3.2.1 General procedure D for the synthesis of tertiary alcohol of FA ... 97

3.2.1.1 Furan-2,5-dicarboxylic acid dimethyl ester ... 97

3.2.1.2 2,5-bis[(α-hydroxy-α,α-dimethyl)methyl]furan ... 98

3.2.2 General procedure E for scope MWCNT-CSP catalyst: different nitriles... 98

3.2.2.1 N-(1-phenylethyl)propionamide ... 98

3.2.2.2 N-(1-phenylethyl)benzamide ... 99

3.2.2.3 2-phenyl-N-(1-phenylethyl)acetamide ... 99

3.2.2.4 2-(4-bromophenyl)-N-(1-phenylethyl)acetamide ... 100

3.2.2.5 2-(4-chlorophenyl)-N-(1-phenylethyl)acetamide ... 100

3.2.2.6 N-(1-phenylethyl)-2-(p-tolyl)acetamide ... 101

3.2.3 Scope MWCNT-CSP catalyst: different alcohols ... 101

3.2.3.1 N-(1-(3-methoxyphenyl)ethyl)acetamide ... 101

3.2.3.2 N-benzylacetamide ... 102

3.2.4 General procedure F for the synthesis of N-((5-formylfuran-2- yl)methyl)acetamide ... 102

3.2.4.1 N-((5-formylfuran-2-yl)methyl)acetamide ... 102

3.2.5 General procedure G for the synthesis of N-benzhydrylacetamide ... 103

3.2.5.1 N-benzhydrylacetamide ... 103

3.2.6 General procedure H for the synthesis of monomer via Ugi reaction ... 104

3.2.6.1 N-(tert-butyl)-2-(furan-2-yl)-2-(N-propylacetamido)acetamide ... 104

3.2.7 General procedure I for the synthesis of polymer by employing diformylfuran via Ugi reaction ... 105

3.2.8 General procedure J for the synthesis of polymer by employing malonic acid via Ugi reaction ... 105

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BIBLIOGRAFY ... 107 A APPENDIX ... 2

xxii

L ^{IST OF} S ^CHEMES

Scheme 1. Examples of amide-containing drugs. ... 40 Scheme 2. Representative examples of polyamides in drug-delivery. ... 41 Scheme 3. Common methods to synthesize amides. ... 42 Scheme 4. Ritter reaction proposed mechanism. ... 43 Scheme 5. Isoflavonoids synthesis, reported by Iskandet et al. ... 44 Scheme 6. Ugi reaction proposed mechanism. ... 45 Scheme 7. Fentanil derivates synthesis using Ugi reaction. ... 45 Scheme 8. Lacosamide synthesis, reported by Stecko (A) and Lanigan et al. (B). ... 47 Scheme 9. Amide synthesis using a rhodium-based complex reported by Seagun Kim et al. 47 Scheme 10. Amide synthesis using THBP reported by Sado Raro et al. ... 48 Scheme 11. Polyamide PNIPAAm synthesis employing scCO² reported by Aguiar-Ricardo.

... 49 Scheme 12. Major biopolymers from plant cell wall and respective main components.^72,73 ... 50 Scheme 13. Chemical structure of lignin. ... 51 Scheme 14. Structure of cellulose and its hydrolysis: synthesis of 5-Hydroxymehtylfurfural (5- HMF) and derivates. ... 52 Scheme 15. Structure of hemicellulose (Xylan), with glucuronic acid (α 1→2) and arabinose (α 1→3) and its hydrolysis: synthesis of furfural and derivates. ... 53 Scheme 16. Distinction of homogeneous, heterogeneous and nanocatalysis. ... 55 Scheme 17. Amidation reaction using K10 as catalyst by Kumar et al. ... 55

Scheme 18. Etherification of 5-HMF with t-butanol catalyzed by biochar with p- toluenesulfonic group (CSP) anchored to the catalyst surface by Peixoto et al. ... 56 Scheme 19. One-pot multicomponent condensation reaction among benzaldehyde, naphthol, and benzamide catalyzed by MWCNT-SO³H catalyst by Ahmadi et al. ... 57 Scheme 20. General scheme comprising the principal aims of this master thesis. ... 60 Scheme 21. Amide formation from 1-phenylethanol and acetonitrile, catalyzed by p-TSA^.H²O.

Reaction conditions: 1-phenylethanol (0.33 mmol), acetonitrile (solvent, 1 mL), p- toluenesulfonic acid monohydrate (10 mol%)... 61 Scheme 22. Possible mechanism for bis(1-phenyl)ether formation. ... 62 Scheme 23. Thermogravimetric curves (N², 100 cm³/min) of fresh catalyst (MWCNT-CSP), the used catalyst washed with HCl and without HCl. ... 65 Scheme 24. Amide formation from furfuryl alcohol and acetonitrile, catalyzed by p-TSA^.H²O.

Reaction conditions: Furfuryl alcohol (0.33 mmol), acetonitrile (solvent, 1 mL), p- toluenesulfonic acid monohydrate (10 mol%)... 66 Scheme 25. Proposed structures of polymerized furfuryl alcohol. ... 71 Scheme 26. Preparation of secondary alcohol of FA using Grignard reaction, followed by Ritter reaction catalyzed by p-TSA^.H²O. ... 74 Scheme 27. Preparation of tertiary alcohol of FA using Grignard reaction, followed by Ritter reaction catalyzed by p-TSA^.H²O. ... 76 Scheme 28. Amide formation from 5-HMF and acetonitrile, catalyzed by p-TSA^.H²O. Reaction conditions: 5-HMF (0.33 mmol), acetonitrile (solvent, 1 mL), p-toluenesulfonic acid monohydrate (10 mol%). ... 77 Scheme 29. MWCNT-CSP catalyzed Ritter reaction with different nitriles and alcohols.^a ... 78 Scheme 30. Resonance effect of phenyl group in nitrile group. ... 79 Scheme 31. MWCNT-CSP catalyzed synthesis of amides using nitriles and diverse benzylic alcohols.^a ... 80 Scheme 32. A) Protocol adopted by Zhang et al.; B) Protocol adopted for the synthesis of monomer in this thesis. Reaction conditions: 11.1 (1.0 mmol), 12 (1.0 mmol), 6.1 (1.0 mmol), 13 (1.0 mmol) and methanol (solvent, 2 mL) at room temperature. ... 82 Scheme 33. Proposed mechanism for monomer synthesis via Ugi reaction. ... 83 Scheme 34. Results obtained for monomer synthesis by differ the carboxylic acid source via Ugi reaction procedure. Reaction conditions: Furfural 6.1 (1.0 mmol), propylamine 11.1 (1.0

xxiv

mmol), tert-butyl isocyanide 13 (1.0 mmol), carboxylic acid 12 (1.0 mmol), in methanol (solvent, 2 mL) at room temperature. ... 83 Scheme 35. Results obtained for monomer synthesis via Ugi reaction procedure, by employing water as solvent. Reaction conditions: 11.1 (1.0 mmol), 12.2 (1.0 mmol), 6.1 (1.0 mmol), 13 (1.0 mmol) and water (solvent, 2 mL) at room temperature. ... 85 Scheme 36. Synthetic approach to synthesize the polymer using DFF and ethylenediamine as polymerization source. Reaction conditions: 11.2 (1.0 mmol), 12.2 (2.0 mmol), 6.2 (1.0 mmol), 13 (2.0 mmol) and methanol (solvent, 2 mL) at room temperature. ... 85 Scheme 37. Synthetic approach to synthesize the polymer using malonic acid and ethylenediamine as polymerization source. Reaction conditions: 11.2 (1.0 mmol), 12.3 (2.0 mmol), 6.1 (1.0 mmol), 13 (2.0 mmol) and methanol (solvent, 2 mL) at room temperature. ... 87 Scheme 38. General scheme summarized the main studies of this master thesis. ... 90 Scheme 39. Future work plan by employing Ugi reaction to achieve polyamides polymer with medicinal applications. ... 91

L ^{IST OF} T ^ABLES

Table 1. Representation and characteristics of nanocatalysts. ... 63 Table 2. Results obtained for catalysts screening. ... 64 Table 3. Results obtained for amide formation at different temperatures. ... 68 Table 4. Results obtained for amide formation with different acids. ... 69 Table 5. Effect of additives in polymerization of furfuryl alcohol.^a ... 72 Table 6. Experiments with 1-(2-furyl)ethanol (4.2). Description: n.d.-not detected; S.M.- Starting Material. ... 76 Table 7. Effect of additives in polymerization of furfuryl alcohol. ... 96

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L ^{IST OF} S ^PECTRA

Spectrum 1. ¹H NMR spectrum (CDCl³, at 400MHz) of amide from furfuryl alcohol and acetonitrile. ... 67 Spectrum 2. IR-ATR spectrum of polymerization of furfuryl alcohol with different additives at different concentrations. Description: Black-Na²S²O⁴ (5%w/w); Blue-BHT (1%w/w); Pink- Na²S²O⁴ (10%w/w); Green- Na²S²O⁴ (1%w/w); Yellow-ChCl (1%w/w). ... 73 Spectrum 3. ¹H NMR spectrum (CDCl³, at 400MHz) obtained by overlap the product formed (green) and 1-(2-furyl)ethanol (maroon). ... 75 Spectrum 4. ¹H NMR spectrum (CDCl³, at 400MHz) obtained with acetic acid, where the desired amide monomer can be observed. ... 84 Spectrum 5. ¹H NMR spectrum (CDCl³, at 400MHz) obtained for the dark-brown thick mixture. ... 86 Spectrum 6. ¹H-NMR spectrum of compound 3.1.1. ... 2 Spectrum 7. ¹³C-NMR spectrum of compound 3.1.1. ... 3 Spectrum 8. IR spectrum of compound 3.1.1. ... 3 Spectrum 9. ¹H NMR spectrum of bis(1-phenyl)ether. ... 4 Spectrum 10. ¹³H-NMR spectrum of compound 5.1.1. ... 4 Spectrum 11. ¹³C-NMR spectrum of compound 5.1.1. ... 5 Spectrum 12. IR spectrum of compound 5.1.1. ... 5 Spectrum 13. ¹H-NMR spectrum of compound 10. ... 6 Spectrum 14. ¹H-NMR spectrum of compound 4.3. ... 6 Spectrum 15. ¹H-NMR spectrum of compound 3.1.2. ... 7

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Spectrum 16. ¹³C-NMR spectrum of compound 3.1.2. ... 7 Spectrum 17. IR spectrum of compound 3.1.2. ... 8 Spectrum 18. ¹H-NMR spectrum of compound 3.1.3. ... 8 Spectrum 19.¹³C-NMR spectrum of compound 3.1.3. ... 9 Spectrum 20. IR spectrum of compound 3.1.3. ... 9 Spectrum 21. ¹H-NMR spectrum of compound 3.1.4. ... 10 Spectrum 22. ¹³C-NMR spectrum of compound 3.1.4. ... 10 Spectrum 23. IR spectrum of compound 3.1.4. ... 11 Spectrum 24. ¹H-NMR spectrum of compound 3.1.5. ... 11 Spectrum 25. ¹³C-NMR spectrum of compound 3.1.5. ... 12 Spectrum 26. IR spectrum of compound 3.1.5. ... 12 Spectrum 27. ¹H-NMR of compound 3.1.6. ... 13 Spectrum 28. ¹³C-NMR of compound 3.1.6. ... 13 Spectrum 29. IR spectrum of compound 3.1.6. ... 14 Spectrum 30. m/z spectrum of compound 3.1.6. ... 14 Spectrum 31. ¹H-NMR spectrum of compound 3.1.7. ... 15 Spectrum 32. ¹³C-NMR spectrum of compound 3.1.7. ... 15 Spectrum 33. IR spectrum of compound 3.1.7. ... 16 Spectrum 34. m/z spectrum of compound 3.1.7. ... 16 Spectrum 35. ¹H-NMR spectrum of compound 3.2.1. ... 17 Spectrum 36. ¹³C-NMR spectrum of compound 3.2.1. ... 17 Spectrum 37. IR spectrum of compound 3.2.1. ... 18 Spectrum 38. ¹H-NMR spectrum of compound 3.3.1. ... 18 Spectrum 39. ¹³C-NMR spectrum of compound 3.3.1. ... 19 Spectrum 40. ¹H-NMR spectrum of compound 3.4.1. ... 19 Spectrum 41. ¹³C-NMR spectrum of compound 3.4.1. ... 20 Spectrum 42. IR spectrum of compound 3.4.1. ... 20 Spectrum 43. m/z spectrum of compound 3.4.1. ... 21 Spectrum 44. ¹H-NMR spectrum of compound 3.5.1. ... 21 Spectrum 45. ¹³C-NMR spectrum of compound 3.5.1. ... 22 Spectrum 46. IR spectrum of compound 3.5.1. ... 22

Spectrum 47. ¹H-NMR spectrum of compound 14.2. ... 23 Spectrum 48. ¹³C-NMR spectrum of compound 14.2. ... 23 Spectrum 49. FTIR spectrum of compound 14.2. ... 24 Spectrum 50. m/z spectrum of compound 14.2. ... 24

A BREVIATIONS AND N OMENCLATURE

5-HMF 5-Hydroxymethylfurfural ATR Attenuated total reflectance BHMF 2,5-Bis(hydroxymethyl)furan

BHMTHF 2,5-Bis(hydroxymethyl)tetrahydrofuran

BHT Butylhydroxytoluene

Bio Biochar

ChCl Choline cloride

CLOI Cloisite

CNT Carbon nano tubes

CSA Camphorosulfonic acid

CSP p-Toluenesulfonic acid

DFF Diformylfuran

DMF 2,5-dimethylfuran

FA Furfuryl alcohol

FDCA 2,5-furandicarboxylic acid HMTHF Tetrahydrofurfuryl alcohol

HNT Halloysite

IR Infrared spectroscopy

xxxvi m/z Mass-to-charge ratio

Me Methyl

MWCNT Multi wall carbon nano tubes

PTLC Preparative thin-layer chromatography

RT Room temperature

TFA Trifluoroacetic acid

THF Tetrahydrofuran

TLC Thin-layer chromatography

NMR nomenclature

NMR Nuclear Magnetic Resonance

1H-NMR Proton Nuclear Magnetic Resonance

13C-NMR Carbon Nuclear Magnetic Resonance

s Singlet

d Doublet

dd Doublet of doublets

t Triplet

q Quartet

m Multiplet

δ Chemical shift

1

I NTRODUCTION

Amides are an important functional group in both medicinal and organic chemistry,¹ being relevant intermediates in the synthesis of natural and synthetic products.² Classical am- ide bond forming reactions commonly use stoichiometric or excess quantities of reagents,³ which compromises the sustainability of the catalysis has profoundly changed the synthetic protocols. Consequently, amide bond synthesis has evolved and recently several catalysed methods have been reported^4–6 , as sustainable alternatives to reduce environmental pollution, that occurs on a global scale.⁷

1.1 Amides - relevant groups in medicinal and synthetic chem- istry

An amide bond is a chemical bond established between a carboxylic acid group (- COOH) of one molecule and an amino group (-NH²) of another molecule. The peptide bond is an amide bond between two amino acids, being fundamental for the secondary structure of proteins and for their biological functions. Proteins are complex molecules responsible for many functions in the cell. The structure of proteins is fundamental for the function, and reg- ulation of the tissues and organs in the body.⁸ Since proteins play an important role in our biological system, advantage can be taken by manipulating peptides through chemical modi- fication.⁹

Despite their relevance for the structure of proteins, the amide group plays a crucial role in many biologically active molecules, from synthetic and naturally derived drug molecules, to clinically approved drugs. Thus, in medicinal chemistry, amides are highly attractive func- tional groups for the design of new drugs,³ constituting about a quarter of all drugs on the

40

market and two-thirds of drug candidates.¹⁰ Representative examples are lisinopril, an antihy- pertensive drug acting through inhibition the Angiotensin Converting Enzyme (ACE);¹¹ Tiapride, a benzamide compound, an antipsychotic used to treat Tourette's disorder and ag- gressiveness behaviour;¹² Penicillin G, that operates by blocking the formation of peptide bridges on gram-positive bacteria, antibiotic; ¹³ and ponatinib, for the treatment of leukemia.

(Scheme 1).¹⁴

Scheme 1. Examples of amide-containing drugs.

1.1.1 Polyamides - interesting polymers in drug delivery

Polyamides are an important class of polymers that are constitute by amide bonds link- ing in the repeating units.¹⁵ They are naturally present in several macromolecules composition, such as peptides and proteins. Polyamides exhibit thermal stability, high strength and elonga- tion, chemical resistance and biocompatibility¹⁶ make these polymers an attractive pathway in industry ranging from automotive industry¹⁷ and fibers¹⁸, to medical sector in drug-deliv- ery.^19,20

Drug-delivery systems is designated as a method of administering a drug with pharma- ceutical properties to attain a therapeutic effect.²¹ The principal aim of delivery strategy, is to maximize the bioavailability of the drug, by control the drug pharmacokinetics and physico- chemical properties, reducing the toxicity (to prevent possible side effects) and time-release control, in order to increase the drug activity at the target.²² In drug-delivery, poly(amino

acids) are widely used due to their similarity with natural proteins. For example, poly(lysine) is used as a delivery medium for small and macromolecule drugs; poly(glutamic acid) is ap- plied in preparation of nanoparticles of cisplatin for cancer treatment; and poly(α-L-aspartic acid) is widely used in gene and drug delivery (Scheme 2).²⁰

Scheme 2. Representative examples of polyamides in drug-delivery.

1.2 Amide Bond Synthesis

Undoubtedly, the amide bond is of utmost importance, found in a wide range of bioac- tive molecules which can naturally and synthetically prepared, as well as the main constituent of natural and synthetic polymers.²³

In biological systems, most amide bonds are synthesized at ribosomes. In contrast, syn- thetic chemists do not have access to the body's machinery. Synthetically, the most traditional method for the formation of an amide bond imply activation of a carboxylic acid (hydroxide ion is not a good living group), by a coupling agent, followed by nucleophilic displacement by a free amine to generate a new amide bond.²⁴

1.2.1 Classical methods for amide bond synthesis

Classical methods for amide bond synthesis include the well-established acid-catalyzed Schmidt reaction²⁵ and the Ritter reaction²⁶, among others. Furthermore, the Schotten–Bau- mann reaction,²⁷ that uses acid chlorides, as well as the Passerini²⁸ and the Ugi reaction²⁹ that use an isocyanide derivative also constitute excellent methodologies for the amide bond

42

synthesis. In addition, oximes can be used to establish amide bonds via Beckmann rearrange- ment³⁰ (Scheme 3).

Scheme 3. Common methods to synthesize amides.

Peter A. Smith reported one of the most traditional methodologies to prepare amides known as the Schmidt reaction (Scheme 3, a) in which carbonyl derivatives, such as aldehyde, ketone or carboxylic acids, react with an azide, under acidic conditions to give the amide.²⁵ Another classical method include the Schotten-Baumann reaction, first mentioned by Carl Shotten and Eugen Baumann, where amides are obtained by reacting an acid chloride with a primary or secondary amine, under basic conditions to neutralize the acid formed, and conse- quent protonation of the amide (Scheme 3, b).^27,31 An alternative synthetic methodology is the Beckmann rearrangement reported by Ernst O. Beckmann. This synthetic route involves the removal of the hydroxyl group of imine under acidic conditions, and an alkyl group migration to form a nitrilium species, followed by hydrolysis leading to amide bond formation (Scheme 3, d).³²

1.2.1.1 Ritter Reaction

Ritter reaction is also an important reaction to achieve amides. This reaction, first de- scribed by John Ritter et. al. in 1948²⁶, uses as substrate alcohols or olefins in the presence of

strong acids. A mechanism has been proposed as depicted in Scheme 4.³³ First, the hydroxyl group is protonated by the acid, generating a water molecule and subsequently leading to the formation of the corresponding carbocation, which is attcked by nitrile. The water molecule previously mentioned, will attack the carbon of nitrilium species leading to amide bond for- mation.

Scheme 4. Ritter reaction proposed mechanism.

This is a reliable method to synthesize amides, constituting an atom economic process, since the only by-product is water. Another important aspect is the use of less hazardous and commercially available reagents with environmental risks. What constitutes a disadvantage of the Ritter reaction is the use of stoichiometric quantities of a strong acid. For example, isofla- vonoids are associated with high anti-inflammatory and anti-cancer activity. In 2015, Iskander et al.,³⁴ proposed a single step synthesis of isoflavonoid derived compounds by employing Ritter reaction (Scheme 5). However, this procedure requires high concentrations of strong acids.

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Scheme 5. Isoflavonoids synthesis, reported by Iskandet et al.

Over the past few decades, modified versions of the classical Ritter reaction have emerged, becoming an environmental-friendly alternative. This can be illustrated briefly by a direct conversion of alcohols into corresponding amides via one-pot reaction, using perchlo- rates as electrophilic substrates instead of conventional organic compounds, applied in the synthesis of heterocyclic compounds, among others. ^35–37

1.2.1.2 Ugi Reaction

Initially described by Ivar Karl Ugi, the Ugi is a multi-component reaction requiring an aldehyde, a carboxylic acid, an isonitrile and an amine under mild conditions, and can be carried out in non-toxic solvents, such as water (Scheme 6).²⁹ Unlike the Ritter reaction, in the Ugi reaction polyamides can be formed. This one-pot reaction has been explored in the syn- thesis of monomers, polyamide’s building blocks, with biomedical applications such as, anti- bacterial activity.^38,39 There are numerous advantages of multicomponent reactions, as no pro- tecting groups are needed, while constituting a one-pot methodology, thus atom economic (maximize the reactant atoms and minimize the number of reactional steps to achieve the final product)⁴⁰, and high diversity in structure of the fragments.⁴¹

Scheme 6. Ugi reaction proposed mechanism.

Based on previous studies, a plausible mechanism is proposed as depicted in Scheme 6.^29,42 The synthetic route for this reaction involves: 1) Formation of the imine via nucleophilic attack of the amine to the aldehyde; 2) Protonation of the imine by the carboxylic acid; 3) trap- ping of the iminium ion by isocyanide, and the carboxylate previous formed; 4) Mumm rear- rangement (also known as a [1,3]O,N-acyl shift) which provides the polyamide product.^43,44

Fentanil is a synthetic opioid with analgesic properties. In 2018 Nami's group developed a library of new fentanil derivates via Ugi reaction (Scheme 7).⁴⁵ Some of these compounds revealed to be stronger activity than other fentanil derivates commercialized, like sufentanil and norsufentanil.^45,46

Scheme 7. Fentanil derivates synthesis using Ugi reaction.

Nevertheless, some of these methodologies produce by-products and use stoichiometric amounts of reagents, which are associated to environmental hazards. On the other hand,

46

alternative routes have been developed to increase the sustainability of amide bond formation, mainly focused on the catalytic amide bond formation.

1.2.2 Recent amidation approaches

In this context, Ana Santos et al. compiled recently, the most green and sustainable ap- proaches for amide bond synthesis.⁴ Boron chemistry, metal catalysts and metal-free processes appear as the more sustainable options.

1.2.2.1 Boron chemistry

Boron reagents are frequently applied as Lewis acids due to their strong electrophilic nature. Boron trihalides (BX³, X=F, Cl) are extremely efficient, but hard to handle because of volatile nature.⁴⁷ With the development of greener catalysts, boronic acids⁴⁸ and borate esters⁴⁹ have emerged. In 2014, Setcko reported a general procedure to synthesize lacosamide (an an- tiepileptic drug) that would avoid partial racemization during the O-methylation step (Scheme 8, A).⁵⁰ However, this synthesis involve six steps and use of highly toxic reagents, whereas its industrial scale production become less sustainable. In 2016, Lanigan et al. pub- lished a direct amidation in two steps by employing boron ester catalyst, B(OCH²CF³)³, (Scheme 8, B).⁵¹

Scheme 8. Lacosamide synthesis, reported by Stecko (A) and Lanigan et al. (B).

1.2.2.2 Metal catalysts

The use of metal catalysts for amide bond synthesis have appeared as a sustainable alternative to the common methods. Herein, the catalysts consist in transition-metal centre including, ruthenium (Ru), cobalt (Co), copper (Cu) and rhodium (Rh). Thus, manganese (Mn) and iron (Fe) have the advantage of being the most ample in earth and, at the same time, less expensive and non-toxic.^52,53 Metal catalysis is involved in several amidation transformations e.g., addition to unsaturated C-C bonds⁵⁴; intramolecular cyclization⁵⁵; and via C-H bond acti- vation. The latter has been explored to achieve organic molecules, such as natural and phar- maceutical products since the C-H bond are the most abundant organic constituent.⁵⁶ In 2020, Seagun Kim et al. reported a Rh-catalyzed C-H amidation of 2-aryl quinazolin-4(3H)-one deri- vates, with multiple pharmaceutical applications (Scheme 9).⁵⁷

Scheme 9. Amide synthesis using a rhodium-based complex reported by Seagun Kim et al.

48 1.2.2.3 Metal-free processes

Despite of the great success of amide formation with metal-mediated methods, there are some significant drawbacks on an industrial scale, for instance some of these metals are asso- ciated with high costs, need of harsh conditions and absence of air.⁵⁸ For this purpose, metal- free catalysts have been reported as a sustainable approach for amide synthesis. Sadu Raro et al. disclosed, in 2017, an oxidative amidation via one-pot metal-free process using I² and tert- butyl hydroperoxide (TBHP), by C-H bond cleavage (Scheme 10).⁵⁹

Scheme 10. Amide synthesis using THBP reported by Sado Raro et al.

Recently, besides catalysis, the reuse of natural substrates coming from renewable sources has been emerging a promising research field.

1.2.3 Synthesis of Polyamides

Traditionally polyamides are synthesized by condensation between amines and carbox- ylic acids. However, it is required a pre-activation of the carboxylic acid to convert into acyl chlorides⁶⁰, or activated by coupling reagents⁶¹, to be used later in polymer synthesis. These requirements show some significant drawbacks such as requirement of harsh conditions or production of toxic wastes.⁶²

In recent years, green methodologies emerged as an alternative to conventional ap- proaches. Poly(N-isopropylacrylamide) (PNIPAAm), a thermosensitive hydrogel, are widely applied in drug release.⁶³ In 2006, Aguiar-Ricardo has reported⁶⁴ the synthesis of PNIPAAm from N,N-methylenebisacrylamide (MBAM) and N-isopropylacrylamide (NIPA) under super- critical dioxide (scCO²) conditions (Scheme 11).

Scheme 11. Polyamide PNIPAAm synthesis employing scCO² reported by Aguiar-Ricardo.

At normal pressure CO² is a gas, although by reducing the pressure of the system, the separation step of solvent from the polymer becomes very easy, achieving high purity of the desired products.⁶⁴ The synthesized polymer with this green-solvent offer diverse advantages over traditional solvents, including non-toxicity, non-flammable, low costs and highly availa- ble.^64,65 scCO² have been widely employed in polyesters, polyurethanes, polyureas and poly- amides.⁶⁵ Other green alternatives to synthesize polyamides are multicomponent reactions (MCRs) including Ugi reaction, as previously mentioned.^66,67

Over the past years there have been an increasing concern about environmental prob- lems. Consequently, several researchers use bio-based compounds as a feedstock to synthesize polymers.^66,68,69

1.3 Biomass Valorization

Per year, biomass production reaches billion tons digits.⁷⁰ This involves some disad- vantages such as space requirements, harmful environmental impacts, and costs. This renew- able material emerged as an excellent alternative to non-renewable fossil fuels. The major bi- omass sources are animal residues, agricultural/forest residues, sullage, and aquatic crops, from both ground and aquatic biomass representing 1.8 billion tons and 4 billion tons, respec- tively.⁷¹

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Scheme 12. Major biopolymers from plant cell wall and respective main components.^72,73

Products derived from plant biomass are widely used in diverse fields such as agro- chemicals, fragrances, food, cosmetics, pharmaceuticals, chemical industry, etc.⁷⁴ Biomass is a complex bio-organic/inorganic solid produced by nature mainly composed by three essential biopolymers: 35-50% cellulose, 20-35% hemicellulose, and 10-25% lignin, which are found in the plant cell wall (Scheme 12).⁷⁵ Its composition varies according to the plant's source, method/date of cultivation, age or growth state, and storage.⁷⁶ Separation of these three mac- romolecules from the cell walls involves different separation methods such as: steam explo- sion (physicochemical process which uses saturated steam at high pressure injected into a batch/reactor for few minutes), organsolv (use of organic solvents possessing short chain ali- phatic alcohols, polyols, organic acids, acetone, dioxane and phenol), kraft (which requires high pressure and temperature in a sodium sulfide and sodium hydroxide), among others.^77–

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1.3.1 Lignin

As a source of aromatic compounds, lignin (Scheme 13) confers structural support and impermeability to the plant while providing high resistance against oxidative stress, and

microbiological attack. Structurally, lignin is composed of three major hydroxycinnamyl alco- hols monomers: p-hydroxyphenyl monomer (H), guaiacyl monomer (G), and syringyl mono- mer (S) (Scheme 13).^71,81,82

Scheme 13. Chemical structure of lignin.

Depolymerization of lignin can be performed by both biological and chemical meth- ods. Fragmentation through biologic methods involve enzymatic oxidation, where radical spe- cies are generated and extation of radical chain reactions occur, leading to cleavage of ether and C-C bonds.⁸³ The chemical methods, such as pyrolysis, use high temperatures leading to material degradation. However, this method needs an additional separation step due to low product selectivity.⁸⁴ Hydrogenation, is also a chemical method used to depolymerize lignin, which operates under mild conditions and uses hydrogen as reducing agent.⁸⁵ Alternative chemical approaches includes hydrolysis, oxidation and gasification.⁷¹ Finally, diverse aro- matic compounds such as benzene, toluene, xylene, phenol, and vanillin can be obtained from lignin.

1.3.2 Cellulose

Considered the most abundant organic compound in nature, cellulose confers stability to the plant structure.⁸⁶ Cellulose has the common formula (C⁶H¹⁰O⁵)ⁿ, and consists of a linear chain covalently bonded by glucose units through an oxygen bond from C¹ of one glucose to C⁴ of the following glucose molecule, called β 1→4 glycosidic bond, where degree of polymer- ization (n) can be n=10 000 to 15 000, depending on the cellulose source.⁸⁷ This linear and

52

fibrous structure is insoluble in water due to the van der Walls and hydrogen bonds estab- lished between hydroxyl groups of inter-chains, generating compact and extremely resistant fibrils.⁸⁸

Scheme 14. Structure of cellulose and its hydrolysis: synthesis of 5-Hydroxymehtylfurfural (5-HMF) and deri- vates.

Depolymerization of cellulose can be performed by hydrolysis reaction, either by en- zymatic hydrolysis under mild conditions or chemical hydrolysis using solid acid catalysts, which cleavage the β 1→4 glycosidic bond.^89,90 Hydrolysis of cellulose originates several prod- ucts, among them 5-hydroxymethylfurfural (5-HMF), is one of the most relevant, being formed by a triple dehydration of hexose sugars (Scheme 14). The 5-HMF is an important building block and precursor for the synthesis of bio-based compounds with different appli- cations, ranging from biofuels, solvents, platform chemicals, to the synthesis of monomers for polymer formation.⁹¹

1.3.3 Hemicellulose

Being the second most abundant organic compound in nature, hemicellulose is respon- sible for supporting the matrix of cellulose, which is linked by hydrogen bonds.^92–94

Unlike cellulose, hemicellulose is structurally more diverse due to variety of side-branch groups and carbohydrates which include arabinose, mannose, galactose, glucose, xylose, and glucuronic acid (Scheme 15).⁹⁵ The properties of this biopolymer make this structure less re- sistant than cellulose. Due to its acidic groups, water molecules are more easily attracted mak- ing this macromolecule more hygroscopic, and consequently more easily degradable than cel- lulose.⁹⁶

Scheme 15. Structure of hemicellulose (Xylan), with glucuronic acid (α 1→2) and arabinose (α 1→3) and its hy- drolysis: synthesis of furfural and derivates.

Conversion of hemicellulose into sugars can be conducted by enzymatic methods, hot water, or acid pre-treatment.^97,98 Several products are obtained from the hydrolysis of hemicel- lulose, among them is furfural, obtained from hemicellulose through acid catalysed dehydra- tion of xylose (Scheme 15). This heterocycle, an aromatic aldehyde, is the starting material to synthesize diverse molecules with several application such as, pharmaceutics, pesticide activ- ities, industrial solvents, productions of resins and polymers.⁹¹

Biomass based monomers are not the only by-product derived from degradation pro- cesses of biomass, biochar is also generated. This by-product is a carbon-rich material orga- nized and hoarded by aromatic carbon rings, produced by thermal decomposition of lignocel- lulosic biomass and other organic materials.^99,100 However, new alternative strategies have been developed to reclaim this side product with important applications in nanocatalysis.^101,102

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1.4 Homogeneous, heterogeneous catalysis and nanocatalysis

Catalysis is a pillar of green chemistry and a powerful tool in organic synthesis. Since catalysis is the key for chemical and biological transformations, during the last decades signif- icant efforts have been made to improve the use of catalysts in chemical transformations. Het- erogeneous and homogeneous catalysis, both present advantages and disadvantages. In the homogeneous catalysis, all the reagents are in the same phase most often the liquid phase. ^103,104 Homogeneous catalysis is associated with high selectivity and mild reaction conditions. How- ever, despite of the high selectivity presented by homogeneous catalysts, often there are issues associated with the difficult separation and recycling of the catalyst from the reactional media.

In addition, some homogeneous catalysts are poorly stable, expensive, and some present high toxicity.^105,106 In contrast, heterogeneous catalysis has attracted much attention, offering several advantages, ranging from high surface area and nanosize, to their rapid separation and recov- ery through filtration/centrifugation, (re)activated and be used for further reactions, while maintaining their selectivity in chemical reactions. Unfortunately, some heterogeneous cata- lysts also require long reaction time and are less active than homogeneous catalysis.¹⁰⁶

Nano catalytic systems combine the positive aspects of homogeneous and heterogene- ous catalysts, such as selective and efficient chemical transformations, more stable, easily re- coverable and eco-friendly (Scheme 16).¹⁰⁷ Nanocatalysts are composed by nanoparticles sized between 1-100 nm.¹⁰⁸ Aluminium, iron, carbon nanotubes, clays and silica materials have been extensively used as a support in nanocatalysts in the past years.^106,109 Their nano size and high surface area, led to a high contact with the reactants.¹⁰⁷ Nanocatalysts have been widely ap- plied in a wide range of areas, such as hydrogen production, organic synthesis, CO² reduction, air purification systems, and biomass conversion.^110–114

Scheme 16. Distinction of homogeneous, heterogeneous and nanocatalysis.

1.4.1 Clays: K10, Halloysite (HNT) and Cloisite (CLOI)

Clays occur naturally in soil. Prevenient from a very abundant source, clays are consti- tuted by layers with negative charges which are neutralized by cations, for example Na⁺, K⁺ and Ca⁺, between each lamellar structure. Whereas these ions can be replaced by other mole- cules covalently bonded to the surface, modifying the properties of the clays, including the surface area, polarity and acidity.¹¹⁵ The most ordinary clay used in organic synthesis is the montmorillonite type, where the basic unit structure is an octahedral aluminate sheet sand- wiched between two tetrahedral silicate sheets (1:2).^116,117 K10 catalyst, are broadly used in di- rect amidation reaction of carboxylic acids (Scheme 17)¹¹⁸, in the synthesis of benzimidazoles derivatives,¹¹⁹ etc.^120,121 Other montmorillonite type are Cloisite (CLOI). Similarly to K10, the basic unit structure of CLOI is mainly composed by silicon and aluminium sheets with a ratio 2:1 in Si/Al, whereas alumina sheets assume octahedral structure between two tetrahedral sheets of silica.¹²²

Scheme 17. Amidation reaction using K10 as catalyst by Kumar et al.

Halloysite (HNT) is also a clay material constituted by one octahedral aluminate sheet and two tetrahedral silicate sheets (1:1).¹²³ Besides organic synthesis,¹²⁴ HNT have other

Homogeneous Catalysis

Pros:

High selectivity More active Mild conditions Shorter reaction time

Cons:

Less stable High toxicity Difficult to recover

Nano Catalysis More stable

Non-toxic Recoverable

Reusable Selectivity

+active

Heterogeneous Catalysis

Pros:

Non-toxic Easily recoverable

Reusable More stable

Cons:

Less activity Long rection time

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applications. The fact that lumen space ranging from 5 to 70 nm, it is possible to carrying drugs and agents for drug-delivery.¹²⁵

The performance of this catalysts can be affected when it is treated with strong acids to functionalize the support. The layers of the clay structure can be affected, which may affect the efficiency of these catalysts.^116,123

1.4.2 Biochar (Bio)

Biochar is a solid residue produced from thermochemical conversion of lignocellulosic biomass. The performance of this catalyst depends on the raw material and the conditions that led to its formation.¹²⁶ This type of catalyst can be obtained through thermochemical tech- niques such as pyrolysis, carbonization, and gasification.⁹⁹ Biochar is inexpensive and an en- vironmentally benign catalyst, that can be functionalized by surface sulfonation, surface ami- nation or surface oxidation. ¹²⁷ Biochar catalyst exhibit high performance in a wide range of chemical transformations, such as acid-catalyzed chemical reactions, for example in etherifi- cation reactions (Scheme 18), biodiesel production, and hemicellulose hydrolysis using bio- char-derived catalyst. 124,128,129

Scheme 18. Etherification of 5-HMF with t-butanol catalyzed by biochar with p-toluenesulfonic group (CSP) an- chored to the catalyst surface by Peixoto et al.

1.4.3 Multi Wall Carbon Nano Tubes (MWCNT)

Due to the excellent mechanical, thermal, and electrical properties, MWCNT offer some advantages over other nanocatalysts. This catalyst exhibits a single or multiple graphene layers rolled into cylinders.¹³⁰ MWCNT present additional advantages which include their na- nosize and well-defined structure and homogeneous composition.¹³¹ Due to their nature CNT are insoluble in most organic and aqueous solvents, resulting in agglomeration due to van der Walls force between the nano tubes of the catalyst. As a result, functionalization of the surface is required. To improve the solubility of this catalyst, direct covalent functionalization is pre- ferred, however, this can modify the original structure and properties of CNT.¹³²

In the past years, green methodologies have been reported with MWCNT-functionalized in chemical transformations to overcome the classical catalyst with associated hazards (Scheme 19).¹³³

Scheme 19. One-pot multicomponent condensation reaction among benzaldehyde, naphthol, and benzamide cat- alyzed by MWCNT-SO³H catalyst by Ahmadi et al.

In this section, the biological and synthetic relevance of amides was presented. Most of traditional methodologies to prepare this functional groups are non-environmentally friendly, presenting some significant drawbacks. In order to overcome the issues associated with the traditional synthesis of amides and improve the sustainability in the synthesis of amides, al- ternative catalytic methods have been explored. In the field of catalysis, nanocatalysis has an important role, in particular the use of nanocatalysts derived from biomass promises great potential and has been rarely explored in the synthesis of amides.

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2

D ISCUSSION AND R ^ESULTS

2.1 Background and objetives

Amides are important and robust functional groups, being present in many natural and synthetic molecules. Small molecule drugs possessing an amide group are able to establish interactions with biomolecules and many marketed drugs possess an amide group. In addi- tion, amides are also the crucial functional group in natural and synthetic polyamides, the most important families of polymers. Classical amide bond synthesis involves the condensa- tion of an amine with an activated carboxylic acid. However, this reaction requires stoichio- metric amounts of reagents in order to activate the carboxylic acid moiety. In this context, nanocatalysis has emerged as a promising and greener alternative.124,134–136

The main aim of this Master thesis was to explore the sysnthesis of amides catalysed by biomass-derived catalysts, in order to provide a synthetic environmentally friendly and atom- economical route to achieve amides, that could later be applied in polymerization reactions.

The Ritter reaction was selected, as amides can be attained from alcohols and nitriles, under acid catalysis.³³

Peixoto et al. have recently disclosed new natural clays, multiwalled carbon nano tubes (MWCNTs) and biomass-based catalysts, functionalized with sulfonic groups.¹²⁴ Thus, this work started with the screening of different heterogeneous catalysts developed by Peixoto et al. and their efficiency compared to traditional organic acid catalysts, such as para-toluenesul- fonic acid (p-TSA). Our aim was to apply these catalysts to convert biomass-derived alcohols, such as furfuryl alcohol (FA) into amides, using the Ritter reaction. In a second part of the project, it was planned to test the formation of amides under supercritical CO² (scCO²) condi- tions, a green alternative to conventional solvents, to achieve polyamides using 2,5-bis(hy- droxymethyl)furan (BHMF). General scheme is summarized in Scheme 20.

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Furfuryl Al cohol

Scheme 20. General scheme comprising the principal aims of this master thesis.

2.2 Nanocatalysis - A New Approach for Amide Synthesis from Ritter Reaction

2.2.1 Amide synthesis via 1-phenylethanol - Finding the optimal conditions

Ritter reaction can occur among alcohols or olefins and nitriles under acidic conditions.

When olefins are used as substrates, require an additional step to achieve the amide. With this in mind, we initiated our experiments by employing 1-phenylethanol and acetonitrile as model molecules. The first aim was to find the best nanocatalyst to perform the Ritter reaction using the model substrates, and later apply to different biomass-derived alcohols that could be further used in polymerization reactions. Thus, concerning the catalyst, control experiments were carried out with p-toluenesulfonic acid monohydrate (p-TSA^.H²O) (Scheme 21), due to the similarity with p-toluenesulfonic group (CSP) anchored to catalyst surface prepared at Peixoto Lab. Thus, guided by some previous reported conditions^33,134, we started the screening of the catalyst.

Scheme 21. Amide formation from 1-phenylethanol and acetonitrile, catalyzed by p-TSA^.H²O. Reaction condi- tions: 1-phenylethanol (0.33 mmol), acetonitrile (solvent, 1 mL), p-toluenesulfonic acid monohydrate (10 mol%).

The reaction was monitored by TLC, and 1 hour after, the TLC of the crude revealed a remarkable spot at R^f 0.17 by using UV light and phosphomolybdic acid stain (visible blue spot). After reaction completion, the product was isolated, and characterized by NMR and IR which proved the presence of amide (Spectrum 6, 7 and 8 Appendix). We also investigated the same reaction with dry p-TSA to see the influence of the water, and approximately the same yield, 72%, was achieved (Table 2, entry 11).

Besides the amide, it was detected by TLC another slightly spot at R^f 0.94 with the same eluent.

Previous studies,³³ report that under acidic conditions, 1-phenylethanol dimerizes to bis(1- phenyl)ether. The presence of this side product was established by ¹H NMR (Spectrum 9, Appendix). A possible mechanism is presented in Scheme 22. When carbocation species is

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generated, is subsequently trapped by other 1-phenylethanol molecule leading to the for- mation of ether.

Scheme 22. Possible mechanism for bis(1-phenyl)ether formation.

With these results in hands, by following the outlined synthetic plan, we initiated the screening of different heterogenous catalysts with 1-phenylethanol and compared their effi- ciency with p-TSA^.H²O.

2.2.2 Screening of Different Nanocatalysts

Catalysts prepared at Peixoto Lab, containing acidic functionalities were next investi- gated using the conditions used in the model reaction (Scheme 21). The addition of CSA (chlorosulfonic acid) group on materials can be conduct by employing direct sulfonation with H²SO⁴ or ClSO³H¹³⁷, while the CSP (2-(4-chlorosulfonylphenyl)ethyltrimethoxysilane) func- tionality were prepared with CSPTMS (2-(4-chlorosulfonylphenyl)ethyltrimethoxysilane).¹³⁴ Catalysts characterization are represented in Table 1.

Table 1. Representation and characteristics of nanocatalysts.

Material

Specific surface area

(m²/g)

V^pore (cm³/g)

Acidity (mmol H⁺/g)

K10-CSA 38 0.162 5.84

K10-CSP 155 0.245 0.80

CLOI-CSA 13 0.03 1.78

CLOI-CSP 5 0.049 0.88

Bio-CSA 129 0.088 0.33

Bio-CSP 113 0.061 0.98

HNT-CSP 10 0.075 0.82

MWCNT-CSP 181 0.47 0.40

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We initiated our experiments by employing 1-phenylethanol and acetonitrile for screening different nanocatalysts, prepared by Peixoto et al. and compared their efficiency with p-TSA^.H²O (Table 2, entry 10).

Table 2. Results obtained for catalysts screening.

Entry Catalyst Yield (%)

1 K10-CSA 34

2 K10-CSP 37

3 Bio-CSA 52

4 Bio-CSP 58

5 CLOI-CSA 54

6 CLOI-CSP 56

7 HNT-CSA 41

8 HNT-CSP 49

9 MWCNT-CSP 75

10 p-TSA^.H2O 73

11 p-TSA 72

Reaction conditions: 1-Phenylethanol (0.33 mmol), acetonitrile (solvent, 1 mL) and catalyst (50 mg).

All catalyst afforded amide in moderate to good yields. Higher conversions were ob- served for catalysts bearing a p-toluenesulfonic group (CSP) anchored to the catalyst surface (Table 2, entries 2, 4, 6, 8 and 9), rather than the sulfonic group (CSA) (Table 2, entries 1, 3, 5 and 7). This can be explained by the affinity of tolyl group with aromatic ring from 1-phe- nylethanol.¹³⁸ MWCNT-CSP showed to be the best catalyst affording the correspondent amide in 75% yield (Table 2, entry 10). As once the same experiment was performed using p-TSA^.H²O as catalyst, the target molecule was achieved with a slightly lower yield then MWCNT-CSP, 73% (Table 2, entry 10). As we can see in table 1, MWCNT-CSP possesses a higher surface of contact (181 m²/g) and pore volume (0.47 cm³/g), thus facilitating the access of substrate, and consequently protonation of the alcohol. Here the protons are widely dispersed onto support