1

“Abnormal” N-heterocyclic carbenes- from discovery to

isolation of C-4/5 imidazolylidene

Yiming Qian

N

NR

R

RR

2

1

34

5 N

NR

R

R

2

1

34

5

R

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.

H H F F Ar Ar

3

Reactions of classical carbenes

• Cyclopropanation

CH2+

CH2+RnX Y RnX CH2 Y

• Ylide formation

• Insertion reactions

CH2RnX RnX CH2+

4

Singlet vs triplet carbenes

p

Triplet

linear

p

p

R

Rp

R

Rp

Singlet Tripletbent

R R

• 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, 28Ann. Chim. Phys. 1839, 71, 427Ann. 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. 1991 113, 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:

p

N

N

R

R

N

N

R

R

N

N

N

R

RR=alkyl or aryl

N

N N

N

R

R

S

N

R

R

R

N

N

R

R

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)

N

NAd

Ad

HN

NAd

Ad

N

N

N

N

IMes SIMes

J. Am. Chem.Soc. 1991 113, 3122

9

Quantitatively

Angew. Chem. Int. Ed. 1997,36, 2162-2187

10

NHCs as organocatalysts

• NHCs are nucleophilic: inaccessible “vacant” 2p orbital of carbene

• Benzoin condensation

J. Am. Chem. Soc. 1958, 80, 3719-26

N

N

NH2

N S

OH

thiamin

B BH+

thiamin:B

Ph H

O

OHHPh

N S

BH

S

N OH

Ph

Ph H

O

Ph O

OHPh

thiamin

PT

OH

O Ph

thiamin

OPh

PhHO

Ph H

ON

N

NH2

N S

OH

Cl

Base Ph

O

Ph

OH

Thiamin

11

Pyruvate decarboxylation

The organic chemistry of biological pathways 179

N

S

R

R' O

O

O

N

SR'

R

B

BH H

OO

HO

S

N

R

R'

N

S

R

HOR'

N

S

R

HOR'

S

N

R

ROH

H

H

O

AB

H

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

N

NPh

Ph

H

CCl3

-CHCl3

N

NPh

PhN

NPh

Ph

N

NPh

Ph

Angew. Chem. Int. Ed. 1962, 1, 75-80Angew. Chem. Int. Ed. 1968, 7, 141-142

NCH

N

C6H5

C6H5

2 ClO4 Hg(OAc)22 AcOH N

CN

C6H5

C6H5

Hg CN

N

C6H5

C6H5

22 ClO4

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

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, 2162-2187

15

NHCs as ligands for high oxidation state metal complexes

First cationicMo(IV)complex

First examples of NHC-metal-oxo Complexes charaterized by x-ray

Angew. Chem. Int. Ed. 1997,36, 2162-2187

16

The NHC-Metal bond• Generally, single bond of σ bond

character mainly with limited π back donation

• Charge deposition analysis (CDA)• d NHCMetal σ donation• b MetalNHC π back donation• d/b ratios: 2.59-3.99 for Pd-NHC;

5.23-5.88 for Au-NHC; 7.8-12.68 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

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

Angw. Chem Int. Ed. 1995, 34, 2371-2374

ClR

COOtBu

Pd(OAc)2 (2 mol%)

IMes-HCl (4 mol%)

Cs2CO3 (2 equiv)DMAc, 120 C

COOtBu

91-100%

R

NN Mes

Mes

NN

Mes

Mes

PdCl

Cl

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, 3343-3352

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

N

NR

R

HStrong Base

ClTHF N

NR

R

iPr

iPr

SK metal

THF Reflux

iPr

iPr

N

N

NPh

PhPh

H

OMeN

N

NPh

PhPh

80 C/0.01mbar

Deprotonation of imidazolium Desulfurization

J. Am. Chem.Soc. 1991 113, 3122 Synthesis-struttgart. 1993 561Angew. Chem. Int. Ed. 1995 34, 1021 Angew. Chem. Int. Ed. 1997 36, 1709Angew. Chem. Int. Ed. 1962, 1, 75-80

Thermolysis Photolysis

N

NR

R

O

O N

NR

R

254 nm

10K in matrix

N

NR

RN

NR

R

heatH

CCl3

21

Synthetic strategies to NHC-metal complex

N

N

N

NR R

R R

M MN

N N

NR

R

R

R

Lappert method

In situ deprotonation

N

NR

R

X strong or weak base

N

NR

R

MLn

Oxidative additon

N

NR

R

Xlow valent metal or metal hydride

N

NR

R

MLn

Transmetallation from NHC-Ag complex

N

NAg

R

RN

NR

R

MLn

N

NR

R

MLn

Direct metallation

N

NR

R

M(OAc)2N

NM

R

RN

NR

R

X

X

AcOH

Mix free carbene with metal complex with labile ligands

N

NR

R

MLnN

NR

R

MLn-1

X=H, Me, Cl, Br, I

N

NR

R

MLn

Coord Chem Rev 2007 251, 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?

N

NN

H

R

BF4

IrH5L2

2H2N

NN

R

IrL

LH

H

2

5

4

BF4

R=iPr, nBu L=PPh3

Chem. Commun. 2001 21, 2274

[2.100(6) Å]

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. 2001 21, 2274

24

Evidence of oxidative addition

J. Am. Chem. Soc. 2002 124, 10473-10481Angew. Chem. Int. Ed. 2005, 44, 444 –447

N

NN

IrL

LH

HR

N

NN

HBF4

IrH5L2

N

NH

IrL

LH

HR

N

HH2

-H2 Observed by time-dependent NMR

N

NN

R

IrL

LH

H

NN

Fc

N

N

(PF6)2

Ir(COD)Cl2

NEt3/CH3CNIr

Cl

N

N

FcNN

PF6

Base not needed IrN

NH

Fc

NN

Cl

PF6

Ir (III)

25

Counteranion effect and wingtip R group sterics in abnormal bonding mode

Eq 1

J. Am. Chem. Soc. 2005, 127, 16299-16311

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

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, 16299-16311

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

J. Am. Chem. Soc. 2004 5046- 5047

29

Catalytic hydrogenation

1 atm H2

Cat.Cat.=

N

N

N

NH

Pd NCMe

NCMe

(BF4)2

Angew. Chem. Int. Ed. 2007, 46, 6293 –6296

aNHC NHC

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

Coord Chem Rev 2007 251, 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

J. Am. Chem. Soc. 2005 127, 3290

NN

H

Mes

HX

NaH/cat. KOtBu

NN

H

Mes

NN

H

Mes

PhX

KN(SiMe3)2N

N Mes

Ph

NN Mes

Ph

III

Se61%

NN Mes

Ph

Se

Rh(COD)Cl2KN(SiMe3)2

NN Mes

Ph

RhCl

39%

This N is not stablizing the carbeneto the same extent due to delocalization

C1-C9 bond is 1.388 Alonger than the C1=C9in 1 (1.354 A)

1

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

N

NR

R

R

R

N

NR

R

R

R

17kcal/mol

N

NR

R

R

R

20kcal/mol

Isolable!

Chem. Asian J. 2007 2,1555 Science 2009 326, 556-557

N

NPh

Dip

Dip

Ph

35

Synthesis of Bertrand’s abnormal NHC

NH

NiPr

iPr

iPr

iPr

O

Br K2CO3

iPrOH reflux 24hrs

N

NiPr

iPr

iPr

iPrO

HX X=BF4- Br- Cl-

N

N

Acetic anhydride

Ph

iPr

iPr

iPr

iPr

Ph X-

X= Br- Cl-

N

NPh

iPr

iPr

iPr

iPr

Ph X-

Li

nBuLi

[12]crown-4

25oC 15 minutesN

NPh

iPr

iPr

iPr

Ph X-

12

3

4

56

KN(SiMe3)2

N

NPh

iPr

iPr

iPr

iPr

Ph50oC48h

7

5 6

20.3kcal/mol

6kcal/mol

Too reactive to be isolated?

Science 2009 326, 556

36

Crystal structures of precursor and aNHC

1.383Å1.417Å1.368Å 1.355Å

108o 101o

Science 2009 326, 556-557

37

FMO proof of enhanced donor ability/basicity

HOMO aNHC HOMO-1 aNHC

• aNHC HOMO (-4.403 eV) and HOMO-1 (-4.879 eV)are higher in energy than their normal counterparts with C-5 protected with phenyl group (-5.000 eV for HOMO and -5.279 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 2009 326, 556-557

38

Potential use in organocatalysis and metal catalysis

N

NPh

iPr

iPr

iPr

iPr

Ph

7 CO2(Me2S)AuCl

N

NPh

iPr

iPr

iPr

iPr

Ph

AuCl N

NPh

iPr

iPr

iPr

iPr

Ph

O

O

aNHC behaves similar to their normalcousins, due to their enhanced basicitythey are likely to promote both metal catalysis and organocatalysisResearch continues….

Science 2009 326, 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

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