Highly chemoselective reduction of nitroarenes over non-noble metal nickel-molybdenum oxide catalysts

ORGANIC CHEMISTRY SELECT


Highly chemoselective reduction of nitroarenes over non-noble metal nickel-molybdenum oxide catalysts

Green Chem., 2017, 19,809-815
DOI: 10.1039/C6GC03141B, Paper
Haigen Huang, Xueguang Wang, Xu Li, Chenju Chen, Xiujing Zou, Weizhong Ding, Xionggang Lu
A non-noble Ni-MoO3/CN@SBA-15 catalyst exhibits unprecedented catalytic activity and chemoselectivity for the reduction of nitroarenes to anilines in ethanol with hydrazine hydrate.

Highly chemoselective reduction of nitroarenes over non-noble metal nickel-molybdenum oxide catalysts

Haigen Huang,a  Xueguang Wang,*ab  Xu Li,a  Chenju Chen,b  Xiujing Zou,b  Weizhong Dingab and  Xionggang Lu*ab  
*Corresponding authors
aState Key Laboratory of Advanced Special Steel, Shanghai University, Shanghai 200072, China
E-mail: wxg228@shu.edu.cn, luxg@shu.edu.cn
bShanghai Key Laboratory of Advanced Ferrometallurgy, Shanghai University, China
Green Chem., 2017,19, 809-815

DOI: 10.1039/C6GC03141B

The chemoselective reduction of…

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Synthesis of tetrazines from gem-difluoroalkenes under aerobic conditions at room temperature

ORGANIC CHEMISTRY SELECT

Synthesis of tetrazines from gem-difluoroalkenes under aerobic conditions at room temperature

Green Chem., 2017, Advance Article
DOI: 10.1039/C6GC03494B, Paper
Zheng Fang, Wen-Li Hu, De-Yong Liu, Chu-Yi Yu, Xiang-Guo Hu
A procedure for the synthesis of tetrazines from gem-difluoroalkenes under aerobic conditions has been developed.

Synthesis of tetrazines from gem-difluoroalkenes under aerobic conditions at room temperature

Zheng Fang,a  Wen-Li Hu,a  De-Yong Liu,a  Chu-Yi Yuab and  Xiang-Guo Hu*a  
*Corresponding authors
aNational Engineering Research Center for Carbohydrate Synthesis, Jiangxi Normal University, Nanchang 330022, P. R. China
E-mail: huxiangg@iccas.ac.cn
bBeijing National Laboratory for Molecular Science (BNLMS), CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China
Green Chem., 2017, Advance Article

DOI: 10.1039/C6GC03494B, http://pubs.rsc.org/en/Content/ArticleLanding/2017/GC/C6GC03494B?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

An efficient and green procedure for the synthesis of tetrazines has…

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Photobiocatalytic alcohol oxidation using LED light sources

Photobiocatalytic alcohol oxidation using LED light sources

Oxidative lactonization of meso-3-methyl-1,5-pentanediol to (S)-4-methyltetrahydro-2H-pyran-2-one using horse liver alcohol dehydrogenase (HLADH) and photocatalytic, aerobic regeneration of NAD+.

Green Chem., 2017, 19,376-379
DOI: 10.1039/C6GC02008A, Communication
Open Access Open Access
Creative Commons Licence  This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.
M. Rauch, S. Schmidt, I. W. C. E. Arends, K. Oppelt, S. Kara, F. Hollmann
The photocatalytic oxidation of NADH using a flavin photocatalyst and a simple blue LED light source is reported.

Photobiocatalytic alcohol oxidation using LED light sources

M. Rauch,a   S. Schmidt,a   I. W. C. E. Arends,a   K. Oppelt,b  S. Karac and   F. Hollmann*a  
*Corresponding authors
aDepartment of Biotechnology, Delft University of Technology, van der Maasweg 9, 2629HZ Delft, The Netherlands
E-mail: f.hollmann@tudelft.nl
bInstitute of Inorganic Chemistry, Johannes Kepler University Linz, Altenberger Strasse 69, 4040 Linz, Austria
cInstitute of Technical Biocatalysis, Hamburg University of Technology, Denickestrasse 15, 21073 Hamburg, Germany
Green Chem., 2017,19, 376-379

DOI: 10.1039/C6GC02008A, http://pubs.rsc.org/en/Content/ArticleLanding/2017/GC/C6GC02008A?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

image file: c6gc02008a-s1.tif
Scheme 1 Aerobic oxidation of reduced nicotinamide cofactors (NAD(P)H) to the corresponding cofactors (NAD(P)+) using photoexcited flavin catalysts. Upon photoexcitation (λ = 450 nm) the redox potential of the oxidised flavin catalyst increases dramatically enabling fast hydride transfer from NAD(P)H to the flavin. The reduced flavin reacts spontaneously in a dark reaction with molecular oxygen

The photocatalytic oxidation of NADH using a flavin photocatalyst and a simple blue LED light source is reported. This in situ NAD+ regeneration system can be used to promote biocatalytic, enantioselective oxidation reactions. Compared to the traditional use of white light bulbs this method enables very significant reductions in energy consumption and CO2 emission.

Synthesis of (S)-4-methyltetrahydro-2H-pyran-2-one catalyzed by HLADH The synthesis of (S)-4-methyltetrahydro-2H-pyran-2-one was performed as previously reported by Kara et al. (2013).[3] For this, a stock of meso-3-methyl-1,5-pentanediol (0.5 M), NAD+ stock (25 mM), acetosyringone stock (2 mM), and HLADH stock (3 gL–1 ) were freshly prepared in 50 mM Tris-HCl buffer at pH 8. The laccase was applied as delivered (0.2 mM solution). The mixture of meso-3- methyl-1,5-pentanediol stock (1 mL), acetosyringone stock (1 mL), NAD+ stock (0.2 mL) and buffer (6.7 mL) was incubated at 30 °C for 5 min. Finally, laccase (0.1 mL) and HLADH solution (1 mL) were added. The starting concentrations were: 50 mM meso-3-methyl-1,5-pentanediol, 0.5 mM NAD+ , 200 µM acetosyringone, 0.3 gL–1 HLADH and 2 µM laccase. The reaction mixture (10 mL) was orbitaly shaken at 600 rpm in 50 mL Falcon tubes at 30 °C. Samples (50 µL) were taken at defined time intervals and mixed with 200 µL EtOAc (containing 5 mM acetophenone). The mixture was vortexed and dried over anhydrous MgSO4. A conversion of 72 % to the enantiopure (S)-4-methyltetrahydro- 2H-pyran-2-one (ee > 99% according to GC analysis) was achieved after 16 hours. The reaction mixture (10 mL) was then saturated with NaCl and extracted with EtOAc (3 x 10 mL). After each extraction step the mixture was centrifuged (4000 rpm, 10 min). The collected clear organic phase was dried over anhydrous MgSO4 and the solvent was removed under reduced pressure to give a yellowish oily compound (39 mg). Purification of the crude product was attempted by column chromatography (Pasteur pipette filled with Silica gel 60, 70-230 mesh particle size; solvent petroleum ether: ethyl acetate 9:1).

. Picture of the reaction setup. Commercially available LED bands (3 colored) were wrapped around a thermostatted reaction vessel and used for illumination of the reaction mixture inside (S)-4-Me-DVL (R)-4-Me-DVL (generally in a Schlenk vessel) a slight overpressure was achieved by an air-filled balloon to reduce O2-transfer limitations to the reaction mixture

//////////Photobiocatalytic alcohol oxidation,  LED light sources

Asymmetric synthesis of (S)-phenylacetylcarbinol – closing a gap in C–C bond formation

Graphical abstract: Asymmetric synthesis of (S)-phenylacetylcarbinol – closing a gap in C–C bond formation

image file: c6gc01803c-f3.tif
Fig. 3 Stereoselectivities of the new ApPDC-variants for the synthesis of (S)-PAC. The different variants were tested as wet cells, crude cell extracts, and purified enzymes. Reaction conditions: wet cells – 20 mM benzaldehyde; 200 mM pyruvate; 50 mM KPi-buffer (pH 6.5), 2.5 mM MgSO4; 0.1 mM ThDP; 20 °C; 800 rpm, 800 μL reaction volume in 1.5 mL closed glass vials, whole cell catalyst concentration of 50 mg mL−1. Crude cell extract – 20 mM benzaldehyde; 200 mM pyruvate; 50 mM KPi-buffer (pH 6.5), 2.5 mM MgSO4; 0.1 mM ThDP; 20 °C; 800 rpm, 500 μL reaction volume in a 96-well sheet; see ESI chapter 2.1.4–2.1.5 for the catalyst concentration. Purified enzyme – 40 mM benzaldehyde; 200 mM pyruvate; 50 mM KPi-buffer with three different pH values, 2.5 mM MgSO4; 0.1 mM ThDP; 22 °C; 800 rpm, 800 μL reaction volume in 1.5 mL closed glass vials; protein concentration of 1 mg mL−1.

Asymmetric synthesis of (S)-phenylacetylcarbinol – closing a gap in C–C bond formation

*Corresponding authors
aInstitute of Bio- and Geosciences, IBG-1: Biotechnology, Forschungszentrum Jülich GmbH, Leo-Brandt-Str. 1, 52425 Jülich, Germany
E-mail: do.rother@fz-juelich.de
bHERBRAND PharmaChemicals GmbH, Brambachstr. 31, 77723 Gegenbach, Germany
cAlbaNova University Center, Royal Institute of Technology – School of Biotechnology, Roslagstull 21, Stockholm, Sweden
dInstitute of Pharmaceutical Sciences, Albert-Ludwigs-University Freiburg, Albertstrasse 25, 79104 Freiburg, Germany
eMerz Pharma GmbH & Co. KGaA, Am Pharmapark, D-06861 Dessau-Rosslau, Germany
fInstitute of Technical Biochemistry, University of Stuttgart, Allmandring 31, 70569 Stuttgart, Germany
gTRUMPF GmbH+Co.KG, Ditzingen Johann-Maus-Straße 2, 71254 Ditzingen, Germany
hEnzymicals AG, Walther-Rathenau-Str 49a, 17489 Greifswald, Germany
Green Chem., 2017,19, 380-384

DOI: 10.1039/C6GC01803C

(S)-Phenylacetylcarbinol [(S)-PAC] and its derivatives are valuable intermediates for the synthesis of various active pharmaceutical ingredients (APIs), but their selective synthesis is challenging. As no highly selective enzymes or chemical catalysts were available, we used semi-rational enzyme engineering to tailor a potent biocatalyst to be >97% stereoselective for the synthesis of (S)-PAC. By optimizing the reaction and process used, industrially relevant product concentrations of >48 g L−1 (up to 320 mM) were achieved. In addition, the best enzyme variant gave access to a broad range of ring-substituted (S)-PAC derivatives with high stereoselectivity, especially for meta-substituted products.

image file: c6gc01803c-f2.tif
Fig. 2 Schematic representation of the active site of ApPDC. The legends explain the effect of different amino acid residues on the preferred orientation of the ThDP-bound donor substrate acetaldehyde, derived from pyruvate after decarboxylation (green rectangle) and the aromatic acceptor aldehyde (blue hexagon). The relative orientation of both substrates to each other defines the stereoselectivity of the product. (The figures refer to the stereoselectivities achieved with purified enzyme.)

///////////////Asymmetric synthesis, (S)-phenylacetylcarbinol,  C–C bond formation

http://pubs.rsc.org/en/Content/ArticleLanding/2017/GC/C6GC01803C?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

Pd/Cu-free Heck and Sonogashira cross-coupling reaction by Co nanoparticles immobilized on magnetic chitosan as reusable catalyst

ORGANIC CHEMISTRY SELECT

Pd/Cu-free Heck and Sonogashira cross-coupling reaction by Co nanoparticles immobilized on magnetic chitosan as reusable catalyst

Green Chem., 2017, Advance Article
DOI: 10.1039/C6GC03377F, Paper
Abdol R. Hajipour, Fatemeh Rezaei, Zahra Khorsandi
Chitosan (CS) is a porous, self-standing, nanofibrillar microsphere that can be used as a metal carrier. Amino groups on CS enable to modulate cobalt coordination using a safe organic ligand (methyl salicylate).

Pd/Cu-free Heck and Sonogashira cross-coupling reaction by Co nanoparticles immobilized on magnetic chitosan as reusable catalyst

aDepartment of Chemistry, Isfahan University of Technology, Isfahan 84156, Iran
E-mail: haji@cc.iut.ac.ir
Fax: +98 311 391 2350
Tel: +98 311 391 3262
bDepartment of Neuroscience, University of Wisconsin, Medical School, Madison, USA
Green Chem., 2017, Advance Article

DOI: 10.1039/C6GC03377F

Department of Chemistry
Office : College of Chemistry…

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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