Adventures in Organophosphorus Chemistry James W. Dulaney, III (Faculty Mentor: David E. Lewis) Department of Chemistry, University of Wisconsin-Eau Claire, Eau Claire, WI 54702-4004 Background Challenges with the Mitsunobu reaction What is required in a replacement to make the reaction Azodicarboxylates, an important component of the re- “green”? Organophosphorus compounds have been an increasingly important part of organic synthesis since the discovery action, are very hazardous: of the Arbuzov rearrangement in 1905. In the century that followed this discovery, the applications of phosphorus- O Green? based reagents in synthesis has grown to incorporate the Wittig and Horner-Wadsworth-Emmons reactions for OEt • They are highly explosive (especially diethyl azodi- N alkene formation, as well as the Mitsunobu inversion reaction, which is used to convert alcohols to a wide range carboxylate). N Green reactions are run under more environmentally sustainable conditions with a view to of products with inversion of configuration. O minimizing environmental impact: • They are highly toxic (especially diethyl azodicar- OEt boxylate). diethyl azodicarboxylate • They are highly regulated. (DEAD) • Wherever possible, renewable sources are used • Wherever possible, hazardous materials are eliminated completely or replaced by The Wittig reaction Ph Ph Ph BuLi Ph less hazardous materials P R P R Regulations have been put into place by the DOT that O Ph Ph O-i-Pr • Wherever possibler, catalytic reactions are used Reaction between an ylide and an aldehyde or ketone to give an alkene. make azodicarboxylic esters even more difficult to ob- N • Hazardous waste is minimized wherever possible (e.g. organic solvents can be re- Reaction gives mainly the Z isomer with aldehydes O tain and use. N R' O placed by water, hazardous Lewis acids are replaced by photochemistry, etc.) H O-i-Pr Reaction is known to proceed through an oxaphosphetane intermediate, • They may not be shipped by air. • Wherever possible, energy use is minimized Ph Ph R diisopropyl azodicarboxylate Ph H R • They may not be shipped by road or rail unless the (DIAD) which undergoes a fragmentation to give the phosphine oxide and the Ph Ph P P + O azodicarboxylic ester is present in a concentration The green replacement compound should have the following properties: alkene Ph O H R' R' of less than 40% w/w. • The compound must be a good Michael acceptor. • The compound must be redox active. • The reaction is driven by oxidation of the phosphine. A brief history of indigo • The azodicarboxylate is reduced in the reaction. The Horner-Wadsworth-Emmons reaction O O O O • The compound must be less hazardous than the azodicarboxylate. RO NaH RO P P RO R' RO R' • Has been known for approximately 4,000 years. Reaction between the conjugate base of a phosphonate ester and an al- • Referenced in Sanskrit writings Answer: One possibility is indigo: it is environmentally benign, redox active, and poten- O dehyde or ketone to give an alkene. The reaction may involve either an R" • Cloths dyed with indigo found on Egyptian mummies and tially a suitable Michael acceptor. oxaphosphetane or a betaine intermediate. H graves of the Inca O O OH OH H H H H • Ancient Briton warriors painted their bodies with it to fright- N N N N O O HO R' Reaction gives mainly the E isomer with aldehydes. O O H RO R' en Roman invaders almost 2,000 years ago R' P N N N N RO + RO H H H H P • Used as dye by Europeans by infusing woad (from Isa- O O O R O RO O O R R R" H R" tis tinctoria) leaves. China, India, Southwest Asia and P P R R O R O R P the East Indies, and West Africa used sources outside P R' O R R R R HN R R" of woad. Indians and Southwest Asians used true indigo O O R' O (Indigofera sumatrana). Around 1500 A.D., woad was re- R" O placed by true indigo as main plant used in production NH O O OR O throughout Europe (especially France). CO2R • Indigo might function because of the strong oxygenophilicity of the phosphine OR HN CO2R • Huge industry formed in South Carolina during late 18th N PPh3 H N N • The product is leucoindigo, which can be easily recycled by oxidation in air N a PPh R O N CO2R 3 century, colonial America… until the Revolutionary War. The Mitsunobu reaction RO C O 2 Ph3P H b • Synthetic indigo, which was developed by Johann Fried- R Ra Rb H Involves the reaction between an alcohol and a carbox- rich Wilhelm Adolf von Bayer, replaced natural (biosyn- ylate anion in the presence of triphenylphosphine and a thetic) indigo in the industry. O O • Is the dye found in your jeans Initial attempts to make the Mitsunobu reaction dialkyl azodicarboxylate. c R “green” The reaction proceeds with inversion at carbon. H O OR Ra Rb + O PPh3 + HN CO2R O O We attempted the formation of isopentyl N Ph3P, CH2Cl2 H c Unexpected isomerization of triethyl OH OAc ? R acetate (“banana oil”) by the reaction of AcOH, indigo phosphite the alcohol and acetic acid in the pres- air, r.t. ence of indigo. Ph3P O We focused our initial efforts on de- EtO catalyst EtO None of the desired ester was observed, but the formation of triphenylphosphine oxide termining if the failure of the Mitsuno- EtO P EtO P O X solvent bu coupling was due to steric effects. EtO H was observed. Because the triphenylphosphine oxide might have been formed by oxida- The Arbuzov (Michaelis-Arbuzov) rearrangement R R tion of the phosphine by atmospheric oxygen during the reaction, we repeated the reac- Phopshite esters are strongly oxygeno- catalyst: indigo, hydroquinone, methyl salicylate O R' X O solvent: CH2Cl2, CHCl3 tion under an atmosphere pf carbon dioxide. No significant difference in the reaction out- Reaction converts a trialkylphosphite (tricoordinate) into a dialkyl alkylphosphonate O P O P R' philic, and have a significantly smaller R O R O come was observed. This rules out the involvement of molecular oxygen in the reaction. (tetracoordinate) R R cone angle than triphenylphosphine. The reaction again failed to give any coupled product, but 31P NMR What happened? A molecule of the alkyl halide is produced in the same reaction spectroscopy showed that the triethyl phosphite had been c0nverted to diethylphosphonate, in a reaction reminiscent of the Arbuzov rear- O X There are two possible rationalizations why the coupling reaction failed: Mechanism was elucidated by Arbuzov in 1905 + P rangement. To test this possibility, we treated triethyl phosphite with R RO R' RO two weak Lowry-Brønsted acids: hydroquinone and methyl salicylate. In both cases, the reaction proceeded smoothly. A kinetic study of the • The triphenylphosphine may have been too sterically hindered same reaction revealed that the reaction proceeded much faster in di- to react effectively with the indigo (i. e. its “cone angle” is too M chloromethane than in chloroform. large) P • This could be remedied by using a tricoordinate phosphorus R R We focused our initial efforts on determining if the failure of the Mitsu- nucleophile with a smaller cone angle R nobu coupling was due to steric effects. Phopshite esters are strongly • phosphite esters, tributylphosphine Acknowledgments oxygenophilic, and have a significantly smaller cone angle than triphe- nylphosphine. A possible mechanism for this reaction is shown below: • The triphenylphosphine may not have been nucleophilic enough (Tolman’s electronic We extend special thanks to University of Wisconsin-Eau Claire Office of Research and Sponsored parameter may have been too large — the nucleophile strength may have been too low) EtO EtO EtO • This could be remedied by using a more nucleophilic phosphine (e.g. tributylphos- Programs and the Ronald E. McNair Post-baccalaureate Achievement Program for funding and supporting EtO P H O EtO P H O EtO P H this research, and we thank Learning and Technology Services for printing this poster. We also thank Mr. EtO Ar O H Ar O phine) Malik Shagosh for help with the early experiments..