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1 “Abnormal” N-heterocyclic carbenes- from discovery to isolation of C-4/5 imidazolylidene Yiming Qian.

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Presentation on theme: "1 “Abnormal” N-heterocyclic carbenes- from discovery to isolation of C-4/5 imidazolylidene Yiming Qian."— Presentation transcript:

1 1 “Abnormal” N-heterocyclic carbenes- from discovery to isolation of C-4/5 imidazolylidene Yiming Qian

2 2 What are carbenes? Reactive intermediates that defy octet rule 6 valence electrons on carbon (electron deficient) Highly reactive and short lived, prior to 1960, thought to be too reactive to be isolated Classical carbenes: Methylene, difluorocarbene, diarylcarbene, etc.

3 3 Reactions of classical carbenes Cyclopropanation Ylide formation Insertion reactions

4 4 Singlet vs triplet carbenes ΔGst=E(electronic repulsion)-E(electron promotion) Dependent on electronic and steric factors of R’s Singlets are like carbocation and carbanion in one Triplets are diradicals

5 5 More than a century ago, we wanted to isolate carbenes! In 1835 and 1839, Duma and Renault attempted to dehydrate methanol by means of PO 5 or conc. H 2 SO 4 In the late 19 th century,Nef announced that stable carbenes will be available in the near future It has been the dream of carbene chemists to isolate free carbenes so we can understand and harness this reactive intermediate Ann. Chim. Phys. 1835, 58, 28 Ann. Chim. Phys. 1839, 71, 427 Ann. 1897, 298, 202

6 6 First isolated free Carbene Not until about 100 years after Nef’s ambitious announcement, in 1991,Arduengo et al. produced the first crystalline carbene: also a very stable N- heterocyclic carbene (mp.241degree)--IAd. No insertion reactions,no dimerization, no cyclopropanation, sensitive to air and moisture J. Am. Chem.Soc , 3122

7 7 What are N-heterocyclic carbenes? Persistent diamino carbenes with the carbenic carbon being part of a N-containing heterocycle NHCs are singlets! Large ΔGst~80kcal/mol (due to small angle and electronics of N) Conjugate bases of corresponding azolium salts Salts are weak acids, so they are strong (neutral) bases Examples include:

8 8 Why is Arduengo’s imidazolylidene bottle-able? NHCs are mainly electronically (orbital overlay) and partially sterically stabilized Thermodynamically stable and kinetically protected Heteroatom N’s act as σ attractor and π donor (push- pull system) Aromaticity is not required for stability (but it helps) Crystal structure shows both N-C carbene are longer than C=N and the N-C-N angle is more acute than its imidazolium precursor (from 109 to 102 degree) J. Am. Chem.Soc , 3122

9 9 Quantitatively Angew. Chem. Int. Ed. 1997,36,

10 10 NHCs as organocatalysts NHCs are nucleophilic: inaccessible “vacant” 2p orbital of carbene Benzoin condensation J. Am. Chem. Soc. 1958, 80,

11 11 Pyruvate decarboxylation The organic chemistry of biological pathways 179

12 12 N-heterocyclic carbenes as metal complex ligands 1960, Wanzlick investigated NHCs’ reactivity and stability and came tragically close to isolating the free carbene Reported the first application of NHCs as ligands for metal complexes Angew. Chem. Int. Ed. 1962, 1, Angew. Chem. Int. Ed. 1968, 7,

13 13 NHCs vs phosphines Neutral donors Stronger σ-donors N-Rs point towards metal Sterics and electronics can be fine tuned independently Stable towards oxidizing conditions Neutral donors Weaker σ-donors P-Rs point away from metal Changing R’s induces change in both sterics and electronics Cannot be used as ligand of oxidizing complexes Prone to degradation of P-C

14 14 NHCs form complexes with a majority of the elements From early earth metals to late transition metals to non-metals and lanthanides One of the hardest lewis acids Angew. Chem. Int. Ed. 1997,36,

15 15 NHCs as ligands for high oxidation state metal complexes First cationic Mo(IV)complex First examples of NHC-metal-oxo Complexes charaterized by x-ray Angew. Chem. Int. Ed. 1997,36,

16 16 The NHC-Metal bond Generally, single bond of σ bond character mainly with limited π back donation Charge deposition analysis (CDA) d NHC  Metal σ donation b Metal  NHC π back donation d/b ratios: for Pd-NHC; for Au-NHC; for Ag-NHC (*good transmetalating agent) J. Organomet. Chem. 2006, 691, 3797–3805. Inorg. Chem. 2008, 47, 4153–4165. Chem.-Eur. J. 2008,6646–6655

17 17 Examples of NHCs metal catalyst ligands Heck Reaction: -1 st catalytic application of Pd- NHC complexes by Herman et al. - A standard for new palladium systems (reactivity and stability: long rxn times/harsh conditions) - R.T and short reaction times with aryl diazonium salts Angw. Chem Int. Ed. 1995, 34,

18 18 Palladium-Catalyzed Aerobic Alcohol Oxidation: - Broad scope of substrates -Single NHC ligand able to withstand the aerobic oxidation conditions (higher temperature 60 degree) -Despite numerous cycling between Pd(II) and Pd(0),catalyst still active - This suggests the ligand does not dissociate from the palladium centre Examples of NHCs metal catalyst ligands J. Org. Chem. 2005, 70,

19 19 Grubbs II vs Grubbs I Grubbs 1 is more substrate-tolerating than Shrock catalyst 3, but not as active with electron poor and sterically hindered olefins NHC has higher trans effect, which labilizes the trans phosphine, resulting in an increased catalytic activity and stability of 2 than that of 1 and 3 J. Am. Chem. Soc. 2003, 125, 2546.

20 20 Formation of NHCs Deprotonation of imidazoliumDesulfurization J. Am. Chem.Soc , 3122 Synthesis-struttgart Angew. Chem. Int. Ed , 1021 Angew. Chem. Int. Ed , 1709 Angew. Chem. Int. Ed. 1962, 1, Thermolysis Photolysis

21 21 Synthetic strategies to NHC-metal complex Coord Chem Rev , 596–609

22 22 C-2 vs C-4 imidazolylidene Due to lower pKa, C-2 are usually carbene centres Crabtree discovered an iridium metal hydride complex that contains a C-4 metalated abnormal NHC How does this happen? Kinetic or thermodynamic product? Chem. Commun , 2274 [2.100(6) Å]

23 23 How can the wrong-way bonding occur? Theoretical calculations reveals that the free carbene at C4 lies 20kcal/mol above the expected C2 carbene Computations show C4 metalated complex is higher in energy than normal C2 complex (aNHC complex should be the kinetic product) pKa difference of C2-H and C4-H is large (pKa C4 proton 33 is 8-9 units higher than C2 proton 24) Chem. Commun , 2274

24 24 Evidence of oxidative addition J. Am. Chem. Soc , Angew. Chem. Int. Ed. 2005, 44, 444 –447

25 25 Counteranion effect and wingtip R group sterics in abnormal bonding mode Eq 1 J. Am. Chem. Soc. 2005, 127,

26 26 Regioselectivity of metalation Ir(I) complex’s ability to oxidatively add to C4- H BF 4 Counterion is insensitive to H- Bonding, disfavouring heterolytic C 2 -H abstraction Sterically bulky wingtip groups hinders C2, favouring C4

27 27 After the discovery of aNHC… It is not safe to assume the formation of NHC-metal complex, especially when the activation of NHC from its imidazolium is in situ However, the σ-donor ability of aNHC is experimentally found to be significantly larger than their normal counterparts by Tolman electronic parameter v(CO), where the IR stretching frequency (wavenumber) of CO trans to the ligand in question is inversely proportional to the donor strength Recall: donor strength aNHCs>NHCs>phosphines Catalytic applications? J. Am. Chem. Soc. 2005, 127,

28 28 Heck olefination 2004, Nolan et al. made Catalyst 2 (aNHC- catalyst) via direct palladation Proton abstraction method (Cs 2 CO 3 ) gave only normal catalyst 1 Note: When weaker base (dimethylaniline) was used, catalyst 2 was the major product Indicating an oxidative addition mechanism of the aNHC metalation J. Am. Chem. Soc

29 29 Catalytic hydrogenation Angew. Chem. Int. Ed. 2007, 46, 6293 –6296 aNHCNHC

30 30 aNHC vs NHC Stronger σ donor, even less π backbonding Metal centres are more electron rich However the C-M bond is weaker, more dissociable aNHC-metal complex are hard to generate Few compounds have been characterized

31 31 Research on aNHC-metal complex Coord Chem Rev , 596–609

32 32 Methods of forming aNHC-metal complexes Block C-2 with an aryl or hindered alkyl, then abstract C-4 proton with strong hindered bases Oxidative addition (C-H, C-halogen) Transmetalation by Ag-aNHC complex Direct metalation of carbene (attractive and cost effective, but requires free isolable carbenes) Are aNHCs too reactive to be isolated?

33 33 Towards isolable aNHC J. Am. Chem. Soc , 3290 This N is not stablizing the carbene to the same extent due to delocalization C1-C9 bond is A longer than the C1=C9 in 1 (1.354 A) 1

34 34 Isolation of the first metal free aNHC Not many think aNHCs are isolable, until four years later… Bertrand et al. inspired by Lassaletta’s work and the fact that these aNHC are merely 17kcal/mol higher Chem. Asian J ,1555 Science ,

35 35 Synthesis of Bertrand’s abnormal NHC Too reactive to be isolated? Science , 556

36 36 Crystal structures of precursor and aNHC 1.383Å 1.417Å 1.368Å1.355Å 108 o 101 o Science ,

37 37 FMO proof of enhanced donor ability/basicity HOMO aNHC HOMO-1 aNHC aNHC HOMO ( eV) and HOMO-1 ( eV)are higher in energy than their normal counterparts with C-5 protected with phenyl group ( eV for HOMO and eV for HOMO-1) Can the electronics be tuned with such an all-substituted NHC? -The phenyl groups are not sterically hindering and participates in the HOMO-1 of aNHC, so we can vary substituents on the ring to tune the electronics of the carbene heterocycle Science ,

38 38 Potential use in organocatalysis and metal catalysis aNHC behaves similar to their normal cousins, due to their enhanced basicity they are likely to promote both metal catalysis and organocatalysis Research continues…. Science , 556

39 39 Summary Background of carbenes History of isolation of first singlet carbene N –heterocyclic carbenes and their structures and reactivities Discovery of aNHC and their use as metal ligands Endeavor to isolate aNHCs

40 40 Concluding Remark “Somehow, I can’t believe that there are any heights that can be scaled by a man who knows the secret of making dreams come true. This special secret, it seems to me, can be summarized in four Cs ; they are curiosity, courage, confidence and constancy. And the greatest of all is confidence, when you believe in a thing, believe in it all the way implicitly and unquestionably.” -Walt Disney

41 41 Acknowledgements Professor John Pezacki Lab Members Neda Nasheri Ardakan Sylvie Bélanger Dr. David Blais Jenny Cheng Dana Danielson Mohamed El-Salfiti Dr. Robert Faragher Matthew Goodmurphy Kelly Hoop Dr. David Kennedy Kasia Kieliszkiewicz Dr. Roger Koukiekolo Rodney Lyn Craig McKay Dr. Joseph Moran Yanouchka Rouleau Dr. Selena Sagan Ragunath Singaravelu Ingrid van der Wiel Ellen Wakarchuk Guangsheng Yuan...& everyone in attendance

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