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

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

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

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 Reactions of classical carbenes
Insertion reactions Cyclopropanation Ylide formation

4 Singlet vs triplet carbenes
If the carbene unit werw linear, it should have two degenerate p orbitals, and Hund’s first rule would predict a triplet ground state where each orbital has one electron and electrons are of the same spin. When the carbene unit is not linear, the two orbitals become different. The orbital prependicular to the plane defined by the three atoms is designated as p, while that parallel to this plane is called sigma, the sigma orbital will acquire s charater and thereby become stabilized while the p remains largely unchanged Most carbenes are not linear, the ground state multplicity depends on the relative energy of the singlet and triplet states Triplet has two The magnitude of energy difference between triplet and singlet is roughly equal to the electron repulsion minus the energy required to promote an elecron from sigma to p orbital When Energy separation between sigma and p increases, the promotion energy becomes large enough to overcome the repulsion energy-singlet 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 More than a century ago, we wanted to isolate carbenes!
In 1835 and 1839, Duma and Renault attempted to dehydrate methanol by means of PO5 or conc. H2SO4 In the late 19th 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 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 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: NHC are singlets because the geometry is bent, and according the fleming, N highers the 2p orbital of the carbene thus increases the gap between p and sigma orbitals

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-Ccarbene are longer than C=N and the N-C-N angle is more acute than its imidazolium precursor (from 109 to 102 degree) The carbene is planar, but the J. Am. Chem.Soc , 3122

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

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

11 Pyruvate decarboxylation
First the thiamine pyophosphate gets activated by base to yield the carbene, then carbene attacks the beta-ketone of pyruvate to yield this structure on the right, this intermediate then decarboxylates to form A which resonates to give B, which then undergoes elimination of the thiazolylidene to give acetaldehyde The organic chemistry of biological pathways 179

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 Vii does not react with electronic olefins (nucleophilic) Angew. Chem. Int. Ed. 1962, 1, 75-80 Angew. Chem. Int. Ed. 1968, 7,

13 NHCs vs phosphines Neutral donors 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 Neutral donors Stronger σ-donors N-Rs point towards metal Sterics and electronics can be fine tuned independently Stable towards oxidizing conditions Backbone sub gives electronic tuning, wingtip sub gives steric tuning

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 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 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) Due to the fact that silver is an antibiotic, NHC-silver complexes been extensively studied in medicine J. Organomet. Chem. 2006, 691, 3797–3805. Inorg. Chem. 2008, 47, 4153–4165. Chem.-Eur. J. 2008,6646–6655

17 Examples of NHCs metal catalyst ligands
Heck Reaction: 1st 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 Talk about how phosphine degrade under same conditions and requires large excess Angw. Chem Int. Ed. 1995, 34,

18 Examples of NHCs metal catalyst ligands
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 J. Org. Chem. 2005, 70,

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 Formation of NHCs Deprotonation of imidazolium Desulfurization
Thermolysis Photolysis J. Am. Chem.Soc , 3122 Synthesis-struttgart Angew. Chem. Int. Ed , 1021 Angew. Chem. Int. Ed , 1709 Angew. Chem. Int. Ed. 1962, 1, 75-80

21 Synthetic strategies to NHC-metal complex
several strategies used to form NHC-metal complexes. Coord Chem Rev , 596–609

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? [2.100(6) Å] Chem. Commun , 2274

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) Agostic interaction is a term in organometallic chemistry for the interaction of a coordinately-unsaturated transition metal with a C-H bond, Chem. Commun , 2274

24 Evidence of oxidative addition
If it was oxidative addition, there should be an higher oxidation state of Ir intermediate at least during the reaction J. Am. Chem. Soc , Angew. Chem. Int. Ed. 2005, 44, 444 –447

25 Counteranion effect and wingtip R group sterics in abnormal bonding mode
Eq 1 The anion used during the synthesis decides the ratio, not the anion subsequently added J. Am. Chem. Soc. 2005, 127,

26 Regioselectivity of metalation
Ir(I) complex’s ability to oxidatively add to C4-H BF4 Counterion is insensitive to H-Bonding, disfavouring heterolytic C2-H abstraction Sterically bulky wingtip groups hinders C2, favouring C4 Abnormal and normal bondiong go through entirely different mechanisms

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 Heck olefination 2004, Nolan et al. made Catalyst 2 (aNHC-catalyst) via direct palladation Proton abstraction method (Cs2CO3) 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 Weak base is unable deprotonate eaither protons J. Am. Chem. Soc

29 Catalytic hydrogenation
aNHC NHC Change example please!! Angew. Chem. Int. Ed. 2007, 46, 6293 –6296

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 Research on aNHC-metal complex
A structural database search was conducted to get an approximate measure of the relative abundance of abnormal NHC complexes in the second half of the d-block, Fig. 10. It is notable that iridium has the greatest prevalence of abnormally bound carbene chemistry in a relatively small number of complexes. A high number of ruthenium and palladium complexes have been reported, although the structurally characterised carbene complexes are most numerous for rhodium and palladium. It remains unclear as to whether the large number of homogeneous cata- Coord Chem Rev , 596–609

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 Towards isolable aNHC This N is not stablizing the carbene
to the same extent due to delocalization 1 C1-C9 bond is A longer than the C1=C9 in 1 (1.354 A) Lassselaa saw the opportunity to generate an abnormal carbene by blocking normal C-2Lasselate isolated Rh-aNHC complex also supported that aNHC are more like carbene instead of ylides. J. Am. Chem. Soc , 3290

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 People did not think aNHC can ever be isolated Chem. Asian J ,1555 Science ,

35 Synthesis of Bertrand’s abnormal NHC
Deprotonation of bf4 salts all failed, Li crown Too reactive to be isolated? Science , 556

36 Crystal structures of precursor and aNHC
Both are planar, indicating delocalization. 1.383Å 1.417Å 1.368Å 1.355Å 101o 108o Science ,

37 FMO proof of enhanced donor ability/basicity
HOMO aNHC HOMO-1 aNHC Homo is sigma type lone pair at C5, second highest Homo is pi bonding at C4-C5 and antiboding at the phenyl ring 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 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 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 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 Hideo Tomioka isolated first triplet carbene

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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