AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER
Oct 172017
 

DOI: 10.1039/C7GC02521A, Tutorial Review
M. Rabnawaz, I. Wyman, R. Auras, S. Cheng
Approximately 99% of the plastics used in the packaging industry today are petroleum-based. However, the adoption of biobased plastics could help to greatly reduce the environmental footprint of packaging materials and help to conserve our non-renewable petroleum resources. This tutorial review provides an overview of renewable polyesters and their potential packaging materials.

A roadmap towards green packaging: the current status and future outlook for polyesters in the packaging industry

 Author affiliations

Muhammad Rabnawaz

Assistant Professor

Muhammad Rabnawaz

rabnawaz@msu.edu
Telephone: 517-432-4870


Rabnawaz’s Research Group
School of Packaging

Shouyun Cheng at Michigan State University

Shouyun Cheng

Doctor of Philosophy
Research Associate
Michigan State University
East Lansing, MI, United States

Dr. Cheng earned his PhD from South Dakota State University in May 2017. He has extensive research experiences in biomass pyrolysis and liquefaction, bio-oil catalytic cracking and hydrodeoxygenation, catalyst design, preparation, characterization and evaluation, food extruding, nano cellulose and protein peptides production, polymer synthesis, characterization and application.

Project Titles worked on: Innovation for Improved Sustainability: Scalable Approach for the Preparation of Thermoplastic Starches and their Composites for Applications in Biodegradable Packaging .

Duration in the group: August 2017- Present

Areas of Interest: Polycarbonates and polyesters synthesis, characterization and application.

MSU email Id: chengsho@msu.edu

Ian Wyman

Education: Ph.D., Queen’s University, Kingston, Ontario
M.Sc., St. Francis Xavier University, Antigonish, Nova Scotia
B.Sc. Chemistry, Dalhousie University, Halifax, Nova Scotia

Email: wymani@chem.queensu.ca

Abstract

Approximately 99% of the plastics produced today are petroleum-based, and the packaging industry alone consumes over 38% of these plastics. In this review, we argue that renewable polyesters can provide a key milestone as renewable plastics in the route toward green packaging. This review describes different classes of polyesters with particular regard to their potential use as packaging materials. Some of the families of polyesters discussed include poly(ethylene terephthalate) and its renewable analogs, poly(lactic acid), poly(hydroxyalkanoates), and poly(epoxy anhydrides). The synthesis of polyesters is discussed from a green chemistry perspective. A structure–property correlation among the various polyesters is also discussed. The challenges that currently hinder the widespread adoption of polyesters as leading packaging materials are reviewed. The environmental footprint and end of life scenario of polyesters are discussed. Finally, future research directions are summarized as a possible roadmap towards the widespread adoption of renewable polyesters as sustainable packaging materials.

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Muhammad Rabnawaz

Assistant Professor

Muhammad Rabnawaz

rabnawaz@msu.edu
Telephone: 517-432-4870

Michigan State University white graphic


Rabnawaz’s Research Group
School of Packaging


Research Interests

I have published more than 20 research articles in the field of polymer and materials sciences. Our initial endeavors can be divided into three broad categories:

  1. Polymer synthesis from renewable feedstocks.
  2. Design and preparation of smart materials.
  3. Polymer composites.

Our projects are highly applied, and we expect close collaboration with world-leading industries. These partnerships will offer unique training and career opportunities for the group members.

Experience

  • Assistant Professor, School of Packaging, Michigan State University (2016-currrent)
  • Postdoctorate, University of Illinois, Urbana-Champaign, 2015-2016
  • Postdoctorate, Queen’s University, Canada, 2013-2015

Education

  • Ph.D., Chemistry, Queen’s University, Canada, 2013
  • M.Sc., Chemistry, University of Peshawar, Pakistan, 2004

 

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Oct 162017
 

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Diethyl Isosorbide (DEI): []D 20 +95.9 (c 1, in MeOH);

1H NMR (400 MHz; CDCl3; Me4Si):  4.63 (t, J = 4.2 Hz, 1H, H-4), 4.51 (d, J = 4.1 Hz, 1H, H-3), 4.06–3.90 (m, 5H, H- 1, H-2, H-5, H-6), 3.80–3.69 (m, 1H, CH2-OC-5), 3.63–3.49 (m, 4H, H-6, CH2-OC-5, CH2- OC-2), 1.23 ppm (dt, J = 17.8, 7.0 Hz, 6H, CH3CH2O-C-2, CH3CH2O-C-5);

13C NMR (101 MHz; CDCl3; Me4Si):  86.57 (C-3), 84.45 (C-2), 80.36 (C-5), 80.27 (C-4), 73.64 (C-1), 69.81 (C-6), 66.28 (CH2-O-C-5), 65.24 (CH2-O-C-2), 15.49 ppm (CH3-CH2OC-5), 15.44 (CH3-CH2OC-2);

MS (70 eV): m/z 202 (M+ , 6%), 157 (1), 113 (17), 89 (33), 69 (100), 57 (11), 44 (39).

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Oct 162017
 

 

 

Green Chem., 2017, Advance Article
DOI: 10.1039/C7GC01912B, Tutorial Review
C. Dussenne, T. Delaunay, V. Wiatz, H. Wyart, I. Suisse, M. Sauthier
This review gives an overview of the catalysts and technologies developed for the synthesis of isosorbide, a platform molecule derived from biomass (sorbitol and cellulose).

Synthesis of isosorbide: an overview of challenging reactions

 Author affiliations

Abstract

Isosorbide is a diol derived from sorbitol and obtained through dehydration reactions that has raised much interest in the literature over the past few decades. Thus, this platform chemical is a biobased alternative to a number of petrosourced molecules that can find applications in a large number of technical specialty fields, such as plasticizers, monomers, solvents or pharmaceuticals. The synthesis of isosorbide is still a technical challenge, as several competitive reactions must be simultaneously handled to promote a high molar yield and avoid side reactions, like degradation and polymerization. In this purpose, many studies have proposed innovative and varied methods with promising results. This review gives an overview of the synthesis strategies and catalysts developed to access this very attractive molecule, pointing out both the results obtained and the remaining issues connected to isosorbide synthesis.

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Up to now, isosorbide has been used to access a large panel of molecules with relevant applicative properties and industrial reality (Scheme 2).12 Isosorbide dinitrate is used since several decades as vasodilator.13, 14 The dimethyl isosorbide is for example used as solvent in cosmetics15-17 and isosorbide diesters18-22 are actually industrially produced and commercialized as surfactants23-27 and PVC plasticizer28, 29 . The rigid scaffold associated to the bifunctionality of the molecule has attracted a strong interest in the field of polymers chemistry. Isosorbide and derivatives have thus been shown as suitable monomers for the industrial production of polycarbonates30, 31, polyesters32-41 or polyamides42-44, with attractive applicative properties. For example, isosorbide allows the increase of Tg, improves the scratch resistance and gives excellent optical properties to polymers. Polyesters and polycarbonates containing isosorbide have now commercial developments in food packaging, spray container, automotive, material for electronic devices … .

Conclusions

Isosorbide is a versatile platform molecule that shows key features to make it a credible alternative to petro-based products. The molecule is already available on large industrial scale (tens of thousands tons per years), which allows its development in commercial products such as active pharma ingredient, additive for cosmetic, speciality chemicals and polymers (ex: polycarbonates – polyesters). The development of more selective and higher yields syntheses of isosorbide are greatly needed to consolidate isosorbide production in view of a large expansion of its uses. Sorbitol conversion to isosorbide, relying on a starch route, is already a tough challenge. In a farther future, development of a credible path to isosorbide relying on cellulose source could even be thought of, provided that very versatile innovative catalysts will be developed in the next years. In all cases, a key issue is to develop catalysts that will avoid the massive production of “oligomeric/polymeric” by-products in order to access more sustainable processes by limiting the amounts of wastes produced during the synthesis. For this purpose, more selective homogeneous catalysts than the conventional Brønsted acids or alternative reaction conditions would be of strong interest. Selective and recyclable heterogeneous catalysts would be even more profitable as they would allow the continuous production of catalyst free isosorbide. This latter approach faces strong limitations due to the need of high reaction temperatures that often result in high amounts of side-products and the need of frequent and often tedious catalyst regeneration. Innovation concerning isosorbide synthesis is still an open field on which the design of efficient and robust catalysts, either homogeneous or heterogeneous, is a key issue. Such developments would pave the way to high scale effective processes considering altogether synthesis and purification of isosorbide.

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Isosorbide is a heterocyclic compound that is derived from glucose. Isosorbide and its two isomers, namely isoidide and isomannide, are 1,4:3,6-dianhydrohexitols. It is a white solid that is prepared from the double dehydration of sorbitol. Isosorbide is a non-toxic diolproduced from biobased feedstocks, that is biodegradable and thermally stable. It is used in medicine and has been touted as a potential biofeedstock.

Production

Hydrogenation of glucose gives sorbitol. Isosorbide is obtained by double dehydration of sorbitol:

(CHOH)4(CH2OH)2 → C6H10O2(OH)2 + 2 H2O

An intermediate in the dehydration is the monocycle sorbitan.[1]

Application

Isosorbide is used as a diuretic, mainly to treat hydrocephalus, and is also used to treat glaucoma.[2] Other medications are derived from isosorbide, including isosorbide dinitrate and isosorbide mononitrate, are used to treat angina pectoris. Other isosorbide-based medicines are used as osmotic diuretics and for treatment of esophageal varices. Like other nitric oxide donors (see biological functions of nitric oxide), these drugs lower portal pressure by vasodilation and decreasing cardiac output. Isosorbide dinitrate and hydralazineare the two components of the anti-hypertensive drug isosorbide dinitrate/hydralazine (Bidil).

Isosorbide is also used as a building block for bio based polymers such as polyesters.[3]

References

  1. Jump up^ M. Rose, R. Palkovits (2012). “Isosorbide as a Renewable Platform chemical for Versatile Applications—Quo Vadis?”. ChemSusChem5 (1): 167–176. PMID 22213713doi:10.1002/cssc.201100580.
  2. Jump up^ CID 12597 from PubChem
  3. Jump up^ Bersot J.C. (2011). “Efficiency Increase of Poly (ethylene terephthalate‐co‐isosorbide terephthalate) Synthesis using Bimetallic Catalytic Systems”. Macromol. Chem. Phys212 (19): 2114–2120. doi:10.1002/macp.201100146.
Isosorbide
Isosorbide.svg
Names
Other names

D-Isosorbide; 1,4:3,6-Dianhydro-D-sorbitol; 1,4-Dianhydrosorbitol
Identifiers
3D model (JSmol)
ChemSpider
ECHA InfoCard 100.010.449
KEGG
PubChem CID
UNII
Properties
C6H10O4
Molar mass 146.14 g·mol−1
Appearance Highly hygroscopic white flakes
Density 1.30 at 25 °C
Melting point 62.5 to 63 °C (144.5 to 145.4 °F; 335.6 to 336.1 K)
Boiling point 160 °C (320 °F; 433 K) at 10 mmHg
in water (>850 g/L), alcoholsand ketones
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

From the net

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1H Nuclear magnetic resonance (NMR) spectra of PTMG, isosorbide, HDI, and polyurethane.HDI: hexamethylene diisocyanate; PTMG: poly(tetramethylene glycol).

1H Nuclear magnetic resonance (NMR) spectra of PTMG, isosorbide, HDI, and polyurethane.HDI: hexamethylene diisocyanate; PTMG: poly(tetramethylene glycol).

 

Image result for ISOSORBIDE SYNTHESIS

REF

http://www.rsc.org/suppdata/gc/c4/c4gc01822b/c4gc01822b1.pdf

Synthesis of five- and six-membered heterocycles by dimethyl carbonate with catalytic amount of nitrogen bicyclic bases

http://pubs.rsc.org/en/content/articlelanding/2015/gc/c4gc01822b#!divAbstract

F. Aricò, a,*S. Evaristoa and P. Tundoa,*

Catalytic amount of a nitrogen bicyclic base, i.e., DABCO, DBU and TBD is effective for the one-pot synthesis of heterocycles from 1,4-, 1,5-diols and 1,4-bifunctional compounds via dimethyl carbonate chemistry under neat conditions. Nitrogen bicyclic bases, that previously showed to enhance the reactivity of DMC in methoxycarbonylation reaction by BAc2 mechanism, are herein used for the first time as efficient catalysts for cyclization reaction encompassing both BAc2 and BAl2 pathways. This synthetic procedure was also applied to a large scale synthesis of cyclic sugars isosorbide and isomannide starting from D-sorbitol and D-mannitol, respectively. The resulting anhydro sugar alcohols were obtained as pure crystalline compounds that did not require any further purification or crystallization.

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Larger scale synthesis of isosorbide: In a round bottom flask equipped with a reflux condenser, D-sorbitol (0.05 mol, 1.00 mol. eq.), DMC (0.44 mol, 8.00 mol. eq.), DBU (2.70 mmol, 0.05 mol. eq.) and MeOH (20.00 mL) were heated at reflux while stirring. The progress of the reaction was monitored by NMR. After 48 hours the reaction was stopped, cooled at room temperature and the mixture was filtered over Gooch n°4. Finally, DMC was evaporated under vacuum and the product was obtained as pure in 98% yield (7.90 g, 0.05 mol). Characterization data were consistent with those obtained for the commercially available compound.

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File:Isosorbide dinitrate synthesis.png

 

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Oct 162017
 

 

io

Renzo Luisi Ph.D.

Professor of Organic Chemistry
email: 
renzo.luisi@uniba.it

tel. +39-080-5442762

fax. +39-080-5442539

Address: Via E. Orabona, 4

70125 Bari – Italy

logo-uniba

Leonardo Degennaro at Università degli Studi di Bari Aldo Moro

Contribution of microreactor technology and flow chemistry to the development of green and sustainable synthesis

How to cite this article:
Fanelli, F.; Parisi, G.; Degennaro, L.; Luisi, R. Beilstein J. Org. Chem. 2017, 13, 520–542. doi:10.3762/bjoc.13.51

Department of Pharmacy – Drug Sciences, University of Bari “A. Moro”, FLAME-Lab – Flow Chemistry and Microreactor Technology Laboratory, Via E. Orabona 4, 70125, Bari. Italy

  1.  Corresponding author email

This article is part of the Thematic Series “Green chemistry”.

Guest Editor: L. Vaccaro
Beilstein J. Org. Chem. 2017, 13, 520–542. doi:10.3762/bjoc.13.51
Received 14 Nov 2016, Accepted 20 Feb 2017, Published 14 Mar 2017

Abstract

Microreactor technology and flow chemistry could play an important role in the development of green and sustainable synthetic processes. In this review, some recent relevant examples in the field of flash chemistry, catalysis, hazardous chemistry and continuous flow processing are described. Selected examples highlight the role that flow chemistry could play in the near future for a sustainable development.

Keywords: flash chemistry; flow chemistry; green chemistry; microreactor technology; sustainable synthesis

 

Introduction

Green chemistry’s birth was driven by the necessity to consider and face the urgent question of sustainability. Chemical production concerns an extended range of fields such as textiles, construction, food, cosmetic components, pharmaceuticals and so forth. An innovative approach to the chemistry world requires new strategies and criteria for an intelligent chemistry. It is understood that all this matter has big implications in economy and politics. Recent studies predicted a growth of green chemical processing up to $100 billion in 2020 (Pike Research study) [1]. All this offers important and arduous challenges expressed in terms of new synthetic strategies using sustainable, safe, and less toxic materials. On green chemistry we can read Paul Anastas and John Warne’s 12 principles, set up in 1998, which illustrate the characteristics of a greener chemical process or product [2]. Microreactor technology and flow chemistry could play a pivotal role in the context of sustainable development. In fact, flow chemistry is becoming a new technique for fulfilling several of the twelve green chemistry principles. The microreactor approach, could provide protection, preserves atom economy, guarantees less hazardous chemical synthesis and allows the use of safer solvents and auxiliaries. Furthermore, it pushes towards designing of chemistry with a lower environmental and economic impact, enhance the importance of catalysis, allows real-time analysis for pollution prevention and provides inherently safer chemistry (Figure 1[3]. Without claiming to be exhaustive, in this review we report recently published representative synthetic applications that demonstrate the growing contribution of flow chemistry and microreactor technology in green and sustainable synthesis [4-7].

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Figure 1: Microreactor technologies and flow chemistry for a sustainable chemistry.

 

 

Review

 

Flow microreactors: main features

The peculiar properties of microreactors [8] derive from their small size and can be ascribed mainly to the following characteristics: a) fast mixing: in a flow microreactor, in striking contrast to batch conditions, mixing takes place by molecular diffusion so that a concentration gradient can be avoided; b) high surface-to-volume ratio: the microstructure of microreactors allows for a very rapid heat transfer enabling fast cooling, heating and, hence, precise temperature control; c) residence time: it is the period of time the solution of reactants spend inside the reactor, and it gives a measure of the reaction time. The residence time is strictly dependent on the characteristics of the reactor (i.e., length of the channels, volume), and on the flow rate. The residence time is one of the crucial factors to be considered in optimizing flow reactions, especially when unstable or short-lived reactive intermediates are concerned. Microreactor technology provides also several benefits. Safety benefits, because of the high efficiency in heat exchange, and avoided accumulation of unstable intermediates. Economy benefits, due to lower manufacturing and operating costs, reduced work-up procedures, use of less raw materials and solvents and reduced waste. Chemistry benefits associated to the use of microreactor technology are the improved yields and selectivities, the possibility to conduct reactions difficult or even impossible to perform in batch, and the use of reaction conditions that allow exploring new chemical windows [9].

 

Contribution of flash chemistry to green and sustainable synthesis

The concept of flash chemistry as a “field of chemical synthesis using flow microreactors where extremely fast reactions are conducted in a highly controlled manner to produce desired compounds with high selectivity” was firstly introduced by Yoshida [10]. Flash chemistry can be considered a new concept in both organic and sustainable synthesis involving chemical transformations that are very difficult or practically impossible to conduct using conventional batch conditions. With the aim to show how flow microreactor technology and flash chemistry could contribute to the development of a sustainable organic synthesis, very recent examples have been selected and will be discussed here. In the context of green chemistry [11], protecting-group free organic synthesis has received particular attention in the last years, because of atom economy [12-15] and reduction of synthetic steps [16]. It has been demonstrated by Yoshida that protecting-group-free synthesis could be feasible using flash chemistry and microreactor technology [17,18]. Recently, Yoshida and co-workers developed flash methods for the generation of highly unstable carbamoyl anions, such as carbamoyllithium, using a flow microreactor system [19]. In particular, they reported that starting from different substituted carbamoyl chloride 1 and lithium naphthalenide (LiNp) it was possible to generate the corresponding carbamoyllithium 2, that upon trapping with different electrophiles provided several amides and ketoamide 3(Scheme 1).

[1860-5397-13-51-i1]

Scheme 1: A flow microreactor system for the generation and trapping of highly unstable carbamoyllithium species.

The use of an integrated microflow system allowed the preparation of functionalized α-ketoamides by a three-component reaction between carbamoyllithium, methyl chloroformate and organolithium compounds bearing sensitive functional groups (i.e., NO2, COOR, epoxide, carbonyl) (Scheme 2).

[1860-5397-13-51-i2]

Scheme 2: Flow synthesis of functionalized α-ketoamides.

It should be stressed that this kind of sequential transformations are practically impossible to perform using conventional batch chemistry because of the incompatibility of sensitive functional groups with organolithiums, and because of the high chemical and thermal instability of the intermediates.

In 2015 Yoshida reported another remarkable finding on the use of protecting-group-free organolithium chemistry. In particular, the flash chemistry approach was exploited for generating benzyllithiums bearing aldehyde or ketone carbonyl groups [20]. This reaction could be problematic for two reasons: a) the competing Wurtz-type coupling, (i.e., the coupling of benzyllithiums with the starting benzyl halides); b) the nucleophilic attack of organolithium species to aldehyde or ketone carbonyl groups (Scheme 3).

[1860-5397-13-51-i3]

Scheme 3: Reactions of benzyllithiums.

The authors reported that the extremely fast micromixing avoided undesired Wurtz-type coupling [21,22]. It is well known, that competitive reactions can be controlled or even avoided under fast micromixing [23-27]. Moreover, high-resolution residence time control was essential for survival of carbonyl groups. In fact, this transformation can be achieved only with a residence time of 1.3 ms at −78 °C. Under these flow conditions, the aldehyde or ketone carbonyl moiety can survive the nucleophilic organolithium attack. Remarkably, the flow microreactor system allowed also the generation of benzyllithiums at 20 °C, rather than under cryogenic (−95 °C) conditions adopted with a conventional batch protocol. In addition, THF could be used in place of mixed solvents (Et2O/THF/light petroleum). Under the optimized conditions, the reactions of benzyllithiums with different electrophiles, gave adduct products in good yields (Scheme 4).

[1860-5397-13-51-i4]

Scheme 4: Trapping of benzyllithiums bearing carbonyl groups enabled by a flow microreactor. (Adapted with permission from [18], copyright 2015 The Royal Society of Chemistry).

Another useful aspect of the flash chemistry relies on the possibility to generate highly reactive intermediates, such as halomethyllithium carbenoids, that need to be used under internal-quenching technique in batch mode. In 2014, the first example of effective external trapping of a reactive chloromethyllithium (CML) has been reported [28]. α-Haloalkyllithiums are a useful class of organometallic reagents widely employed in synthetic chemistry. In fact, they allow the direct homologation of carbonyl compounds and imines leading to β-halo-alcohols and amines that are useful building blocks [29-31]. This work represents a remarkable example of flash chemistry, and has elements of sustainability considering that in batch macroreactors, in order to avoid metal-assisted α-elimination, in situ quenching, an excess of reagents, and very low temperature are required [32,33].

Running the reaction in a flow system at −40 °C, by using residence times between 0.18–0.31 s high yields of homologated products have been obtained under external quenching conditions (Scheme 5).

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Scheme 5: External trapping of chloromethyllithium in a flow microreactor system.

The results described above nicely show the potential, as green technology, of flow microreactor systems for synthetic processes involving highly unstable intermediates. Another nice example on the use of microreactor technology for the development of sustainable chemical processes, is represented by the direct introduction of the tert-butoxycarbonyl group into organometallic reagents [34]. The reaction between organolithium reagents and di-tert-butyl dicarbonate run under flow conditions, allowed a straightforward preparation of several tert-butyl esters. The use of a flow process resulted more efficient, versatile and sustainable compared to batch. Moreover, this operationally simple procedure complements well with the already available strategies for the preparation of tert-butyl esters, avoiding the use of inflammable and explosive gaseous isobutylene [35], the use of harsh conditions [36], the use of peroxides [37], the use of toxic gas such as CO or transition metals [38-42]. The flow process, for the direct C-tert-butoxycarbonylation of organolithiums, has been optimized in a green solvent such as 2-MeTHF by a precise control of the residence time, and without using cryogenic conditions (Scheme 6). In addition, many organolithiums were generated from the corresponding halo compounds by a halogen/lithium exchange reaction using hexyllithium as a more sustainable base [43,44].

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Scheme 6: Scope for the direct tert-butoxycarbonylation using a flow microreactor system.

The concept of flash chemistry has been successfully employed for outpacing fast isomerization reactions. The accurate control of the residence time, realized in a microreactor, could suppress or avoid isomerization of unstable intermediates. This is often unavoidable when the same reactions are run in batch mode [45-47].

Yoshida and Kim recently provided an astonishing example on the potential of flash chemistry in controlling fast isomerization of organolithiums [48]. The authors designed a chip microreactor (CMR), able to deliver a reaction time in the range of submilliseconds (0.33 ms) under cryogenic conditions. By using such an incredible short residence time, it was possible to overtake the very rapid anionic Fries rearrangement, and chemoselectively functionalize ortho-lithiated aryl carbamates (Scheme 7).

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Scheme 7: Control of anionic Fries rearrangement reactions by using submillisecond residence time. (Adapted with permission [43], copyright 2016 American Association for the Advancement of Science).

This CMR has been developed choosing a fluoroethylene propylene–polymide film hybrid for fabrication because this material offers exceptional physical toughness at low temperature and high pressure as well as chemical inertness. The most relevant aspect of this microreactor, concerns the 3D design of the mixing zone (Figure 2). The mixing efficiency was evaluated on the basis of computational fluids dynamics (CFD). The simulation results showed that serpentine 3D-structured channels (Figure 2), possessing five turns after each mixing point in a total length of 1 mm, was able to deliver the highest mixing efficiency. The inner volume for the reactor was of 25 μL. This CMR provides mixing efficiency levels of 95% with a total flow rates of 7.5 mL/min corresponding to a residence time of about 0.3 milliseconds.

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Figure 2: Chip microreactor (CMR) fabricated with six layers of polyimide films. (Reproduced with permission from [43], copyright 2016 American Association for the Advancement of Science).

To show the potential use of this microdevice in organic synthesis, the synthesis of Afesal [49], a biologically active compound having anthelmintic activity was reported as application.

This outstanding result by Yoshida and Kim, demonstrates how microdevices and flash chemistry could contribute to the development of new sustainable synthetic strategies, and how microreactor technology could help in taming the reactivity of unstable species [50].

 

Contribution of continuous-flow metal-, organo-, and photocatalysis in green chemistry

The development of continuous-flow catalysis is appealing because it combines the advantages of a catalytic reaction with the benefits of flow microreactors. Under homogeneous conditions a soluble catalyst, which flows through the reactor together with the reactants, is employed. At the end of the process, a separation step would be required in order to remove the catalyst and byproducts. On the other hand, heterogeneous catalysis is widely used in the synthesis of bulk and fine chemicals. In a continuous-flow process, the catalyst can be fixed on a suitable hardware, and the reaction mixture allowed to flow through the system. The use of recyclable catalysts in continuous-flow conditions represents an innovative strategy for the development of more environmentally friendly synthesis. In the last decade, organic photochemistry got a sort of renaissance, emerging as useful approach in modern sustainable and green synthesis.

Concerning the heterogeneous catalysis with palladium, practical procedures for recovering and reusing of the catalysts have been recently reported [51-53]. A versatile Pd-catalysed synthesis of polyfunctionalized biaryls, using a flow microreactor, has been recently reported by Yoshida [54]. Using the integrated microflow system reported in Scheme 8, arylboronic esters were prepared by a lithiation/borylation sequence, and used in a Suzuki–Miyaura coupling in a monolithic reactor. A remarkable aspect of the process was the use of an integrated supported monolithic Pd(0) catalyst that allowed to perform cross-coupling reactions in continuous flow mode (Scheme 8).

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Scheme 8: Flow microreactor system for lithiation, borylation, Suzuki–Miyaura coupling and selected examples of products.

This integrated microflow system allow to handle the borylation of aryl halides (Ar1X), and the subsequent Suzuki–Miyaura coupling using different aryl halide (Ar2X). Without requiring the protection of sensitive functionalities, running the flow system using a residence time (tR) of about 4.7 min at a temperature above 100 °C, high yields of coupling products were obtained. Noteworthy, the Suzuki–Miyaura coupling did not require the use of a base. The authors applied the presented method to the synthesis of adapalene, used in the treatment of acne, psoriasis, and photoaging.

Fluorinated aromatic compounds are extremely important in agrochemical, pharmaceutical and medicinal fields [55-58]. Buchwald and co-workers suggested a telescoped homocatalysis procedure consisting of a three-step sequence (metalation, zincation and Negishi cross-coupling) which furnishes an easy access to a variety of functionalized 2-fluorobiaryl and heteroaryl products (Scheme 9[59]. This strategy is rightfully considered green because it guarantees the employment of readily available and cheap starting materials, the safe handling of highly thermally unstable or dangerous intermediates, and the use of higher temperature with respect to the batch mode in which the proposed reactions have to be carried out at −78 °C.

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Scheme 9: Experimental setup for the flow synthesis of 2-fluorobi(hetero)aryls by directed lithiation, zincation, and Negishi cross-coupling. (Adapted with permission from [53], copyright 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim).

The use of 2-MeTHF as greener solvent, contributes to further validate the green procedure. The 2-MeTHF solutions of fluoroarenes 4 together with the hexane solution of n-BuLi were pumped into the flow system at −40 °C. The generated organozinc intermediate meets the solution of haloarenes and the catalyst, leading to the formation of the desired products 5a–j (Scheme 9). Noteworthy, the homogeneous catalysis requires only 1% of the XPhos-based palladium catalyst. A sonication bath was employed to prevent clogging and the reaction required a residence time of 15 min.

Next, they turned their attention to the arylation of fluoro-substituted pyridines. The regioselective lithiation of halopyridines with lithium diisopropylamide (LDA) was conducted under mild conditions on substrate 6(Scheme 10). The addition of a little amount of THF was necessary in order to avoid clogging and the tendency of the lithiated intermediate to eliminate.

[1860-5397-13-51-i10]

Scheme 10: Experimental setup for the coupling of fluoro-substituted pyridines. (Adapted with permission from [53], copyright 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim).

The optimized conditions were suitable for the functionalization of 2-fluoropyridine, 2,6- difluoropyridine and 4-(trifluoromethyl)pyridine leading to products 7a–g reported in Scheme 10. Another promising field is the sustainable flow organocatalysis, and recently Pericàs reported an interesting synthesis and application of a recyclable immobilized analogue of benzotetramisole (BMT) used in a catalytic enantioselective Michael addition/cyclization reactions under continuous-flow conditions (Scheme 11[60].

[1860-5397-13-51-i11]

Scheme 11: Continuous flow process setup for the preparation of 11 (Reproduced with permission from [54], copyright 2015 American Chemical Society).

Resin-bound catalyst 10 was swollen with dichloromethane in a medium-pressure chromatography column used as a reactor. Dichloromethane solutions of substrate 9 reacted with the mixed phenylacetic pivalic anhydride (deriving from phenylacetic acetic (8) and pivaloyl chloride) inside the catalytic reactor producing the expected products 11. This ingenious system was equipped with an in-line FTIR probe, for monitoring the transformation, and an in line liquid–liquid separator to avoid tedious work-up procedures, thus saving solvents, resources and optimizing work times. This system was demonstrated to work for 11 h with higher conversion and enantioselectivity (er >99.9%) in comparison to the batch mode [61]. Pericàs and co-workers taking advantage of the high catalytic activity, robustness and recyclability of the supported catalyst, performed also straightforward gram synthesis of target compounds.

In the context of photocatalysis and oxidations using flow microreactors [62,63], Noël reported a metal-free photocatalytic aerobic oxidation of thiols to disulfides under continuous-flow conditions [64]. Disulfides are useful molecules employed as drugs, anti-oxidants or pesticides as well as rubber vulcanizating agents [65]. Symmetric disulfides are generally obtained by oxidative coupling of thiols [66]. Noël and co-workers set up a microflow system equipped with a mass flow controller (MFC) able to introduce pure oxygen as the oxidant to oxidize a solution of thiol containing 1% of Eosin Y. The flow stream was exposed to white LED light in order to activate the reaction, and a dilution with pure EtOH was needed at the output to avoid clogging (Scheme 12). The residence time of 20 min guaranteed a limited irradiation time and high purity of the products.

[1860-5397-13-51-i12]

Scheme 12: Continuous-flow photocatalytic oxidation of thiols to disulfides.

The disulfides were obtained with excellent yields, and the process was executed on challenging thiols as in the case of disulfide 12 (Scheme 12), used as food flavour additive [67]. To demonstrate the usefulness of the flow methodology, and its applicability, the photocatalytic aerobic oxidation of a peptide to obtain oxytocin in continuous flow was reported (Scheme 12). Full conversion was achieved in water with 200 s of residence time.

Noël optimized, for the first time, a trifluoromethylation of aromatic heterocycles by continuous-flow photoredox catalysis. The process benefited from the use of microreactor technology and readily available photocatalysts. The process was also employable for perfluoroalkylation. The developed process occurred in less time with respect to batch mode, and under milder conditions. The set-up of the reactor allowed for the use of gaseous CF3I by means of a mass flow controller. Selected examples of trifluoroalkylated products are reported in Scheme 13 [68].

[1860-5397-13-51-i13]

Scheme 13: Trifluoromethylation by continuous-flow photoredox catalysis.

Tranmer reported a “traceless reagents” chemistry with the continuous-flow photosynthesis of 6(5H)-phenanthridinones, poly(ADP-ribose) polymerase (PARP) inhibitors [69]. The relevance of the work resides in the use of green solvents, the absence of heavy metals, the use of convenient temperatures, and the increased safety by eliminating UV-exposure locating the UV lamp within the microreactor. Hazard of fires caused by the hot UV lamps approaching the auto-ignition temperature of flammable solvents, very often underestimated, is totally prevented thanks to a specific cooling system. 2-Halo-N-arylbenzamides were converted into 6(5H)-phenanthridinones by a photocyclization reaction. In order to run this step, a flow system with a photochemical reactor equipped with a medium pressure Hg lamp and 10 mL reactor coil, was employed. Good yields were obtained from different 2-chlorobenzamides disclosing that either electron-donating or electron withdrawing ortho-substituents were tolerated (Scheme 14).

[1860-5397-13-51-i14]

Scheme 14: Flow photochemical synthesis of 6(5H)-phenanthridiones from 2-chlorobenzamides.

A metal- and catalyst-free arylation procedure carried out under continuous-flow conditions was recently reported by Fagnoni [70]. This photochemical process allowed for the preparation of a wide range of synthetic targets by Ar–Csp3, Ar–Csp2 and Ar–Csp bond-forming reactions. The use of a photochemical flow reactor, consisting of a polyfluorinated tube reactor wrapped around a 500 W Hg lamp, allowed to overcome batch limitations paving the way for metal-free arylation reactions via phenyl cations. Derivatives 14a–g were prepared with this greener flow approach (Scheme 15) starting from mesitylene 13, and haloarenes using short irradiation times (<6 h), and a 5:1 MeCN/H2O mixture.

[1860-5397-13-51-i15]

Scheme 15: Synthesis of biaryls 14a–g under photochemical flow conditions.

The reported results show how photochemistry hold the potential to become a green tool for the development of sustainable photochemical flow synthesis.

 

Hazardous chemistry by using green and sustainable continuous-flow microreactors

We have already shown how continuous-flow technology could play an important role in improving chemical processes [5,71], providing different advantages over traditional batch mode. However, the hazardous nature of some chemicals makes handling at conventional lab or industrial scale difficult. The use of microreactors and continuous-flow chemistry offers the possibility to perform reactions using dangerous or hazardous materials that cannot be used in batch mode. In other word, syntheses previously “forbidden” for safety reasons, such as those involving diazo compounds, hydrazine, azides, phosgene, cyanides and other hazardous chemicals could be performed with relatively low risk using flow technology [72-76].

Several research groups investigated this aspect, as highlighted by several available reviews [77,78]. Here we describe very recent reports with the aim to highlight the potential of flow chemistry in the field of hazardous chemistry under a greener perspective.

Diazo compounds are recognized as versatile reagents in organic synthesis. Nevertheless, diazo compounds are also considered highly energetic reagents [79,80]. For this reason, the in situ generation of such reagents has been investigated under flow conditions. Moody and co-workers reported a new method for the in situ generation of diazo compounds as precursors of highly reactive metal carbenes (Scheme 16[81].

[1860-5397-13-51-i16]

Scheme 16: Flow oxidation of hydrazones to diazo compounds.

As reported in Scheme 16, diazo species 18 could be generated from simple carbonyls 15 and hydrazine (16). Intermediate hydrazones 17 can be converted into the corresponding diazo compounds by oxidation using a recyclable oxidant based on N-iodo-p-toluenesulfonamide potassium salt. The possibility to regenerate a functionalized resin by simple washing with aqueous KI3/KOH solution makes the process more sustainable. This method produces KI solution as waste, and it is an alternative way for the direct oxidation of hydrazones, that often requires the use of heavy metals such as HgO, Pb(OAc)4 and AgO [82,83].

The diazo compounds could be collected as solution in dichloromethane at the output of the flow system, and obtained sufficiently pure for further use without requiring handling or isolation. Further mixing of solutions containing diazo derivatives to a solution containing a Rh(II) catalyst, and reactants such as amines, alcohols or aldehydes led to a wide range of products as reported in Scheme 17.

[1860-5397-13-51-i17]

Scheme 17: Synthetic use of flow-generated diazo compounds.

Ley’s group developed several continuous-flow approaches for generating diazo species from hydrazones [84,85]. Under flow conditions, diazo compounds were reacted with boronic acids in order to generate reactive allylic and benzylic boronic acids further employed for iterative C–C bond forming reactions [86]. The generation of unstable diazo species was possible using a cheap, recyclable and less toxic oxidant, MnO2. The flow stream was accurately monitored by in-line FTIR spectroscopy in order to maximize the formation of the diazo compound (Scheme 18[87].

[1860-5397-13-51-i18]

Scheme 18: Ley’s flow approach for the generation of diazo compounds.

Starting from this initial investigation, Ley and co-workers developed an elegant application of this strategy for a sequential formation of up to three C–C bonds in sequence, by an iterative trapping of boronic acid species. The sequence starts with the reaction of diazo compound 20, generated under flow conditions, and boronic acid 19 (Scheme 19). Further sequential coupling with diazo compounds 21 and 22 led to boronates 23 or protodeboronated products 24 at the end of the sequence (Scheme 19).

[1860-5397-13-51-i19]

Scheme 19: Iterative strategy for the sequential coupling of diazo compounds.

With the aim to exploit the versatility of this approach, Ley and co-workers reported the allylations of carbonyl electrophiles such as aldehydes using the above reported strategy for the generation of allylboronic acids. The flow protocol considers the reaction of diazo compounds 25 (generated in flow) with boronic acid 26 and aldehyde 27 (Scheme 20). By this new iterative coupling it was possible to obtain alcohols as products. The usefulness of the method was demonstrated with the preparation in good yield (60%) of a precursor of the natural product bakuchiol 28 (Scheme 20[88].

[1860-5397-13-51-i20]

Scheme 20: Integrated synthesis of Bakuchiol precursor via flow-generated diazo compounds.

The microreactor technology offers the advantage to handle hazardous components such as hydrazine and molecular oxygen, which represent alternative reagents for selective reduction of C=C double bonds. In fact, combination of hydrazine hydrate (N2H4·H2O) and O2 provide diimide (HN=NH) as reducing agent. Nevertheless, this strategy is rarely used in traditional batch chemistry for safety reason. Kappe and co-workers recently developed a reduction of the alkene to the corresponding alkane, by a catalyst-free generation of diimide by oxidation of hydrazine monohydrate (N2H4·H2O) with molecular oxygen [89,90]. The flow system set-up is reported in Scheme 21, and consists in a HPLC pump for delivering the alkene and hydrazine monohydrate, while O2 was delivered by a mass-flow controller (MFC) from a standard compressed-gas cylinder. After combination of the reagent streams, the resulting segmented flow was pumped through a heated residence unit (RTU) consisting in a fluorinated tube with low gas permeability (Scheme 21).

[1860-5397-13-51-i21]

Scheme 21: Kappe’s continuous-flow reduction of olefines with diimide.

The flow system reported in Scheme 21 was able to reduce alkenes with high yields and selectivity by using residence times in the range of 10 to 30 min at 100 °C, and by employing a slight excess of hydrazine. Importantly, this strategy is compatible with sensitive functional groups such as silyl ether, halogenes, and benzyl groups. A very nice application of this approach was the highly selective reduction of artemisinic acid to dihydroartemisinic acid, which are of interest in the synthesis of the antimalarial drug artemisinin. This industrially relevant reduction was executed by using O2 at 20 bar, four residence units at 60 °C and consecutive feedings with N2H4·H2O in order to obtain full conversion in dihydroartemisinic acid (29, DHAA, Scheme 22).

[1860-5397-13-51-i22]

Scheme 22: Multi-injection setup for the reduction of artemisinic acid.

 

Continuous-flow sustainable production of APIs

With the aim to demonstrate the potential of microreactor technology and flow chemistry in sustainable synthesis, recent outstanding “proof of concepts” will be described. Kobayashi and co-workers reported a multistep continuous-flow synthesis of a drug target via heterogeneous catalysis. The developed process not requiring any isolation of intermediates, separation of the catalyst or other work-up procedures can be considered sustainable [91]. The syntheses of (S)-rolipram and a γ-aminobutyric acid (GABA) derivative were accomplished. Readily available starting materials and columns containing chiral heterogeneous catalysts to produce enantioenriched materials were employed. It is worth mentioning that this work represents a very nice example on the use of chiral catalysis in a multistep flow synthesis of a drug target on gram scale. The multistep synthesis of (S)-rolipram reported in Scheme 23 begins from a benzaldehyde derivative which undergoes a Henry-type reaction with nitromethane in the first flow step (Flow I). The resulting nitroalkene undergoes an asymmetric addition catalyzed by a supported PS–(S)-pybox–calcium chloride catalyst at 0 °C using two columns (Flow II). This is the enantio-determining step of the process. The stereochemistry of the adduct can be simply switched to the opposite enantiomer, by using the enantiomeric supported catalyst PS–(R)-pybox–calcium chloride. The enantiomeric excess of the products was about 96%. Two more steps consisting in a Pd-catalyzed hydrogenation reaction and a decarboxylation (Flow III and Flow IV) led to the target (S)-rolipram in 50% overall yield. The systems was designed in order to keep the level of the palladium in solution as low as possible (<0.01 ppm).

[1860-5397-13-51-i23]

Scheme 23: Flow reactor system for multistep synthesis of (S)-rolipram. Pumps are labelled a, b, c, d and e; Labels A, B, C, D, E and F are flow lines. X are molecular sieves; Y is Amberlyst 15Dry; Z is Celite. (Reproduced with permission from [84], copyright 2015 Nature Publishing Group).

Another outstanding proof of concept, which demonstrates the potential of flow chemistry for sustainable pharmaceutical manufacturing, has been recently reported by Jensen and his research team. The research team set up a compact and reconfigurable manufacturing platform for the continuous-flow synthesis and formulation of active pharmaceutical ingredients (APIs) [92]. The “mini” plant (reported in Figure 3) was very compact in size [1.0 m × 0.7 m × 1.8 m, (W × L × H)], and low-weighing (about 100 kg) and was able to perform complex multistep synthesis, work-up procedures as well as purification operations such as crystallization. This platform was also equipped with devices for real-time monitoring and final formulation of high purity APIs. For the preparation of target molecules, commercially available starting materials were employed. The platform was tested for the production and supply of hundreds to thousands doses per day of diphenhydramine hydrochloride, lidocaine hydrochloride, diazepam and fluoxetine hydrochloride.

Remarkably, for future applications of the platform, the produced medicines also met the U.S. Pharmacopeia standards.

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Figure 3: Reconfigurable modules and flowcharts for API synthesis. (Reproduced with permission from [85], copyright 2016 American Association for the Advancement of Science).

The future use of this kind of platform would concern the “on-demand” production or the “instantaneous” production of short-lived pharmaceuticals (Figure 4). Other advantageous concerns of this reconfigurable platform are the lower production costs, the higher safety, the automation (computer controlled processes), the reduced waste (production could be done where is needed and in the right amount).

[1860-5397-13-51-4]

Figure 4: Reconfigurable system for continuous production and formulation of APIs. (Reproduced with permission from [85], copyright 2016 American Association for the Advancement of Science).

 

 

Conclusion

Flow chemistry and manufacturing engineering have become largely acknowledged as viable and very often superior alternative to batch processing. Continuous-flow techniques offer increased safety, scalability, reproducibility, automation, reduced waste and costs, and accessibility to a wide range of new chemical possibilities, seldom not accessible through classic batch chemistry. All those benefits are even more noteworthy and outstanding than what they might seem, because they widely fulfil most of the green chemistry principles. In this short overview, we tried to highlight progresses and potential of flow chemistry in the field of sustainable synthesis. Thus, it is expected that flow chemistry and microreactor technology could deeply change the way to perform sustainable chemical production in the near future [93].

 

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How to cite this article:
Fanelli, F.; Parisi, G.; Degennaro, L.; Luisi, R. Beilstein J. Org. Chem. 2017, 13, 520–542. doi:10.3762/bjoc.13.51

© 2017 Fanelli et al.; licensee Beilstein-Institut.
This is an Open Access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
The license is subject to the Beilstein Journal of Organic Chemistry terms and conditions: (http://www.beilstein-journals.org/bjoc)

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io

Renzo Luisi Ph.D.

Professor of Organic Chemistry
email: 
renzo.luisi@uniba.it

tel. +39-080-5442762

fax. +39-080-5442539

Address: Via E. Orabona, 4

70125 Bari – Italy

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Department of Pharmacy – Drug Sciences

Welcome to my personal web page!!

As an organic chemist I’m involved in the development of new sustainable synthetic methodologies for the construction of new molecules with defined stereochemistry and functional properties.

Jointly with my coworkers we are involved in three main research themes:

1. Heterosubstituted Organolithiums. We mainly explore the reactivity of lithiated 3,4,5,6-membered N,S,O-heterocycles (aziridines, azetidines, oxazetidines, thietanes, oxazolines, piperazines, morfolines) and their utility in stereoselective synthesis. Our approach is focused in establishing the chemical and configurational stability of the lithiated intermediates as well as their structure in solution by using modern spectrometric and spectroscopic techniques such as in line -IR, in line-MS, NMR and DOSY.


2. Microreactor Technology and Flow-Chemistry. With the aim to design more sustainable synthetic processes, we set up, at the Depatment of Pharmacy, a well equipped “flow chemistry laboratory” named FLAME-Lab, for the development of continuous-flow microreactor-mediated organometallic and organocatalytic synthesis in both homegenous and heterogenous conditions.

3. Molecular DynamicsAs a “curiosity driven” research activity, we investigate the dynamic behavior of small molecules that could function as molecular switches with “on-off” states and as versatile scaffolds useful in catalysis and in “dynamic-controlled and predictable reactivity”.

Leonardo Degennaro at Università degli Studi di Bari Aldo Moro
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Oct 142017
 

 

 

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Shobha crasto receiving my Pharma excellence award for Outstanding contribution to Pharma industry from Arab health on 12 oct 2017 in Dubai, UAE..

Award at the “The Middle East Healthcare Leadership Awards” held on 12th October, 2017. At The Address,Dubai Mall – Dubai UAE….Mohammed Bin Rashid Boulevard, Downtown Dubai – Dubai – United Arab Emirates

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Oct 102017
 

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Total synthesis of (-)-aritasone via the ultra-high pressure hetero-Diels-Alder dimerisation of (-)-pinocarvone

Org. Biomol. Chem., 2017, Advance Article

DOI: 10.1039/C7OB02204B, Paper
Maliha Uroos, Phillip Pitt, Laurence M. Harwood, William Lewis, Alexander J. Blake, Christopher J. Hayes
The total synthesis of aritasone via the proposed biosyntheic hetero-Diels-Alder [4 + 2] cyclodimerisation of pinocarvove, has been achieved under ultra-high pressure (19.9 kbar) conditions

Total synthesis of (−)-aritasone via the ultra-high pressure hetero-Diels–Alder dimerisation of (−)-pinocarvone

 Author affiliations

Christopher Hayes

Abstract

This paper describes a total synthesis of the terpene-derived natural product aritasone via the hetero-Diels–Alder [4 + 2] cyclodimerisation of pinocarvove, which represents the proposed biosyntheic route. The hetero-Diels–Alder dimerisation of pinocarvone did not proceed under standard conditions, and ultra-high pressure (19.9 kbar) was required. As it seems unlikely that these ultra-high pressures are accessible within a plant cell, we suggest that the original biosynthetic hypothesis be reconsidered, and alternatives are discussed.

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Aritasone (1) A solution of pinocarvone (()-2) (100 mg, 0.66 mmol) in dichloromethane (5 mL) was pressurized to 19.9 kbar for 120 h. The 1H NMR spectrum of the crude reaction mixture showed significant change in the composition as compared to the starting material. The solvent was evaporated and the residue was purified by column chromatography (pentane/Et2O; 25/1) to afford aritasone (1) (20 mg, 40%) as a white solid; mp 101- 103 C; (lit3 mp 105-106 °C); []D 26 26.1 (c 0.40 in CHCl3); (lit3 []D 9 118); max/cm-1 (CHCl3) 2926, 2359, 1722, 1689, 1601, 1467, 1372, 1305, 1152; H (400 MHz; CDCl3, 298 K) 2.67 (2H, app dd, J 4.8, 2.5, H-2a, H-2b), 2.45-2.32 (3H, m, H-7a, H-15a, H-3), 2.15-2.01 (4H, m, H-10, H-12, H-15b, H-16a), 1.91-1.80 (2H, m, H-4, H-16b), 1.66 (1H, ddd, J 13.8, 6.4, 3.4, H-7b), 1.38 (3H, s, CH3), 1.29-1.22 (7H, br s, CH3, H-13a, H-13b, H-8a, H- 8b), 0.90 (3H, s, CH3), 0.80 (3H, s, CH3); C (100 MHz; CDCl3, 298 K) 209.5 (C), 142.9 (C), 112.8 (C), 80.8 (C), 45.2 (CH), 44.3 (CH), 43.7 (CH2), 40.9 (CH), 40.5 (C), 39.4 (CH), 38.3 (C), 33.2 (CH2), 32.7 (CH2), 27.7 (CH3), 27.3 (CH2), 27.3 (CH3), 26.3 (CH3), 22.5 (CH2), 22.1 (CH2), 20.9 (CH3); HRMS m/z (ES+ ) found 301.2162 (M + H) C20H29O2 requires 301.2162 and 323.1981 (M + Na) C20H28O2Na requires 323.1982. These data were consistent to those previously reported, 5, 7 however the value of the specific rotation5 differs significantly from that measured during the original isolation work.3

Christopher Hayes

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Biography

Prof. Christopher Hayes began his academic career here in Nottingham with his B.Sc. in July 1992. Remaining at Nottingham, he completed his Ph.D. studies in organic chemistry, under the supervision of Professor Gerald Pattenden, in September 1995. In January 1996, on a NATO Postdoctoral Fellowship, he moved to the University of California at Berkeley where he worked in the group of Professor Clayton H. Heathcock. In September 1997, he returned to Nottingham as a Lecturer in Organic Chemistry, and has subsequently been promoted to Reader (2003), Associate Professor (2006) and Professor of Organic Chemistry (2011).

Research Summary

Research is centred in main-stream synthetic organic chemistry, focusing on the organic chemistry of biologically active molecules. His current research interests span a number of areas such as (i)… read more

Recent Publications

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Oct 092017
 

 

CrystEngComm, 2017, 19,5703-5706
DOI: 10.1039/C7CE01275F, Communication
Christopher S. Frampton, James H. Gall, David D. MacNicol
In the trigonal CCl4quasiracemic clathrate, space group R3, formed from host components S-(-)-Dianin’s compound, 4, and its (+)-2R,4R 2-nor methyl analogue, 2, the unprecedented complete ordering of a C-Cl bond of the guest with respect to the c-axial direction and the participation of an unexpected host conformation is reported for the first time.

Total CCl4 guest alignment in a quasiracemic clathrate closely related to Dianin’s compound

 Author affiliations

Abstract

Single crystal X-ray analysis at 100 K reveals that in the trigonal CCl4quasiracemic clathrate, space group R3, formed from host components S-(−)-Dianin’s compound and its (+)-2R,4R 2-nor methyl analogue there is an unprecedented complete ordering of a C–Cl bond of the guest with respect to the c-axial direction. In this clathrate and that formed from the (+)-2R,4R and (+)-2R,4S epimers the participation of an unexpected host conformation is reported for the first time.

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Oct 092017
 

 

Catal. Sci. Technol., 2017, Advance Article
DOI: 10.1039/C7CY01621B, Paper
Youming Ni, Lei Shi, Hongchao Liu, Wenna Zhang, Yong Liu, Wenliang Zhu, Zhongmin Liu
Halide-free and noble metal-free pyridine-modified H-mordenites exhibit high stability and selectivity in methanol carbonylation to acetic acid.

A green route for methanol carbonylation

 Author affiliations

Abstract

Acetic acid is one of the most important bulk commodity chemicals and is currently manufactured by methanol carbonylation reactions with rhodium or iridium organometallic complexes and halide-containing promoters named Monsanto or BP Cativa™ homogeneous processes, respectively. Developing a halide-free catalyst and a heterogeneous process for methanol carbonylation is of great importance and has recently attracted extensive research attention. Here, we report a green route for direct synthesis of acetic acid via vapor-phase carbonylation of methanol with a stable, selective, halide-free, and noble metal-free catalyst based on pyridine-modified H-mordenite zeolite. Methanol conversion and acetic acid selectivity can reach up to 100% and 95%, respectively. Only little deactivation is observed during the 145 hour reaction.

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