Guanidinophosphazenes: Synthesis, Application and Basicity in THF and in the Gas Phase Alexander A. Kolomeitsev

Team Dr. Jan Barten Dr. Alexander Kolomeitsev Falko Przyborowski Prof. Dr. Gerd-Volker Röschenthaler Dr. Dmitrij Sevenard

HFC Company Profile 1 Hansa Fine Chemicals GmbH was created as a University of Bremen (Germany) spin-off and was launched as a Limited Company (GmbH) in February The company’s operating base are state of the art laboratories and offices located within the University of Bremen Chemistry Department. HFC is entirely independent of any other companies or research establishments and is solely owned by its working partners. We are used to working within a strictly controlled, confidential and if desired exclusive environment with our clients that ensures all sensitive data, results and analysis is protected. We are a research driven company and offer our clients world leading know-how in the fields of fluoro and phosphorus chemicals, reagents for fluorination, polyfluoroalkylation and fluorinated building blocks for the synthesis of compounds with potential biological activity. These proprietary technologies are new methods that allow the production of complex molecules. It permits the synthesis of novel compounds under commercially accessible conditions for the first time. A key competence is the production of new types of compounds. In many cases complex F-derivatives, which were either too difficult or impossible to prepare by other fluorination methods, can be designed and synthesised. These compounds are ideally suited for high added-value sectors such as healthcare, pharmaceutical, agro-chemical, additives and microelectronics.

HFC Company Profile 2 The core product list encompasses compounds in the following categories: F- and R F -aromatics Fluorinated amines, amino acids and related compounds Fluorinated and non-fluorinated acids and corresponding esters (acrylic, crotonic, pyruvic, glyoxylic, atrolactic etc.) Fluorinated alcohols Fluorinated imines, ketones and ,  -enones Fluorinated 1,2- and 1,3-diketones, 1,3-ketoesters, 1,3,5-triketones,  - aminoenones Fluorinated 3-, 5-, 6-, 7-membered N-, O-, S-, P-heterocycles Special reagents (for perfluoroalkylation, fluorination etc.) Phenacyl bromides Thiosemicarbazides Organophosphorus compounds In addition, Hansa Fine Chemicals, using a variety of synthesis strategies and analysis techniques, offers services in three main areas: Custom fluoro/phosphorus synthesis in gram to kilogram quantities on an ad hoc basis Contract research projects Process analysis and characterisation

HFC Company Profile 3 Synthesis techniques using: –Elemental fluorine –Sulfur tetrafluoride, DAST, Deoxofluor® –Bromine trifluoride –HF/base systems –Perfluoroalkylating reagents –Trifluoromethyl Triflate and Difluorophosgene –Sulfur chloride/bromide pentafluoride –Hexafluoroacetone Special Processes: Fluorination Polyfluoro- and perfluoroalkylation Perfluoroalkoxylation Fluorodenitration Fluorodesulfurisation Halex process Phase transfer / Halex catalysts design Novel organic bases

Hoechst Patents: Preparation of fluorine- containing compounds A.A. Kolomeitsev, S.V. Pazenok. DE /WO /EP /US ; B. Schiemenz, T. Wessel, R. Pfirmann; DE

(R 2 N) 4 PX PT Catalysts (R 2 N) 4 PX are robust PT catalysts which show their best activity between °C. All catalysts of the PN-type exhibit potential dermal toxicity due to traces of HMPT or analogues and are therefore not the best choice for technical purposes. Similar catalysts containing cyclic amine residues exhibit an improved biological profile

2-Azaallenium, Carbophosphazenium, Aminophosphonium and Diphosphazenium Salts

Carbsulfiminium Salts

2-Azaallenium, Carbophosphazenium Salts T. Ishikawa, T. Kumamoto, Guanidines in Organic Synthesis, Synthesis, 2006,

CNC Catalysts Temp. [°C] Cl 3 Benzene 15 Cl 2 F " 18 ClF 2 " 17 F 3 " 16 Rest (side reactions, decomposition) First step (12 h) GC area % CNC + (5 mol%) (NMe 2 ) 3 PNPPh 3 Br 3 (5 mol%) Second step (24 h) CNC + (5 mol%) (NMe 2 ) 3 PNPPh 3 Br 3 (5 mol%) M. Henrich, A. Marhold, A. A. Kolomeitsev, G.-V. Röschenthaler. DE /EP /US (to Bayer AG). A. Marhold, A. Pleschke, M. Schneider, A.A. Kolomeitsev, G-V. Röschenthaler. J. Fluorine Chem., 2004, 125,

A Family of Phosphazene Bases For comprehensive review on application of phosphazene bases see: Strong and Hindered Bases in Organic synthesis www.sigma-aldrich.com/chemfiles. 2003, V. 3, No. 1.

Designations of the "Classical" Phosphazenes and Some Other Bases 1

Designations of the "Classical" Phosphazenes and Some Other Bases 2

Einsatzmöglichkeiten: Aminophosphazene und Phosphazenium Salze, Guanidinophosphazene?

Ring-opening polymerization of siloxanes using Phosphazene P 4 base catalysts Phosphazene bases have been reported in the literature to be strongly basic materials with basicities up to 1 x times stronger than that of diazabicycloundecene (DBU) a strong hindered amine base widely used in org. reactions. A study of these phosphazene bases as catalysts revealed that they can be activated by small amts. of water, which all silicone feed stocks contain, to form an active ionic base catalyst. The use of these base catalysts, and their analogs, as ring-opening polymn. catalysts for cyclosiloxanes is described. P-base catalysts can be used at low concns. To make high mol. wt. polydimethylsiloxanes with short reaction times over a wide temp. range. Mol. wt. can easily be controlled in the presence of suitably functionalized endblockers. Water and carbon dioxide have been shown to have a significant impact on the polymn. rates. Polymers prepd. show excellent thermal stability by thermogravimetric anal. (TGA), following neutralization of the catalyst, with decompn. onset temps. >500°C in some cases. As a result of the extremely low levels of catalyst used, the polymers often do not require filtration. Hupfield, P. et al. (Dow Corning Ltd.) J. Inorg. Organomet. Polymers, 1999, 9,

T. Nobori, M. Kouno, T. Suzuki, K. Mizutani, S. Kiyono, Y. Sonobe, U. Takaki, US (to Mitsui Chemicals), Nov. 23, 1999; V. Schanen, H. J. Cristau, M. Taillefer, WO (to Rhodia Chimie), Nov. 21, Extremely base-rasistant organic cations: Phosphazenium Halex Catalysts For properties of extremely base-rasistant organic cations see: Schwesinger et al., Chem. Eur. J. 2006, 12,

Immobilised Iminophosphatranes Useful for Transesterification Verkade et al. US An active geterogeneous catalyst for production of biodiesel

Our Idea:Guanidino-, Biguanidino- and Triguanidinophosphazenes

Ionic precursors: synthesis A. A. Kolomeitsev, I. A. Koppel, T. Rodima, J. Barten, E. Lork, G.-V. Röschenthaler, I. Kaljurand, A. Kütt, I. Koppel, V. Mäemets, I. Leito.. J. Am. Chem. Soc., 2005, 127,

Liberation of Guanidinophosphazene Bases A. A. Kolomeitsev, I. A. Koppel, T. Rodima, J. Barten, E. Lork, G.-V. Röschenthaler, I. Kaljurand, A. Kütt, I. Koppel, V. Mäemets, I. Leito.. J. Am. Chem. Soc., 2005, 127,

. Figure 1. Molecular structure of [(dma) 2 C=N] 3 P=N-t-Bu N-C pmN=C pm

Figure 2. Molecular structure of [(dma) 2 C=N] 3 P + -N(H)Bu-t BF 4 - „C-N“ pm„C=N“ pm

Results of Basicity Measurements of Guanidinophosphazenes and Related Compounds in THF

Consecutive Replacement of dma Groups by tmg Units: Nearly Additive Bacisity Increase A. A. Kolomeitsev, I. A. Koppel, T. Rodima, J. Barten, E. Lork, G.-V. Röschenthaler, I. Kaljurand, A. Kütt, I. Koppel, V. Mäemets, I. Leito.. J. Am. Chem. Soc., 2005, 127,

Designations of the substituents (IUPAC)

Results of Basicity Calculations at DFT B3LYP G** Level of Guanidinophosphazenes and Related Bases 4 Guanidines Guanidine c Tetramethylguanidine c [(H 2 N) 2 C=N] 2 C=NH Phosphines [(H 2 N) 2 C=N-] 3 P b [(dma) 2 C=N-] 3 P b [(H 2 N) 3 P=N-] 3 P

Results of Basicity Calculations at DFT B3LYP G** Level of Guanidinophosphazenes and Related Bases 1 BaseGBPA Guanidinophosphazenes (H 2 N) 2 [(H 2 N) 2 C=N]P=NH b H 2 N[(H 2 N) 2 C=N] 2 P=NH [(H 2 N) 2 C=N] 3 P=NH b [(H 2 N) 2 C=N] 3 P=N-Me [(H 2 N) 2 C=N] 3 P=N-t-Bu [(H 2 N) 2 C=N] 3 P=N-Ph (dma) 2 [(H 2 N) 2 C=N]P=NH (dma)[(H 2 N) 2 C=N] 2 P=NH [(dma) 2 C=N](H 2 N) 2 P=NH [(dma) 2 C=N] 2 (H 2 N)P=NH [(dma) 2 C=N] 3 P=NH [im](H 2 N) 2 P=NH [im] 2 (H 2 N)P=NH [im] 3 P=NH

Results of Basicity Calculations at DFT B3LYP G** Level of Guanidinophosphazenes and Related Bases 2 Base (H 2 N) 2 (imen)P=NH GB PA (H 2 N)(imen) 2 P=NH (imen) 3 P=NH (H 2 N) 2 [imme]P=NH (imme) 2 (H 2 N)P=NH (imme) 3 P=NH (imen)[(H 2 N) 2 C=N] 2 P=NH (im)[(H 2 N) 2 C=N] 2 P=NH [((H 2 N) 2 C=N) 3 P=N](H 2 N) 2 P=NH [(H 2 N) 2 C=N] 3 P=N-P[(H 2 N) 2 C=N] 2 =NH (H 2 N) 2 [((H 2 N) 2 C=N) 2 C=N]P=NH [((H 2 N) 2 C=N) 2 C=N] 3 P=NH

Results of Basicity Calculations at DFT B3LYP G** Level of Guanidinophosphazenes and Related Bases 3 Other bases Phosphazenes (H 2 N) 3 P=NH (H 2 N) 3 P=N-Me c (H 2 N) 3 P=N-Ph (dma) 3 P=NH c (dma) 3 P=N-Me c (dma) 3 P=N-Ph (H 2 N) 2 (pyrr)P=NH (pyrr) 3 P=NH (H 2 N) 3 P=NP(NH 2 ) 2 (=NH) [(dma) 3 P=N](dma) 2 P=N-Ph [(H 2 N) 3 P=N-] 2 P(NH 2 )(=NH) [(H 2 N) 3 P=N]P(NH 2 ) 2 =N-P(NH 2 ) 2 (=NH) [(H 2 N) 3 P=N] 3 P=NH [(dma) 3 P=N] 3 P=NHca 290

Promising TMG-ligands 1

Promising TMG-ligands 2: Tris(triguanido)phosphine

Biodiesel Catalysts

Mesoporous neutral superbase catalysts

Mesoporous ionic ctalysts for transesterification (Cl- and OH- form)

Ionic Liquids for Halex and other Organic Reactions Proceeding under Extreme Conditions?

Novel Robust Ionic Liquids, Chiral Ionic Reaction Media or dopants?

Novel organic metals? a Chem. Rev. Molecular Conductors. 2004, 104, issue N 11.

Grubbs Ruthenium Catalysts for Alkene Metathesis? To be used instead of PCy 3 or NHC ligands

DLC´s as Mitochondriotropics Mitochondrial research is presently one of the fastest growing disciplines in biomedicine. Dysfunction contributes to a variety of human disorders such as neurodegenerative diseases, diabetes and cancer. During the last five years, mitochondria, the “power houses” of the cell have become accepted as the “motors of cell death” therefore presenting a priviliged pharmacological target for cytoprotective and cytotoxic therapies. Targeting of Low-Melecular Weight Drugs to Mammalian Mitochondria, V. Weissig, S. V. Boddapati, G. G. M. D’Souza, S. M. Cheng, Drug Design Rev. Online 2004, 1, Mitrochondriotropics are compounds having two structural features in common, they are amphiphilic, i.e. hydrophilic charged centers with a hydrophobic core, and a π-electron charge density which extends over at least three atoms or more causing delocalization. Both is crucial for the accumulation in the mitochondrial matrix. Sufficient lipophilicity combined with delocalization if their positive charge to reduce the free energy change when moving from an aqueous to a hydrophobic environment are prerequisites for mitochondrial accumulation.

R-OCF 3 Derivatives The occurrence of R-O-CF 3 compounds has significantly increased in recent years. Some OCF 3 containing structures are presently compiled in chemical databases. 1 1 Leroux, F.; Jeschke, P.; Schlosser, M. Chem. Rev. 2005, 105,

Oxidative Desulfurization-Fluorination Kuroboshi, M.; Kanie, K.; Hiyama, T. Adv. Synth. Catal., 2001, 343,

CF 3 OSO 2 CF 3 : Synthesis and Properties Oudrhiri-Hassani, M.; Germain, A.; Brunel, D. Tetrahedron Lett., 1981, 22, 65. Olah, G. A.; Ohayama, T. Synthesis, 1976, 319.

CF 3 OSO 2 CF 3 : Properties 2 Kobayashi, Y.; Yoshida, T.; Kumadaski, I. Tetrahedron Lett. 1979, 40, 3865.

Adducts of R F OH with triethylamine Cheburkov, Y.; Lillquist, G. J. Fluorine Chem., 2002, 118,

Trifluoromethanol CF 3 OH and Trifluoromethoxide CF 3 OH, b.p. –20°C, > -20°C dec. Kloeter, G.; Seppelt, K.; J. Am. Chem. Soc., 1979,101, CF 3 SH, b.p. 36.7°C

Adducts of R F OH with triethylamine Cheburkov, Y.; Lillquist, G. J. Fluorine Chem., 2002, 118,

Trifluoromethanol CF 3 OH and Trifluoromethoxide CF 3 OH, b.p. –20°C, > -20°C dec. Kloeter, G.; Seppelt, K.; J. Am. Chem. Soc., 1979,101, CF 3 SH, b.p. 36.7°C

Trifluoromethyl triflate CF 3 OSO 2 CF 3, (TMFT, 1) is stable and easy to handle liquid, b. p. 20°C. TMFT Is resistant to hydrolysis by water, but does hydrolyse at 100°C by 0.1 N NaOH. There are very few reports dealing with TMFT reactions, though Alk-OTf belonging to the most powerfull alkylating agents are widely used in organic synthesis.

CF 3 OSO 2 CF 3 : Properties 3 Taylor, S. L.; Martin, J. C. J. Org. Chem., 1987, 52,

Splitting of Trifluoromethyl Triflate Kolomeitsev, A. A. Tetrahedron Lett., 2006, in press.

Trifluoromethoxylation with (Me 2 N) 3 C + CF 3 O -

Straightforward C-Trifluoromethoxylation with TFMT 1

Straightforward Transformation of alcohols into trifluoromethyl ethers Kolomeitsev, A. A. Tetrahedron Lett., 2006,submitted

Summary 1. A new principle of creating nonionic superbases is presented. It is based on attachment of either tetraalkylguanidino-, 1,3-dimethylimidazolidin-2- yliden)amino- or bis(tetraalkylguanidino)­carbimino groups to the central tetracoordinated phosphorus atom of the iminophosphorane group using tetramethylguanidine or easily available 1,3-dimethylimidazolidine-2-imine. 2. Using this principle, a range of new nonionic superbasic tetramethylguanidinosubstituted at P atom phosphazene bases were synthesized and the base strength of these compounds was established in THF solution by means of spectrophotometric titration and the gas-phase basicity was calculated. 3. The enormous basicity-increasing effect has been experimentally verified in the case of the tetramethylguanidino-groups in the THF medium: the basicity increase when moving from (dma) 3 P=N-t-Bu (pK  =18.9) to (tmg) 3 P=N-t-Bu (pK  29.1) is almost ten orders of magnitude. 4. The new superbases could be used as auxiliary bases in organic synthesis. The synthesized and to be synthesized phosphazenes, triguanidino- and tris(triguanido)phosphines a great potential in organic and metal complex chemistry as auxiliary bases and ligands.

Acknowledgement I would like to acknowledge my colleagues from the University of Tartu, Department of Chemistry and Institute of Inorganic & Physical Chemistry, University of Bremen. University of Tartu: Ilmar A. Koppel, Toomas Rodima, Ivari Kaljurand, Agnes Kütt, Ivar Koppel, Vahur Mäemets, Ivo Leito. University of Bremen: Jan Barten, Enno Lork, Gerd-Volker Röschenthaler The support of this work by Professor E. Nicke (Institute of Inorganic Chemistry, University of Bonn) is also gratefuly acknowledged.