Sulfur Trioxide Amine Complexes:

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1 : Versatile Reagets i rgaic Sythesis Dr. Jörg Schrickel Busiess Maager Specialities

2 Cotet Sulfur trioxide chemistry: Itroductio Sulfur trioxide reagets: verview ad Properties Sulfur trioxide amie complexes: Products ad Properties Reactivity Selectivity Sesitivity Diversity Summary 2

3 Sulfur trioxide chemistry: Itroductio Exhibitig a similar reactivity as oxyge, sulfur forms thiols, thioethers, thioketoes ad others. More importat are compouds, where sulfur is preset i a higher oxidatio level: sulfur trioxide derivatives. Sulfur trioxide is a high desity liquid (1.92 g/ml) with a meltig poit of 16.9 C ad a boilig poit of 45 C. It is highly corrosive ad aggressively hygroscopic. I Europe, sulfur trioxide is ot commercially available i bulk quatities. To facilitate hadlig ad to have sulfur trioxide i a available form, dilutios of sulfur trioxide are maily used: chlorosulfoic acid, oleum, sulfuric acid, sulfamic acid. 3

4 Sulfur trioxide chemistry: Itroductio * Liear Alkylbezee sulfoate Deterget S a + + a S 3 S 3 a + Mordat Yellow 20 Dye a + C 2 a + S Dimethyl sulfate Methylatig aget 2 S S S a + Tolueesulfoyl hydrazide Blowig aget for rubber Sulfoated sytree diviylbezee copomylers Io exchage resis Sacchari Artificial Sweeteer Me Me Me S 2 S * CF 2 CF 2 x CF 2 CF 2 y * CF 2 FC CF 2 S 3 F 3 C CF 2 4 Ciesulfuro ("Sailat") Sulfoylurea erbicide Sulfamethoxazol Sulfoamide Atibiotic AFI TM (DuPot) Sulfoated Polymer

5 Sulfur trioxide reagets: verview S 3 trasfer reactios ca be carried out by a rage of (commercially available) sulfur trioxide reagets. These have differet grades of reactivity. CABB offers most of them. S 3 S 3 /air 2 S 4 + S 3 S 3 * 2 S 4 leum Cl + S 3 ClS 3 Chlorosulfoic Acid + 2 S 3 2 S 4 Sulfuric Acid 3 + S 3 2 S 3 Sulfamic Acid R + 3 S 3 S 3 * R 3 Sulfur TrioxideAmie Complexes 5

6 Sulfur trioxide reagets: verview Cl Cl + S 2 S 2 Fie Chemicals ad Custom Sythesis 2 Cl Cl 2 ClS 3 S 2 Cl 2 SCl 2 (C 3 ) 2 S 2 S 3 amie Cl 2 Cl 2 a 2 S 4 oleum S 3 S 2 acl S 6 CABB produces i a itegrated productio system sulfur trioxide ad derived reagets, for sales ad captive use of dowstream products.

7 Sulfur trioxide reagets: Properties Reactivity Selectivity Sesitivity Diversity Process Applicatio high low low limited use dedicated commodities covetioal reagets S 3 S 3 /air leum Sulfuric acid Chlorosulfoic acid Sulfamic acid S 3 amie complexes low high high broad use variable fie chemicals 7

8 Sulfur Trioxide amie complexes: Products S 3 S 3 Me Me S 3 S 3 Trimethylamie S 3 TMAS Triethylamie S 3 TEAS Dimethylailie S 3 DMAS Dimethylformamide S 3 DMFS S 3 S 3 S 3 Pyridie S 3 PSS Polyviylpyridie S 3 PVPS Dioxae S 3 DIS Lewis Base stregth: Trimethylamie > Triethylamie > Pyridie > Dimethyl ailie > Dimethylformamide Reactivity complexes: TMAS < TEAS < PSS < DMAS < DMFS 8

9 Sulfur Trioxide amie complexes: Properties Reactivity: Moderated reactivity compared to covetioal reagets Modificatio of reactivity with Lewis base stregth of amies Cleaer reactios: better uiformity ad reproducibility of ed products Selectivity: Cotrolled selectivity compared to covetioal reagets Sulfatio of carbohydrates with high regioselectivity Selective sulfatio of or atoms Sesitivity: Sulfoatio reagets for acid sesitive compouds (e.g. heterocycles) Sulfatio of polysaccharides without degradatio of polymer backboe o cleavage of acid sesitive bods Diversity: ParikhDoerig oxidatio with Pyridie sulfur trioxide Deoxygeatio ad dehydratio as further reactios 9

10 Reactivity: sulfatio of carbohydrates sulfuric acid or chlorosulfoic acid * S 3 S 3 S 3 Use of covetioal reagets for sulfatio of polysaccharides: Chai cleavage Difficulty to cotrol exted of reactio Discolored decompositio products Uiformity of products, oreproducible viscosity Decreasig reactivity due to formatio of water ad dilutio of the reactio mixture Difficulties with isolatio ad recovery of solvets Low yields of sulfated products Advatages of Sulfur trioxide amie complexes: Reactivity of reagets maitaied o chai cleavage, resultig i reproducible viscosity Superior uiformity of products Better cotrol of reactio Discoloratio ca be preveted Good yield of sulfated products I case of polymeric pyridie S 3 complex: o residual amies, ease of work up 10 Literature: US 3,057,855 (1962); US 4,814,437 (1989); US 4,855,416 (1989); US 2009/ (2009) R.G. Schweiger, Carbohyd. Res. 1972, 21,

11 Selectivity: regioselectivity;, selectivity C 3 chlorosulfoic acid * C 3 S 3 S 3 2 S 3 S 3 * 2 2 Chitosa * PSS Sulfatio epari: of chitosa: aturally Chlorosulfoic occurig acid sulfated i pyridie: polysaccharide Cosists mixture of alteratig sulfatedsulfated glucosamie chitosa ad glucuroic or selective acid sulfatio. uits Shows aticoagulat activity ad is a key player i the regulatory etwork of the cell Pyridie S 3 complex: Chitosa: selective sulfatio aturally occurig polyacetylglucosamie, preset i crab shells Sulfatio of chitosa will lead to products with similar structure as hepari Regioselectivity ca be achieved by the proper choice of the sulfur trioxide amie complex to obtai selective 2 or 6sulfatio i polysaccharides. Atom selectivity is foud i amioalcohols, where sulfur trioxide amie complexes selectively sulfate the itroge whereas chlorosulfoic acid sulfates the hydroxyl groups. * 3 S S 3 C 3 * 11 Literature: W.A. Reeves, J.D. Guthrie; J. Am. Chem. Soc. 1953, 75, 4101 D.T. Warer; L.L. Colema; J. rg. Chem. 1958; 23, US (1999) P. Vogcha; W. Sajomsag; D. Subye; P. Kogtawelert; Carbohyd. Res. 2002, 337,

12 Sesitivity: o degradatio, o cleavage * sulfatio reaget 3 S * Carboxymethyl modified dextrae Sulfatio Carboxymethyl of carboxymethyl modified dextraeas may a lead example to three for the reactios: sulfatio sulfatio of a modified of hydroxyl polysaccharide: groups with differet Dextra degree sulfate (i of sulfatio, form of its cleavage sodiumof salt) the has carboxymethyl medical ad group, pharmaceutical cleavage of applicatios. the glycosidicit bods shows of aticoagulat the polymer backboe. properties, acts The as choice atilipemic of the sulfatio ad atiulcer reaget aget iflueces ad has degree demostrated of sulfatio ati IV (dss), activity. degree of cleavage of carboxymethyl bod (dscm) ad the degradatio of the polymer backboe (reduced sugars). Reaget equivalets coditios dss dscm reduced sugars referece ClS C ClS C DMFS 2 30 C DMFS/2M2B 2 30 C M2B = 2Methyl2butee (acid scaveger) 12 Literature: E. Petit, et al, Macromolecules, 2005, 38, US 2004/

13 Diversity: Sythesis of Geistei a S 3 S 3 a C Geistei C C Geistei belogs to the group of isoflavoes, which are foud i several plats ad which show atihelmitic ad atioxidat properties ad i additio ca act similar to estroge. Geistei Possible methods for the sythesis of Geistei: Boro trifluoride: evirometally ufavorable, high temperatures, moderate yield (61%), activates the methylee group ad deactivates the aromatic rig 1. Amie route: evirometally ufavorable amie waste ad ecoomically ufavorable (high temperatures, multistep sythesis, moderate yields) 2. Sythesis of Geistei usig DMFS 3 : Sythesis with modificatio/activatio of formic acid Moderate reactio coditios Evirometally o cocers Recyclig of DMF igh yields (95%) Literature: 1 Sythesis 1978, J. Chem. Soc. 1953, US 2004/158082; W 2004/

14 Diversity: ParikhDoerig oxidatio ppeauer oxidatio 2 DMS, 2, phase Ettrasfer 3 Swer oxidatio S oxalyl chloride, 3 DMS xidatio methods for primary ad secodary alcohols 1 : ppeauer oxidatio ( 2 2 ad phase trasfer catalyst, poor yields) Swer xidatio (oxalyl chloride ad dimethyl sulfoxide, temperatures below 0 C, release of C, C 2 ad dimethyl sulfide as off gases) ParikhDoerig oxidatio 2 : Excellet yields Excellet results with temperatures above 0 C ly Dimethyl sulfide as off gas 14 Literature: 1 K. v d Bruch, Chemistry Today, 2010; 28, 4850; 2 J.P. Parikh, W.E. Doerig, J. Am. Chem. Soc., 1967, 89,

15 Summary Sulfur trioxide amie complexes exhibit a variety of advatages regardig sulfoatio ad sulfatio reactios over covetioal reagets Sulfur trioxide amie complexes allow further differet reactios to sulfoatio/sulfatio which are ot as easy accessible with other techiques CABB offers: most of the sulfatio/sulfoatio reagets the support to carry out these reactios the facilities ad plats to perform these reactios to optimise these reactios 15

16 Thak you very much. Please visit CABB at booth o. B15, hall 21 Dr. Jörg Schrickel Busiess Maager Specialities Dr. Jörg Schrickel Busiess Maager Specialities CABB AG Dügerstrasse 81 C4133 Prattel/Switzerlad

Sulfur Trioxide Amine Complexes:

Sulfur Trioxide Amine Complexes: : Versatile Reagents in rganic Synthesis Dr. Jörg Schrickel Business Manager Specialities Content Sulfur trioxide chemistry: Introduction Sulfur trioxide reagents: verview and Properties Sulfur trioxide