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Presiden-al Green Chemistry Challenge Awards 

•  Awards have been given since 1996 in five categories: – Greener synthe-c pathways 

•  feedstocks, reagents and catalysts, atom economy – Greener reac-on condi-ons 

•  solvents, energy efficiency – Design of greener chemicals 

•  less toxic, recyclable or biodegradable, safer –  Small business (less than $40 mil in annual sales) – Academic 

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Award Selec-on Criteria 

1.  Science and innova-on –  Must be original and scien-fically valid. 

2.  Human health and environmental benefits –  Should offer these benefits at some point in its 

lifecycle. 

3.  Applicability and impact –  Must be prac-cal and commercially viable, and 

solve a real problem. 

Ch. 7 – Evalua-ng Reac-on Types 

•  Some types of reac-ons are inherently more efficient than others. 

•  Recall the defini-on of atom economy: 

•  Atom economy describes the amount of reactants that end up in the products. 

% Atom economy = FW of atoms utilized

FW of all reactants used

Trost, B. M. The Atom Economy–A Search For Synthe-c Efficiency. Science, 1991, 254, 1471‐1477.   

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Evalua-ng Reac-on Types 

•  What is the atom economy? •  Is a waste inherently generated? •  Is an auxiliary substance required? – Diels‐Alder Reac-on – Wi_g Reac-on – Friedel‐Cra`s Acyla-on – Oxymercura-on‐Demercura-on – Bromina-on of an alkene – Swern oxida-on 

The Future of Green Chemistry 

a few thoughts 

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Ch. 10 – Future Trends in Green Chemistry 

•  Anastas and Warner iden-fy seven areas of focus that are challenging to chemists and poten-ally beneficial to the environment. 

1. Oxida-on reagents and catalysts 

•  Petroleum compounds are o`en oxidized to add func-onality 

•  Tradi-onal reagents – chromium and other toxic metals – chlorine bleaching 

•  New reagents – molecular oxygen – hydrogen peroxide 

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Cataly-c route to ethylene oxide 

•  Developed in 1930s •  Completely superseded chlorohydrin route by 1975 

+ 1/2 O2

Ag O

2. Biomime-c reagents 

•  Currently, synthe-c chemists carry out reac-ons with mul-ple toxic reagents, low yield, and lots of waste. 

•  Nature uses enzymes – highly selec-ve and efficient cataly-c reagents  

•  Chemists are working on adap-ng enzymes for laboratory synthesis, and developing new reagents that mimic enzymes 

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(11, 12). To assess the feasibility of developing anenzyme for sitagliptin synthesis, we generated astructural homology model of ATA-117 (17) todevelop hypotheses for initial library designs.Docking studies using this model suggested thatthe enzyme would be unable to bind prositaglip-tin ketone (Fig. 2B) because of steric interferencein the small binding pocket and potentially un-desired interactions in the large binding pocket(Fig. 2C). By using a substrate walking approach(18) with a truncated substrate (Fig. 2D), we firstengineered the large binding pocket of the en-zyme and then evolved that enzyme for activitytoward prositagliptin ketone.

Consistentwith themodel, ATA-117was poorlyactive on the truncated methyl ketone analog(Fig. 2D), giving 4% conversion at 2 g/l substrateloading (table S2). Site saturation libraries of res-idues lining the large pocket of the active site pro-vided new variants with increased activity towardthe methyl ketone analog. The best variant con-tained a S223 → P223 [S223P (19)] mutation andshowed an 11-fold activity improvement (Fig. 3and table S1). On the basis of this improved var-iant (ATA-117: S223P), we generated a smalllibrary of enzyme variants for potential activityon prositagliptin ketone. Analysis of the enzymemodel suggested four residues that could poten-tially interact with the trifluorophenyl group [V69,F122, T283, and A284 (19)]. Each of these po-sitions was individually subjected to saturationmutagenesis and also included in a combinatoriallibrary that evaluated several residues at each po-sition on the basis of structural considerations[V69→G69 andV69→A69 (V69GA),F122AVLIG,T283GAS, and A284GF; library size of 216 var-iants]. A variant containing four mutations, threein the small binding pocket and one in the largepocket, provided the first detectable transaminaseactivity on prositagliptin ketone (Fig. 3 and tableS3). No detectable activity was identified in anyof the variants from the single amino acid site sat-uration libraries. Initial activity was accomplishedvia an F122I, V, or L mutation in combinationwith V69G or A284G. Docking studies indicatedthat these mutations may relieve the steric inter-ference in the small binding pocket (Fig. 2E). En-zyme loading of 10 g/l provided 0.7% conversionof 2 g/l of ketone over 24 hours, corresponding toan estimated turnover of 0.1 per day. Screeningthe same combinatorial library in the ATA-117context without the S223P large binding pocketmutation did not provide any variant with detect-ible activity toward prositagliptin ketone. Havingattained activity through computer-aided catalystdesign, we started evolving an enzyme variant fora practical, large-scale process.

The variant with the highest activity towardprositagliptin ketone from round 1b was chosenas the parent for the second round of evolution,and all the beneficial mutations from both thesmall-pocket combinatorial library and the large-pocket saturation mutagenesis libraries werecombined into a new library. Screening of this li-brary resulted in a variant with 75-fold increased

Fig. 1. (A) The current synthesis of sitagliptin involves enamine formation followed by asymmetric hy-drogenation at high pressure (250 psi) using a rhodium-based chiral catalyst, providing sitagliptin in 97%e.e.,with trace amounts of rhodium. Recrystallization to upgrade e.e. followed by phosphate salt formationprovides sitagliptin phosphate. (B) Our biocatalytic route features direct amination of prositagliptin ketoneto provide enantiopure sitagliptin, followed by phosphate salt formation to provide sitagliptin phosphate.

Fig. 2. Previous substrate range studies suggested that the active site of transaminase consists of large (L)and small (S, typically limited to substituents about the size of a methyl group) binding pockets as mappedon the structure of acetophenone (A). Accordingly, the structure of prositagliptin ketone (B) can be mappedon these binding pockets and docked intothe active site of the homology model (C). A prositagliptin ketoneanalog (D) was designed to fit the large pocket for initial optimization of this part of the active site. Afterinitial engineering of the large pocket, an enzyme variant was generated with activity on the desiredsubstrate (E) by excavating the small pocket (gray/blue, transaminase homology model; orange, largebinding pocket; turquoise, small binding pocket; green, PLP and catalytic residues).

16 JULY 2010 VOL 329 SCIENCE www.sciencemag.org306

REPORTS3rd genera-on synthesis of sitaglip-n 

•  Employs enzyma-c catalysis instead of Rh. 

•  >99.5% e.e. •  Further 19% reduc-on in waste 

•  3rd genera-on won Presiden-al Green Chemistry Award in 2010. 

•  Savile, C. K. et al. Biocataly-c Asymmetric Synthesis of Chiral Amines from Ketones Applied to Sitaglip-n Manufacture. Science. 2010, 329, 305. 

•  Desai, A. A. Sitaglip-n Manufacture: A Compelling Tale of Green Chemistry, Process Intensifica-on, and Industrial Asymmetric Catalysis. Angew. Chem. Int. Ed. 2011, 50, 1974. 

3. Combinatorial green chemistry 

•  Combinatorial chemistry involves making a large library of compounds and screening those compounds for func-onality 

•  Used mainly for drug and materials discovery •  Combinatorial techniques are being used to test compounds for toxicity – hip://www.voanews.com/english/news/science‐technology/New‐Robot‐can‐test‐10000‐Chemicals‐Weekly‐121260614.html 

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4. Preven-ng and solving pollu-on problems 

•  Using alternate feedstocks that are currently considered waste: – carbon dioxide – biomass – halogenated aroma-c compounds – glycerol 

•  Using waste as a feedstock prevents that waste from entering the environment 

5. Solventless reac-ons 

•  Much of the waste of industrial chemistry is solvents, so elimina-ng solvents eliminates waste. 

•  Alterna-ves to solvents: – molten‐state –  dry‐grind –  plasma –  solid‐supported reac-ons 

•  Instead of heat, chemists can use microwave, ultrasound, or visible light to promote reac-ons. 

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Solventless Biocatalysis 

•  Eastman Chemical developed a solventless, biocataly-c method for making esters for cosme-cs. 

•  Rather than hea-ng  under harsh condi-ons,  an immobilized enzyme  is used. 

•  Won a Presiden-al  Green Chemistry Award  in 2009.  Image from pubs.acs.org 

Alterna-ve solvents •  2011 Presiden-al Green Chemistry Award  •  Bruce Lipshutz (UCSB) – development of surfactants that allow organic reac-ons to take place in water 

•  Allows forma-on of carbon‐carbon bonds in water at room temperature. 

Lipshutz, et al. J. Org. Chem. 2011, 76, 4379‐4391. 

Vitamin E succinic acid 

PEG‐750 

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6. Energy 

•  Energy needs con-nue to grow, but large‐scale alterna-ves to burning carbon have not been developed. 

•  Chemists are working on: – capture (solar panels) – storage (fuel cells) –  transport (hydrogen adsorp-on) 

•  Also – energy‐efficient processes for manufacture of chemical products. 

7. Non‐covalent deriva-za-on 

•  Involves modifica-on of chemical proper-es through non‐covalent interac-ons rather than covalent bonds. 

•  Usually saves on solvent, energy use, and auxiliary substances for purifica-on 

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Polaroid instant photography •  Warner developed a new, less toxic, more economical approach to hydroquinoline stability 

original approach – tradi-onal synthesis that requires hazardous reagents, solvents, and high energy  

new approach – non‐covalent network of molecules that allows development of photo w  

hip://www.warnerbabcock.com/partner_with_wbi/non‐covalent_deriva-za-on.asp 

Other areas 

•  Alterna-ve energy •  Alterna-ves to known toxics – BPA, phthalates, flame retardants, chlorinated compounds, etc. 

•  Educa-on – Requiring toxicology classes of chemistry majors –  Integra-ng green chemistry into all areas of the curriculum 

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Other areas •  Na-onal policy – update to TSCA – Safe Chemicals Act of 2011 (Senate) •  C&EN this week: “Senators want the industry group American Chemistry Council (ACC) to quit griping about legisla-on to reform the na-on’s chemical control law and cough up details of what it wants in the bill.” 

– Toxic Chemicals Safety Act of 2010 (House) – Green Chemistry Policy  

•  John Warner – Intellectual Ecology 

•  hip://vimeo.com/15922167 

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PRESENTATION TOPICS 

Homework 

•  Wriien summary of your final project – due to me by email no later than SUNDAY NIGHT –  I will make correc-ons and give them back to you on Tuesday. 

•  Read Ch. 10 in A&W and paper by Iles •  Prepare some ques-ons to ask Mike Cann on skype 

•  Get ready for the Green Chemistry Café Quiz – Feel free to send me some ques-ons. If I use them you’ll already know the answers!