Endogenous water-triggered and ultrasound accelerated synthesis of 1,5-disubstituted tetrazoles via a solvent and catalyst-free Ugi-azide reaction

ORGANIC CHEMISTRY SELECT

Endogenous water-triggered and ultrasound accelerated synthesis of 1,5-disubstituted tetrazoles via a solvent and catalyst-free Ugi-azide reaction

Green Chem., 2017, Advance Article
DOI: 10.1039/C6GC03324E, Communication
Shrikant G. Pharande, Alma Rosa Corrales Escobosa, Rocio Gamez-Montano
An ultrasound accelerated, environmentally benign Ugi-azide based method was developed for the synthesis of 1,5-disubstituted tetrazoles under solvent and catalyst-free conditions.

Endogenous water-triggered and ultrasound accelerated synthesis of 1,5-disubstituted tetrazoles via a solvent and catalyst-free Ugi-azide reaction

 *Corresponding authors
aDepartamento de Química, División de Ciencias Naturales y Exactas, Universidad de Guanajuato, Noria Alta S/N, Col. Noria Alta, Guanajuato, México
E-mail: rociogm@ugto.mx
Green Chem., 2017, Advance Article

DOI: 10.1039/C6GC03324E,  http://pubs.rsc.org/en/Content/ArticleLanding/2017/GC/C6GC03324E?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

A novel, sustainable, endogenous water-triggered, environmentally friendly, high substrate scope, efficient, solvent-free and catalyst-free Ugi-azide based method for the synthesis of 1,5-disubstituted tetrazoles is described.
N-((1-(tert-butyl)-1H-tetrazol-5-yl)(4-chlorophenyl)methyl)aniline…

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A deeper shade of green: inspiring sustainable drug manufacturing

Graphical abstract: A deeper shade of green: inspiring sustainable drug manufacturing

Green and sustainable drug manufacturing go hand in hand with forward-looking visions seeking to balance the long-term sustainability of business, society, and the environment. However, a lack of harmonization among available metrics has inhibited opportunities for green chemistry in industry. Moreover, inconsistent starting points for analysis and neglected complexities for diverse manufacturing processes have made developing objective goals a challenge. Herein we put forward a practical strategy to overcome these barriers using data from in-depth analysis of 46 drug manufacturing processes from nine large pharmaceutical firms, and propose the Green Aspiration Level as metric of choice to enable the critically needed consistency in smart green manufacturing goals. In addition, we quantify the importance of green chemistry in the often overlooked, yet enormously impactful, outsourced portion of the supply chain, and introduce the Green Scorecard as a value added sustainability communication tool.

http://pubs.rsc.org/en/Content/ArticleLanding/2017/GC/C6GC02901A?utm_medium=email&utm_campaign=pub-GC-vol-19-issue-1&utm_source=toc-alert#!divAbstract

The Green Aspiration Level (GAL) has been constructed on four pillars to ensure consistent application, namely (1) clearly defined synthesis starting points,1 (2) unambiguous complete E factor (cEF)2,3 or Process Mass Intensity (PMI) waste metrics, (3) historical averages of industrial drug manufacturing waste, and (4) complexity of the drug’s ideal manufacturing process (Supplementary Figure 6). cEF or PMI can be used interchangeably in GAL-based analysis enabling organizations using either to calculate their green performance scores. cEF and PMI differ by just one unit (Supplementary Equation 6) and share the same commercial waste goal for an average manufacturing step4 – the transformation-GAL or tGAL – that results in negligible numerical differences from the inclusion of one or the other. The pharmaceutical industry has generally adopted PMI. However, our publication utilizes cEF values due to literature prevalence and potentially broader appeal of E factors.5 It is important to note that all reaction and workup materials are included in the analysis, but excluded are reactor cleaning6 and solvent recycling.7 Standardized process starting points are a critical component of the GAL methodology. A starting material for some may be an intermediate for others. Until recently, the scientific community lacked an unambiguous definition of process starting points in the assessment of process greenness. This has been a bothersome source of inconsistency. Failure to define an appropriate starting material can lead to exclusion of significant amounts of intrinsic raw material waste created during earlier stages of manufacture. We therefore utilize these updated definitions of process analysis starting points to ensuring higher quality of data:8

1) The material is commercially available from a major reputable chemical laboratory catalog company, and its price is listed in the (online) catalog. Materials requiring bulk or custom quotes do not qualify as process starting material. AND 2) The laboratory catalog cost of the material at its largest offered quantity does not exceed US $100/mol. Therefore, published literature must be researched if the material does not qualify as process starting material in order to determine its correct intrinsic cEF. However, we realized that determination of literature cEF values is tedious and involves making assumptions since literature procedures are often incomplete compared to internal or external manufacturing batch records. Thus, standardizing Literature cEF quickly became a desirable goal. In order to facilitate literature analysis we introduced Supplementary Equation 7 that just requires determination of literature step count from ≤$100/mol starting materials without having to retrieve literature waste information.9 The literature step multiplier of 37 kg/kg represents the average literature step cEF across the analyzed projects (Supplementary Table 1), so it equals their average literature cEF (76 kg/kg) divided by average literature step count (2.1). The process cEF and Relative Process Greenness (RPG) derived from the simplified calculated cEF literature values are shown next to their progenitors in Supplementary Table 3. We observe that average calculated and manually determined cEF and RPG values are comparable and within 10% of their means across the three development phases. Thus, we consider the simplified method sound and an importtant element to achieving consistency in green process analysis.

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A deeper shade of green: inspiring sustainable drug manufacturing

 *Corresponding authors
aChemical Development, Boehringer Ingelheim Pharmaceuticals, Ridgefield, USA
E-mail: frank.roschangar@boehringer-ingelheim.com
bPharmaceutical Sciences – Worldwide Research & Development, Pfizer, Groton, USA
cPfizer, Sandwich, UK
dChemical & Analytical Development, Novartis Pharma, 4002 Basel, Switzerland
eAPI Chemistry, GlaxoSmithKline Medicines Research Centre, Stevenage, UK
fSmall Molecule Process Chemistry, Genentech, a Member of the Roche Group, South San Francisco, USA
gSmall Molecule Design and Development, Eli Lilly and Company, Indianapolis, USA
hChemical and Synthetic Development, Bristol-Myers Squibb, New Brunswick, USA
iProcess Chemistry, Merck, Rahway, New Jersey 07065, USA
jProcess Development, Amgen, Thousand Oaks, USA
kMolecular Sciences Institute, School of Chemistry, University of the Witwatersrand, Johannesburg, South Africa
lDelft University of Technology, 2628 BL Delft, Netherlands
Green Chem., 2017,19, 281-285

DOI: 10.1039/C6GC02901A

Frank Roschangar, PhD MBA

Frank Roschangar, PhD MBA

Pharmaceutical process research director, passionate about accelerating drug development and driving green chemistry.

Boehringer Ingelheim
Ingelheim am Rhein, Germany

Research experience

  • Feb 2002–Sep 2015
     Director
    Boehringer Ingelheim
    Germany · Nieder-Ingelheim
  • Aug 1996–Feb 1998
    Postdoc
    The Scripps Research Institute · Skaggs Institute for Chemical Biology · Prof. K.C. Nicolaou
    United States · La Jolla
  • Aug 1992–Aug 1996
    PhD Candidate
    Rice University · Department of Chemistry
    United States · Houston
Supplementary References
1. The $100 per mol laboratory catalog pricing requirement described in Supplementary Discussion 1 does not apply to reagents, catalysts, ligands, and solvents, since they are produced for widespread application and are not specific to the process being evaluated.
2. Since the original E factor has been applied inconsistently, the cEF metric was introduced for the purpose of GAL analysis. cEF accounts for all process reaction and process workup materials, including raw materials, intermediates, reagents, process aids, solvents, and water.
3. All E factors reported herein represent the cEF or sEF contributions of the overall manufacturing process or the sub-process (e.g. external cEF, literature cEF) to produce 1 kg of drug substance.
4. We define a step as a chemical operation involving one or more chemical transformations that form and/or break covalent or ionic bonds and lead to a stable and isolable intermediate, but not necessarily include its isolation. Examples: • Simultaneous removal of two or more protection groups involves multiple transformations, yet it is carried out in one chemical operation  counted as one step • Sequential transformations via a stable and isolable intermediate that are carried out in two operations but without intermediate workup  counted as two steps • Formation of covalent bonds or salts that occur during workup  not counted as an extra step • Separate operation of salt formation from an isolated intermediate  counted as one step • Isolation of a product, following work-up, as a solution that can be stored  counted as one step.
5. A SciFinder search for the terms ‘Process Mass Intensity’, and ‘E factor’ and ‘Environmental impact factor’ on Nov. 14, 2016 revealed that the PMI concept was present in 12, 8, 9, and 12 publications for the years 2013-2016, respectively, while the E factor concept was mentioned 39, 45, 57, and 46 times (76-86%), respectively.
6. The GAL considers only direct process materials, i.e. materials used in the chemical steps and their workups. It does not include solvents and aqueous detergents required for reactor and equipment cleaning between batches or steps, nor the frequency and duration of the equipment and facility specific cleaning operations. These parameters are considered for comprehensive environmental impact in Life Cycle Assessment (LCA) analysis.
7. In US pharmaceutical manufacturing, recycling accounts for 25% of waste handling, while energy recovery burning and treatment constitute 38% and 35%, based on 2012 data from ‘The Right-To-Know Network’ (RTKNET.ORG), Toxic Releases (TRI) Database: http://rtknet.org/db/tri.
8. The $100 per mol commodity pricing criterion was established in ref. 15 of the main article based on the author’s professional experience. The authors of this manuscript consider this figure appropriate and helpful for providing a consistent analysis.
9. If a detailed procedure is available for a particular literature step, its calculated waste can be used in place of the 37 kg/kg default value.
10. J. Li and M. D. Eastgate, Current Complexity: a Tool for Assessing the Complexity of Organic Molecules. Org. Biomol. Chem. 2015,13, 7164–7176.
11. D. P. Kjell, I. A. Watson, C. N. Wolfe and J. T. Spitler, Complexity-Based Metric for Process Mass Intensity in the Pharmaceutical Industry. Org. Process Res. Dev. 2013, 17, 169– 174.
12. R. P. Sheridan, et al., Modeling a Crowdsourcing Definition of Molecular Complexity. J. Chem. Inf. Model. 2014, 54, 1604–1616.
13. M. F. Faul, et al., Part 2: Designation and Justification of API Starting Materials: Current Practices across Member Companies of the IQ Consortium. Org. Process Res. Dev. 2014, 18, 594–600.
14. Besides offering simplicity, the GAL’s process complexity model was selected vs. the alternative structural complexity measures due to its inherent ideality-derived consideration for available synthetic methodology.
15. See main article ref. 16: it defines Construction Reactions (CR) as chemical transformations that form skeletal C-C or C-heteroatom bonds. Strategic Redox Reactions (SRR) are construction reactions that directly establish the correct functionality found in the final product, and include asymmetric reductions or oxidations. All other types of non-strategic reactions are considered as Concession Steps (CS), and include functional group interconversions, non-strategic redox reactions, and protecting group manipulations.
16. M. E. Kopach, et al., Process Development and Pilot-Plant Synthesis of (2-Chlorophenyl)[2-(phenylsulfonyl)pyridin-3- yl]methanone. Org. Process Res. Dev. 2010, 14, 1229–1238.
17. M. E. Kopach, M. M. Murray, T. M. Braden, M. E. Kobierski, O. L. Williams, Improved Synthesis of 1-(Azidomethyl)-3,5-bis- (trifluoromethyl)benzene: Development of Batch and Microflow Azide Processes. Org. Process Res. Dev. 2009, 13, 152–160. 18. RCI (Process B) = 1 − ( ) = 0.25. RCI (Process C) = 1 − ( ) = 0.38

//////////green chemistry, drugs

Overcoming barriers to green chemistry in the pharmaceutical industry – the Green Aspiration Level™ concept

Image result for Frank Roschangar

Image result for Frank Roschangar

Scheme 1. Pfizer’s Commercial Synthesis of sildenafil citrate (Viagra™)

Image result for Overcoming Barriers to Green Chemistry in the Pharmaceutical Industry - The Green Aspiration Level™ Concept

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Image result for Frank Roschangar

Image result for Frank Roschangar

“Green chemistry” refers to the promotion of safe, sustainable, and waste-minimizing chemical processes. The proliferation of green chemistry metrics without any clear consensus on industry standards is a significant barrier to the adoption of green chemistry within the pharmaceutical industry. We propose the Green Aspiration Level™ (GAL) concept as a novel process performance metric that quantifies the environmental impact of producing a specific pharmaceutical agent while taking into account the complexity of the ideal synthetic process for producing the target molecule. Application of the GAL metric will make possible for the first time an assessment of relative greenness of a process, in terms of waste, versus industry standards for the production process of any pharmaceutical. Our recommendations also include a simple methodology for defining process starting points, which is an important aspect of standardizing measurement to ensure that Relative Process Greenness (RPG) comparisons are meaningful. We demonstrate our methodology using Pfizer’s Viagra™ process as an example, and outline aspiration level opportunities for industry and government to dismantle green chemistry barriers.

Graphical abstract: Overcoming barriers to green chemistry in the pharmaceutical industry – the Green Aspiration Level™ concept

Overcoming barriers to green chemistry in the pharmaceutical industry – the Green Aspiration Level™ concept

*Corresponding authors
aChemical Development US, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, USA
E-mail: frank.roschangar@boehringer-ingelheim.com
bDelft University of Technology, Julianalaan 136, 2628 BL Delft, The Netherlands
Green Chem., 2015,17, 752-768

DOI: 10.1039/C4GC01563K, http://pubs.rsc.org/en/content/articlelanding/2015/gc/c4gc01563k#!divAbstract

“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This article is a compilation for educational purposes only.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

///////////green chemistry,  pharmaceutical industry

Production of High-Quality Diesel from Biomass Waste Products

The use of biodiesel has been promoted for the past decade as a substitute for fossil-based diesel fuel. However, it has become evident that its production competes with food production by engrossing cropland. To overcome this Corma has developed a process that uses 2-methylfuran which currently is isolated (280 × 103 tonnes per year) from nonedible biomass ( Angew. Chem., Int. Ed. 2011, 50, 2375−2378). The first step is the trimerization of 2-methylfuran which takes place in water mediated by sulfuric acid in 94% yield. The trimer is then subjected to hydrodeoxygenation using a mixture of Pt/C and Pt/TiO2 and 5 MPa of hydrogen in 97% yield. Of particular note was the use of no organic solvent in the process. This route opens new routes for the production of high-quality diesel from waste biomass.
original image

High-quality liquid fuels are obtained from non-edible carbohydrates by energy-efficient processes. 2-Methylfuran, produced by hydrogenation of furfural, is converted into 6-alkyl undecanes in a catalytic solvent-free process (see scheme with 6-butylundecane). A diesel fuel is produced with an excellent motor cetane number (71) and pour point (−90 °C) and with global process conversions and selectivities close to 90 %.

Production of High-Quality Diesel from Biomass Waste Products

AuthorsProf. Dr. Avelino Corma, ET AL

  • DOI: 10.1002/anie.201007508

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5-hydroxymethylfurfural (0.500 g, 3.95 mmol) was dissolved in 2-methylfuran (2.00 g, 24.4 mmol) at room temperature, Amberlyst-15 (50 mg) was added as catalyst, and the reaction mixture was stirred for 24 h at room temperature. Then, the catalyst was filtered out and washed with ethyl acetate. The filtrate obtained was concentrated under vacuum and the residue was purified by silica gel column chromatography (95 : 5 hexane : ethyl acetate changing to 70 : 30) and 5-[bis(5-methyl-2-furanyl)methyl]-2- furanmethanol was obtained (0.921 g, 3.39 mmol, 86% yield).
I.R. (neat) max: 3407, 3128, 2948, 2917, 1560, 1442, 1207, 1016, 958, 788 cm–1.-
1 H NMR (300 MHz, CDCl3)  = 6.22 (d, 1H, J=3 Hz), 6.05 (d, 1H, J=3 Hz), 5.97 (d, 2H, J=3 Hz), 5.89 – 5.90 (m, 2H), 5.40 (s, 1H), 4.56 (s, 2H), 2.26 (s, 6H), 1.75 (s, 1H).-
13C NMR (75 MHz, CDCl3)  = 153.3, 152.8, 151.6, 150.2, 108.7, 108.0, 106.2, 39.2, 13.6.-
HRMS m/z calculated for C16H16O4: 272.1049. Found: 295. 0970 [M+Na]+ .-
Elemental analysis: C16H16O4 required: C, 70.57; H, 5.92; found: C, 70.57; H, 6.09 %.
Synthesis of trissylvylmethane (2,2′,2”-methylidenetris[5-methylfuran])[20] from 2- methylfuran (Sylvan) and 5-methylfurfural employing a 5 : 1 molar ratio of 2- methylfuran and 5-methylfurfural in presence of para-toluenesulfonic acid as catalyst.
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 In a 1-L three-neck round-bottom flask, equipped with a reflux condenser and a mechanical stirrer, 2-methylfuran (Sylvan, 600 g, 7.25 mol) and para-toluenesulfonic acid (13.8 g, 80.1 mmol) were placed. Under stirring 5-methylfurfural (160 g, 1.45 mol) was added at a rate of 120 mL/h at room temperature. The reaction mixture was stirred at 50 ºC until a total reaction time of 6 h. The aqueous phase was separated and discarded. The organic phase was treated with NaHCO3 and with MgSO4 and the excess 2-methylfuran was distilled off with a rotary evaporator. Distillation provided the desired product 2,2′,2”-methylidenetris[5-methylfuran] as a colorless liquid in 97% purity (120 ºC, 2 HPa; 365 g, 1.35 mol, 93% yield). A distillation residue of 49.1 g was obtained. 1 H NMR (300 MHz, CDCl3) δ = 5.99 (d, J=3.1, 3H), 5.93 – 5.89 (m, 3H), 5.39 (s, 1H), 2.27 (d, J=0.8, 9H).- 13C NMR (75 MHz, CDCl3) δ = 151.4, 150.7, 107.8, 106.2, 39.1, 13.6.

Synthesis of cyclic organic carbonates via catalytic oxidative carboxylation of olefins in flow reactors

 

Synthesis of cyclic organic carbonates via catalytic oxidative carboxylation of olefins in flow reactors

Catal. Sci. Technol., 2017, Advance Article
DOI: 10.1039/C6CY01974A, Paper
Ajay A. Sathe, Anirudh M. K. Nambiar, Robert M. Rioux
The direct catalytic conversion of olefins into cyclic carbonates using peroxide and carbon dioxide is demonstrated using continuous flow reactors.

Synthesis of cyclic organic carbonates via catalytic oxidative carboxylation of olefins in flow reactors

*Corresponding authors
aDepartment of Chemistry, The Pennsylvania State University, University Park, USA
E-mail: rioux@engr.psu.edu
Fax: 814 865 7846
Tel: 814 867 2503
bDepartment of Chemical Engineering, The Pennsylvania State University, University Park, USA
Catal. Sci. Technol., 2017, Advance Article

DOI: 10.1039/C6CY01974A

Methodology for direct catalytic conversion of olefins into cyclic carbonates using peroxide and carbon dioxide under relatively mild conditions is demonstrated. The protocol utilizes packed bed flow reactors in series to couple rhenium catalyzed olefin epoxidation and aluminum catalyzed epoxide carboxylation in a single sequence.

 

 

 

////////Synthesis,  cyclic organic carbonates, catalytic oxidative carboxylation, olefins, flow reactors

Efficient atom and step economic (EASE) synthesis of the “smart drug” Modafinil

Efficient atom and step economic (EASE) synthesis of the “smart drug” Modafinil

Green Chem., 2017, Advance Article
DOI: 10.1039/C6GC02623K, Communication
Shivam Maurya, Dhiraj Yadav, Kemant Pratap, Atul Kumar
We developed a post-sulfoxidation protocol for the synthesis of Modafinil that exhibits improved sustainability credentials, utilizing the recyclable heterogeneous catalyst Nafion-H.

Efficient atom and step economic (EASE) synthesis of the “smart drug” Modafinil

Shivam Maurya,ab   Dhiraj Yadav,a   Kemant Pratapab and  Atul Kumar*ab  
 *Corresponding authors
aMedicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, P.O. Box 173, Lucknow 226031, India
E-mail: dratulsax@gmail.com, atul_kumar@cdri.res.in
bAcademy of Scientific and Innovative Research, New Delhi 110001, India
Green Chem., 2017, Advance Article

DOI: 10.1039/C6GC02623K

Atul Kumar

Atul Kumar

Professor, Academy of Scientific and Innovative Research (AcSIR)/ Senior Principal Scientist at CSIR-CDRI

Central Drug Research Institute

Modafinil (2-[(diphenylmethyl)sulfinyl]acetamide, MOD) is a key psychostimulant drug used for the treatment of narcolepsy and other sleep disorders that has a very low addiction liability. Recently, MOD has been clinically investigated for the treatment of cocaine addiction and used by astronauts in long-term space missions. We have developed a synthetic strategy for “smart drug” Modafinil. An efficient atom and step economic (EASE) synthesis has been carried out by the direct reaction of benzhydrol and 2-mercaptoacetamide using the recyclable heterogeneous catalyst Nafion-H along with post-sulfoxidation. This protocol exhibits improved sustainability credentials. We have also developed a superior pre-sulfoxidation approach for the synthesis of Modafinil.

Modafinil Physical State – White solid; M.p. 158-159ºC,
IR (KBr): 3383, 3314, 3256, 1690, 1 1616, 1494, 1376, 1027, 702 cm-1;
H NMR (CDCl3) δ(ppm): 3.14(d, J=14.3 Hz, 1H); 3.48(d, J=14.3 Hz, 1H); 5.24(s, 1H); 5.88(br s, 1H); 7.09(br s, 1H); 7.29-7.43(m, 7H); 7.43-7.51(m, 3H);
13C NMR (CDCl3) δ(ppm): 52.00, 71.61, 128.80, 128.98, 129.10, 129.58, 129.62, 134.30, 134.74, + 166.46; Molecular formula C15H15NO2S;
ESI-MS (m/z): 274.1 (M+H) .

Dr. Atul Kumar

Senior Principal Scientist

A robust and recyclable polyurea-encapsulated copper(I) chloride for one-pot ring-opening/Huisgen cycloaddition/CO2 capture in water

Green Chem., 2016, 18,6357-6366
DOI: 10.1039/C6GC01956K, Paper
Yun Chen, Wei-Qiang Zhang, Bin-Xun Yu, Yu-Ming Zhao, Zi-Wei Gao, Ya-Jun Jian, Li-Wen Xu
One-pot ring-opening/Huisgen cycloaddition reactions combined with CO2 capture were carried out successfully in the presence of polyurea-encapsulated CuCl.
A robust and recyclable polyurea-encapsulated copper(I) chloride for one-pot ring-opening/Huisgen cycloaddition/CO2 capture in water
Yun Chen,a Wei-Qiang Zhang,a Bin-Xun Yu,a Yu-Ming Zhao,a Zi-Wei Gao,*a Ya-Jun Jiana and Li-Wen Xu*ab
*Corresponding authors
aKey Laboratory of Applied Surface and Colloid Chemistry, Ministry of Education (MOE) and School of Chemistry and Chemical Engineering, Shaanxi Normal University, Xi’an 710062, P. R. China
E-mail: liwenxu@hznu.edu.cn, zwgao@snnu.edu.cn
bKey Laboratory of Organosilicon Chemistry and Material Technology of Ministry of Education, Hangzhou Normal University, No 1378, Wenyi West Road, Science Park of HZNU, Hangzhou 311121, P. R. China
Green Chem., 2016,18, 6357-6366
DOI: 10.1039/C6GC01956K
Multicomponent ring-opening/Huisgen cycloaddition reactions combined with CO2 capture with a polyurea-encapsulated copper salt as a catalyst that in situ formed from simple CuCl and soluble polyurea during the reaction were carried out successfully for the synthesis of β-hydroxytriazoles under exceptionally mild conditions, in which the polyurea-encapsulated copper(I) chloride proved to be a robust and recyclable catalyst system with high yields as well as excellent chemoselectivity in this reaction.
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////////A robust and recyclable,  polyurea-encapsulated, copper(I) chloride,  one-pot,  ring-opening/Huisgen cycloaddition/CO2 capture in water