(H 2 N) 2

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 Profile1 •

Hansa Fine Chemicals GmbH was created as a University of Bremen (Germany) spin-off and was launched as a Limited Company (GmbH) in February 2003. 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 Profile2 • • • • • • •

• • • • • • • • •

The core product list encompasses compounds in the following categories: F- and RF-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 Profile3 • 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 fluorinecontaining compounds EWG

EWG F- source catalyst F

Cl R2

R1 R

N

1

R

2

R

1

P

N 1

N

R

1

Cl (Br) N R2 R

2

2

R , R = different Alkyl, cycloalkyl; -(CH 2)4A.A. Kolomeitsev, S.V. Pazenok. DE 19631854/WO 9805610/EP 9704284 /US 6184425; B. Schiemenz, T. Wessel, R. Pfirmann; DE19934595.

(R2N)4PX PT Catalysts • (R2N)4PX are robust PT catalysts which show their best activity between 170-240°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

EWG

EWG fluoride source catalyst Fn

Cl(Br)n

R2N

+ N

NR2

R2N

R2N

Cl

NR2

R2N

NR2 + N P NR2 NR2 Cl

1

2

CNC+

PNC+

R 2N R 2N

+ NR2 N S NR2 Br3 + SNC

M. Henrich, A. Marhold, A. A. Kolomeitsev, G.-V. Röschenthaler. DE 10129057/EP 1266904/US 2003036667 (to Bayer AG), Dec. 18, 2002; A. Marhold, A. Pleschke, M. Schneider, A.A. Kolomeitsev, G-V. Röschenthaler. J. Fluorine Chem., 2004, in press; M.Henrich, A. Marhold, A. A. Kolomeitsev, N. Kalinovich G.-V. Röschenthaler. Tetrahedron Lett., 2003, 44, 5795-5798.

Carbsulfiminium Salts NMe2 6 equiv. HMG

Me2N C

SCl4 CH2Cl2, -70°C

Me2N C

N NMe2 S N C N NMe2

NMe2

M. Henrich, A. Marhold, A. A. Kolomeitsev, G.-V. Röschenthaler, DE 10129057 / EP 1266904/ US 2003036667 to Bayer AG), Dec. 18, 2002; M.Henrich, A. Marhold, A. A. Kolomeitsev, N. Kalinovich G.-V. Röschenthaler. Tetrahedron Lett., 2003, 44, 5795-5798.

Cl

2-Azaallenium, Carbophosphazenium Salts

NMe2

Me2N

TMG-H

Me2N

F

TMG-SiMe3

F

CH3CN, -30°C

N

N Me2N

HF2

NMe2

Me2N

__ __ (Et2N)3P=NSiMe3

Me2N Me2N

NMe2

Me2N Me2N

NMe2

Me3SiF2

NEt2 N P NEt2 NEt2 Me3SiF2

M. Henrich, A. Marhold, A. A. Kolomeitsev, G.-V. Röschenthaler, DE 10129057/EP 1266904/ US 2003036667(to Bayer AG), December, 18, 2002; A. Marhold, A. Pleschke, M. Schneider, A.A. Kolomeitsev, G.-V. Röschenthaler, J. Fluorine Chem., 2004, 125, 1031-1038. T. Ishikawa, T. Kumamoto, Guanidines in Organic Synthesis, Synthesis, 2006, 737-752

CNC Catalysts KF, catalyst F

Cl

Temp. [°C] First step (12 h)

+

+

sulfolane Cl

Cl

Cl

F

Cl

Cl3 Benzene 15

F

F

Cl

F

F

Cl2F " 18

ClF2 " 17

F3 " 16

Rest (side reactions, decomposition)

GC area %

CNC+ (5 mol%)

230

1

20

61

18

1

230

1

20

60

15

5

CNC+ (5 mol%)

230

0

1

8

87

4

(NMe2)3PNPPh3Br 3 (5 mol%)

230

0

2

46

46

6

(NMe2)3PNPPh3Br (5 mol%)

3

Second step (24 h)

M. Henrich, A. Marhold, A. A. Kolomeitsev, G.-V. Röschenthaler. DE 10129057/EP 1266904/US 2003036667 (to Bayer AG). A. Marhold, A. Pleschke, M. Schneider, A.A. Kolomeitsev, G-V. Röschenthaler. J. Fluorine Chem., 2004, 125, 1031-1038

A Family of Phosphazene Bases Me Me Me

Me2N Me2N Me2N

P=NR

P-alkyl-phosphazenes, Appel

Me2N Me2N (Me2N)3P=N

P=NR

P=NR

P-dialkylamino-phosphazenes, P1 bases, Issleib, Marchenko

Me2N (Me2N)3P=N (Me2N)3P=N

P=NR

(Me2N)3P=N (Me2N)3P=N (Me2N)3P=N

Schwesinger`s P2-P4 phosphazo-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.

P=NR

Designations of the "Classical" Phosphazenes and Some Other Bases1

Measurement Resultsa

pK ip(THF)b

pK (THF)b

29.0 c,d

29.7 c,d

28.4 c

29.1 c

27.9

28.6

27.8

28.9

27.1

28.1

27.0

27.7

26.3

26.8

26.3

27.0

25.9

26.6

25.8

26.9

25.6 e

26.6 e

36b [(pyrr)3P=N-]2(pyrr)P=N-C6H4-4-OMe

24.8 e

25.7 e

36a [(pyrr)3P=N-]2(pyrr)P=N-Ph

24.2 e

25.0 e

23.7

24.3

23.6 e

24.0 e

23.0 e

23.5 e

22.3 e

23.2 e

21.2 e

21.7 e

21.1

21.5

20.9 e

21.5 e

19.4 e

19.9 e

19.3 e

20.2 e

No Compound 8b (tmg)3P=N-Et

0.6

8c (tmg)3P=N-t -Bu 8

(tmg)3P=N-H

40b [(pyrr)3P=N-]3P=N-C6H4-4-OMe 40a [(pyrr)3P=N-]3P=N-Ph 39d [(dma)3P=N-]3P=N-C6H4-4-OMe

0.6 0.07 0.85 0.75 0.08

1.50 0.70

11 (tmg)2(NEt2)P=N-t -Bu 39c [(dma)3P=N-]3P=N-Ph

0.67 0.02 1.17 0.35

33a (pyrr)3P=N-(pyrr)2P=N-Et

0.77

40c [(pyrr)3P=N-]3P=N-C6H4-4-Br [(pyrr)3P=N-]3P=N-C6H4-2-Cl

0.27

1.05 0.97

0.52

8d (tmg)3P=N-Ph

0.11

35b [(dma)3P=N-]2(dma)P=N-C6H4-4-OMe

0.70

35a [(dma)3P=N-]2(dma)P=N-Ph [(pyrr)3P=N-]2(pyrr)P=N-C6H4-4-CF3 [(dma)3P=N-]2(dma)P=N-C6H4-4-CF3 10 (tmg)2(dma)P=N-Phf (pyrr)3P=N-(pyrr)2P=N-C6H4-4-OMe

1.20 0.10 0.23

(dma)3P=N-(dma)2P=N-Ph [(pyrr)3P=N-]2(NEt2)P=N-C6H3-2,5-Cl2

0.13

0.52

8d (tmg)3P=N-Ph

0.11

35b [(dma)3P=N-]2(dma)P=N-C6H4-4-OMe

0.70

35a [(dma)3P=N-]2(dma)P=N-Ph [(pyrr)3P=N-]2(pyrr)P=N-C6H4-4-CF3 [(dma)3P=N-]2(dma)P=N-C6H4-4-CF3

1.20 0.10

10 (tmg)2(dma)P=N-Phf

0.23

(pyrr)3P=N-(pyrr)2P=N-C6H4-4-OMe (dma)3P=N-(dma)2P=N-Ph [(pyrr)3P=N-]2(NEt2)P=N-C6H3-2,5-Cl2

0.13

33b (pyrr)3P=N-(pyrr)2P=N-C6H4-4-Br MTBDg

0.58 1.08 1.25

DBUg 9

(tmg)(dma)2P=N-Ph (pyrr)3P=N-C6H4-4-OMe TMGNg (pyrr)3P=N-Ph

32d (dma)3P=N-(dma)2P=N-C6H4-2-Cl (Me)(dma)2P=N-Ph

0.10 1.44 0.27 0.98

0.36 0.66

0.51

30b (pyrr)3P=N-C6H4-4-NO2 (pyrr)3P=N-C6H4-2-Cl (dma)3P=N-C6H4-2-Cl

0.01 0.80

23.7

24.3

23.6 e

24.0 e

23.0 e

23.5 e

22.3 e

23.2 e

21.2 e

21.7 e

21.1

21.5

20.9 e

21.5 e

19.4 e

19.9 e

19.3 e

20.2 e

19.3

20.0

18.7 e

18.0 e

18.1 e

16.9 e

18.1

18.4

16.8 e

16.8 e

16.5

16.8

16.0 e

16.0 e

15.8

16.3

15.4 e

15.4 e

13.2

13.3

13.2 e

13.2 e

12.5 e

12.5 e

Designations of the "Classical" Phosphazenes and Some Other Bases2

Einsatzmöglichkeiten: Aminophosphazene und Phosphazenium Salze, Guanidinophosphazene? als metallfreie Katalysatoren zur Polymerisation von - Polyepoxiden - Polyurethanen - Polysiloxanen - Polymethacrylaten Vorteile: - geruchsfrei - scharfes Molekulargewicht - spezielle Eigenschaften - keine Kontamination, keine Spuren des cancerogenen HMPTA (Guanidophosphazene) oder seiner Derivaten im Produkt enthalten - kleine Katalysatormengen - vereinfachte Isolierung Anwendung in Kondensatoren

als Polymerisationskatalysator in der Halbleitertechnik als Katalysator zur Synthese von 2-Oxazolidonen (aus Epoxiden und Carbamaten)

Ring-opening polymerization of siloxanes using Phosphazene P4 base catalysts Phosphazene bases have been reported in the literature to be strongly basic materials with basicities up to 1 x 1018 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, 17-34.

Extremely base-rasistant organic cations: Phosphazenium Halex Catalysts NMe2 Me2N NMe2 P Me2N

N

NMe2

Me2N P N P N P NMe2 Cl N

Me2N Me2N

NMe2

P

NMe2 NMe2

R2N

NR2 + R2N P N P NR2 NR2 R2N Cl

Mitsui, Rhodia, Clariant For properties of extremely base-rasistant organic cations see: Schwesinger et al., Chem. Eur. J. 2006, 12, 429-437. T. Nobori, M. Kouno, T. Suzuki, K. Mizutani, S. Kiyono, Y. Sonobe, U. Takaki, US 5990352 (to Mitsui Chemicals), Nov. 23, 1999; V. Schanen, H. J. Cristau, M. Taillefer, WO 02092226 (to Rhodia Chimie), Nov. 21, 2002.

Immobilised Iminophosphatranes Useful for Transesterification

R SiO2

N N

P

N

R

N

N

An active geterogeneous catalyst for production of biodiesel

Verkade et al. US 2005 0176978

Our Idea:Guanidino-, Biguanidino- and

Triguanidinophosphazenes Me

Me

Me

N

N

Me N

N

Me Me

P

N N Me

Me

Me Me

Me

N

P

N N

N

N

Me

Alk

NAlk

NMe2

N P N C (N

Me

N

Me

N

N

Me

NAlk

N N

Me

C(N

N

NMe2

N

N

C (N

N

(I)

NMe2 (III)

(II)

NMe2 N

Me2N

Alk

[

Me

C

N

N

N P N C( N

)2

]3

Alk

NMe2 NMe2 N NMe2

N P N C

N

N

NMe2

Me

C

NMe2

Me2N

N NMe2

(IV) Alk = Me, Et, i-Pr, t-Bu

(V)

NMe2 NMe2

NMe2

Me

Me

)2

)2

)2

Ionic precursors: synthesis NMe2

Me2N Me2N

N

Toluene NH

+

t-BuN PCl3

Me2N

C

NMe2

N Toluene, -30 - 20°C

NMe2

H N Me2N

PCl5

Cl (BF4)

t-Bu N P N

Me2N

6 equiv. TMGH

NMe2

Cl P N C

NMe2 NMe2

N

NMe2

Me2N

Cl

2 equiv. RNH2

NMe2

N R N P N C

NMe2 NMe2

H N

C Me2N

C

C NMe2

Me2N

NMe2

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, 17656-17666.

Cl

Liberation of Guanidinophosphazene Bases

Me2N

C

N P N C H

NMe2 NMe2

N

Cl

t-BuOK, glyme

R

NMe2

N P N C

-30 : 60°C

NMe2

N C

C Me2N

C

NMe2

N

N

R

Me2N

NMe2

NMe2

Me2N

NMe2

R = H, Et, t-Bu, Ph

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, 17656-17666.

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

N5 N6 C6 N4 N10

N2

N1 P1

C1

N3

N7 C11 N8 N9

N-C 138.3 pm .

N=C 128.8 pm

Figure 2. Molecular structure of [(dma)2C=N]3P+-N(H)Bu-t BF4F2

F3 B1 F4

F1 C7 C8

N6 C5 C10

N3

C4 C18

N5

C6 C1 N2

C9

N1

H39

P1 C16

N4

C2

N10

C3 N7

C19

C14

C17

C11 N9 C12

N8 C15 C13

„C-N“ 136.5 pm

„C=N“ 136.0 pm

Results of Basicity Measurements of Guanidinophosphazenes and Related Compounds in THF

Results of Basicity Measurements of Guanidinophosphazenes and Related Compounds in THF

Consecutive Replacement of dma Groups by tmg Units: Nearly Additive Bacisity Increase

N

N

N N

N

N

N P NPh

N P NPh N

N

N

15.3

3.1

18.4

N

21.5

N P NPh

N

N

N

N 3.1

N

N

N P NPh N

N pK pK

N

N 2.8

24.3

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, 17656-17666.

Designations of the substituents (IUPAC)

H2N N

N

N

N N

H2N dma

pyrr

H N

g H N

N N H im

N tmg N

N N H imen

N N imme

Results of Basicity Calculations at DFT B3LYP 6-311+G** Level of Guanidinophosphazenes and Related Bases 4 Guanidines Guanidinec

230.6

237.5

234.3

241.2

235.5

242.4

239.6

-246.2

Tetramethylguanidinec

240.7

248.2

[(H2N)2C=N]2C=NH

248.4

255.1

[(H2N)2C=N-]3Pb

258.9

263.7

[(dma)2C=N-]3Pb

267.1

276.7

[(H2N)3P=N-]3P

275.0

283.3

H N NH N H H N NH N H N NH N

Phosphines

Results of Basicity Calculations at DFT B3LYP 6-311+G** Level of Guanidinophosphazenes and Related Bases 1 Base

GB

PA

(H2N)2[(H2N)2C=N]P=NHb

253.1

259.1

H2N[(H2N)2C=N]2P=NH

261.7

267.7

[(H2N)2C=N]3P=NHb

266.5

272.6

[(H2N)2C=N]3P=N-Me

271.7

278.0

[(H2N)2C=N]3P=N-t-Bu

273.0

278.6

[(H2N)2C=N]3P=N-Ph

264.3

269.6

(dma)2[(H2N)2C=N]P=NH

260.1

264.8

(dma)[(H2N)2C=N]2P=NH

265.0

270.4

[(dma)2C=N](H2N)2P=NH

258.4

266.1

[(dma)2C=N]2(H2N)P=NH

269.7

278.1

[(dma)2C=N]3P=NH

276.1

283.9

[im](H2N)2P=NH

254.3

261.4

[im]2(H2N)P=NH

261.5

267.9

[im]3P=NH

270.5

277.6

Guanidinophosphazenes

Results of Basicity Calculations at DFT B3LYP 6-311+G** Level of Guanidinophosphazenes and Related Bases 2 Base

GB

PA

(H2N)2(imen)P=NH

253.8

261.4

(H2N)(imen)2P=NH

260.2

267.5

(imen)3P=NH

271.5

279.2

(H2N)2[imme]P=NH

257.9

265.7

(imme)2(H2N)P=NH

267.9

275.0

(imme)3P=NH

280.8

287.0

(imen)[(H2N)2C=N]2P=NH

266.8

273.1

(im)[(H2N)2C=N]2P=NH

267.7

273.6

[((H2N)2C=N)3P=N](H2N)2P=NH

276.2

281.9

[(H2N)2C=N]3P=N-P[(H2N)2C=N]2=NH

290.8

296.7

(H2N)2[((H2N)2C=N)2C=N]P=NH

272.6

278.3

[((H2N)2C=N)2C=N]3P=NH

296.2

302.3

Results of Basicity Calculations at DFT B3LYP 6-311+G** Level of Guanidinophosphazenes and Related Bases 3 Other bases Phosphazenes

(H2N)3P=NH

241.7

249.7

(H2N)3P=N-Mec

245.6

253.8

(H2N)3P=N-Ph

238.9

246.9

(dma)3P=NHc

249.6

256.3

(dma)3P=N-Mec

252.3

260.3

(dma)3P=N-Ph

245.3

252.7

(H2N)2(pyrr)P=NH

246.8

254.9

(pyrr)3P=NH

255.0

262.8

(H2N)3P=NP(NH2)2(=NH)

257.0

262.9

[(dma)3P=N](dma)2P=N-Ph

259.2

266.9

[(H2N)3P=N-]2P(NH2)(=NH)

269.3

276.2

[(H2N)3P=N]P(NH2)2=N-P(NH2)2(=NH)

264.8

271.9

[(H2N)3P=N]3P=NH

273.2

279.1

[(dma)3P=N]3P=NH

ca 290

Promising TMG-ligands1 R

NMe2 Me2N

NMe2 NMe2

N

N

R N

P

N

R

N

P N Me2N

N NMe2

still unknown

Proazaphosphotranes pKa ca. 33 (CH3CN)

GB ca. 267 kcal/mol

GB ca. 255 kcal/mol

a

a

-

obtained as dihydrochloride, HCl2 , by Schmutzler, R. et al. Phosphorus, Sulphur and Silicon 1997,123, 57 - 74.

Promising TMG-ligands2: Tris(triguanido)phosphine (Me2N)3P NH

TMG2C NH

GB 268.4 kcal/mol

TMG2 TMG2

TMG2 N

N

TMG2

TMG2

Me2N Me2N

NMe2 P N

P

P

N

N TMG2

Has to be the most basic and hindered phosphine

a

GB 249.6 kcal/mol

Me2N

NMe2 NMe2 P N NMe2

P

NMe2 NMe2

GB ca. 280 kcal/mola,b

DFT calculations: this work. bSynthesis: Marchenko, A. et al. Zh. Obsch. Khim. 1984, 54,1774-1782.

Biodiesel Catalysts

O R C O CH2 O

HO CH2 3 MeOH, Catalyst

O

R C O CH O

3R C

R C O CH2

Biodiesel

O CH3

+

HO CH HO CH2

Triglyceride

Catalyst: TMG3P=NH (0.5% mol., 30 min, 90%; 1% mol., 30 min. quantitative)

Mesoporous neutral superbase catalysts Me

N Me

Me N

N

Me N

N

Me

N

N

N P

C N Spacer-Si(OMe)3

Me

N

N

N

N Spacer-Ti(OAlk)3

N

Me N

Me N

N

Me N

N Me

Me

Me

Me N

Me N Me

C N

Me

N

N

N

N

N SiO2

N P N

N

Me Me N

N Me

TiO2

N

N

Me

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

N Me

Me N

N

Me N

N

Me

C N

Me

N P

SiO2

N

N

N

Me TiO2

N

N

Me OH

N

N

N

Me

Me N

N

Me OH

Me

R R

R N Me

N P R R

N

TiO2

N R

OH

Ionic Liquids for Halex and other Organic Reactions Proceeding under Extreme Conditions? R N F -

N

BF4 / PF6

X -

R

F

-

R = Alkyl, Aryl, Heteroaryl Problems: - Hoffmann-degradation, nucleophilic dealkylation at elevated temperature - low yields (even with CsF) of R-F

N

NMe2

N

N

N Alk C N N Alk

Me2N C Cl, PF6 Me2N C

N

NMe2 N C N C N NMe2

NMe2

Cl, PF6

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

N N N

Me

N

Heteroaryl

N N

N

O

X

CF3

N

N N

N

N N

N

N

N

N

N ( CH2

CH R

N

N

Ar

N

N

2X

O ) CH2 CH n R

N N

N N

X = Cl, Br, BF4, PF6, CF3SO3; R = H, Me; R1 = Alk

X

C 2 F5

Novel organic metals? Me2N

Me2N

N

Me2N

Me2N

C

Me2N Me2N

Me2N Me2N

N

Me

N C

NMe2

C

N

N

NMe2 NMe2

B

A

Me

N

NMe2

S

S

S

S

Me

TMG

Me

TMG

Tetramethyltetrathiofulvalene aChem.

a

S

S

S

S

TMG

TMG

Tetrakis(tetramethylguanidino)tetrathiofulvalene

Rev. Molecular Conductors. 2004, 104, issue N 11.

Grubbs Ruthenium Catalysts for Alkene Metathesis?

N

N N

..

N

N

N

N Cl Cl

Ru PCy3

To be used instead of PCy3 or NHC ligands

N

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. 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.

Ph3PMe+ClTargeting 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, 15-28.

R-OCF3 Derivatives • The occurrence of R-O-CF3 compounds has significantly increased in recent years. Some 30 000 OCF3 containing structures are presently compiled in chemical databases.1

1Leroux,

F.; Jeschke, P.; Schlosser, M. Chem. Rev. 2005, 105, 827-856.

Oxidative Desulfurization-Fluorination

i) NaH (1.2 mol) ii) CS2 (2.0 mol) iii) MeI (2.0 mol)

R

OH

73-95 %

R

OCS2Me

R

OCF3

50 % HF/Py (40 mol) NBS (5.0 mol) CH2Cl2, 0 °C, 1h

25-42 %

Kuroboshi, M.; Kanie, K.; Hiyama, T. Adv. Synth. Catal., 2001, 343, 235-250.

CF3OSO2CF3: Synthesis and Properties CF3SO3H

+

CF3SO3CF3

P2O5

+

H3PO4

(70 %)

(CF3SO2)2O

CF3SO3H

CF3SO3CF3 (100 %)

Oudrhiri-Hassani, M.; Germain, A.; Brunel, D. Tetrahedron Lett., 1981, 22, 65.

25°C

CF3OSO2CF3

+

N

+

-

N CF3 OSO2CF3

Olah, G. A.; Ohayama, T. Synthesis, 1976, 319.

CF3OSO2CF3: Properties2 O +

CF3OSO2CF3

+

H 3O X

N

CF3

(Not formed) +

H 3O

OH

O SO2CF3

SO2CF3

(25 % )

Kobayashi, Y.; Yoshida, T.; Kumadaski, I. Tetrahedron Lett. 1979, 40, 3865.

Adducts of RFOH with triethylamine RFCOF

+

Et3N 3HF+2Et3N

R FCF2OH NEt3

RF : F, C 2F5, i-C3F7

COF2

+

1/3Et3N 3HF+2/3Et3N

CF3OH NEt3 + (CH3)2SO4

70°C, 17 h

CF3OH NEt3

CF3OCH3 49% (Purity 84% )

Cheburkov, Y.; Lillquist, G. J. Fluorine Chem., 2002, 118, 123-126.

-

R FCF2O HNEt3

+

Trifluoromethanol CF3OH and Trifluoromethoxide -

CF3O

F2C=O

+

-

F

CF3OH, b.p. –20°C, > -20°C dec.

CF3SH, b.p. 36.7°C

-120°C

CF3OCl

+

HCl

CF3OH

Kloeter, G.; Seppelt, K.; J. Am. Chem. Soc., 1979,101, 347-349.

+

Cl2

Adducts of RFOH with triethylamine RFCOF

+

Et3N 3HF+2Et3N

R FCF2OH NEt3

RF : F, C 2F5, i-C3F7

COF2

+

1/3Et3N 3HF+2/3Et3N

CF3OH NEt3 + (CH3)2SO4

70°C, 17 h

CF3OH NEt3

CF3OCH3 49% (Purity 84% )

Cheburkov, Y.; Lillquist, G. J. Fluorine Chem., 2002, 118, 123-126.

-

R FCF2O HNEt3

+

Trifluoromethanol CF3OH and Trifluoromethoxide -

F

-

CF3O

F2C=O

CF3OH, b.p. –20°C, > -20°C dec.

CF3SH, b.p. 36.7°C

-120°C

CF3OCl

+

HCl

CF3OH

Kloeter, G.; Seppelt, K.; J. Am. Chem. Soc., 1979,101, 347-349.

+

Cl2

Trifluoromethyl triflate O CF3-O-S-CF3 O CF3OSO2CF3, (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.

O Alk-O-S-CF3 O 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.

CF3OSO2CF3: Properties3 Sealed tube

CF3OSO2CF3

+

25 °C

CF3SO2F

C5H 5N

+ +

N CF2OSealed tube

CF3OSO2CF3

+

CsF

CF3SO2F

+

Taylor, S. L.; Martin, J. C. J. Org. Chem., 1987, 52, 4148-4156

COF2

1 atm

COF2 + C5H5N

Splitting of Trifluoromethyl Triflate

CF3SO2OCF3

Q+ F-

Q+ CF3O-

-

Q+ F = (Me2N)3C+ Me3SiF2-, Me4NF, (Me2N)4P+ F-, Et3N/3HF, CsF, KF (s.d.), AgF

Kolomeitsev, A. A. Tetrahedron Lett., 2006, in press.

(97-100%)

Trifluoromethoxylation with (Me2N)3C+ CF3OMe

Me

COOEt

Me

OCF3

COOEt

OCF3

COOEt

Me

COOEt

OTf

Me

OTf

Me

85%

77%

CH2Br

HMG+CF3OMe COOEt

Ph OTf (in situ)

CH 2OCF3 Ph

Me OCF3

COOEt 90%

90%

Straightforward C-Trifluoromethoxylation with TFMT1

Me

Ph

Base,pentane +

CF3OSO2CF3

Ph

-30 - +20°C

OH

OCF3

Et3N ( 0.5% ), Py ( - ), (Et2N)3P=N-Me,

[(Me2N)3P=N](NMe2)2P=N-Bu-t,

Me

CH3CN

CH3CN

pKa ca. 28 ( 17%)

pKa ca. 33 ( 42%)

[(Me2N)2C=N]3P=NH (ca. 40%)

+

Straightforward Transformation of alcohols into trifluoromethyl ethers F N

OAlk AlkOH, Et3N

X

N

N

N

X

+

Et3NH+ F- (ca. 100% )

THF, 0 - 20°C

-

X = BF4 , OSO2CF3, OSO2CH3

Alk = CH(COOEt)CH3 (1); CH(CH3)Ph(2)

OAlk N

N

X

+

+

Et3NH F

-

+

CF3OSO2CF3

THF, -30 -20°C

AlkOCF3 66% (1); 87% (2)

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-2yliden)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)3P=N-t-Bu (pK =18.9) to (tmg)3P=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.