the carbon-lithium bond - university of...

Andrea AmbrosiDenmark group meeting

March 12, 2013

The Carbon-Lithium bond

Streitwieser, A.; Williams, J. E.; Alexandratos, S.; McKelvey, J. M. J. Am. Chem. Soc. 1976, 98, 4778Streitwieser, A. J. Org. Chem. 2009, 74, 4433

CH3—Li2.02 Å

80% ionic

Tight ion‐pair with little covalent bonding

BUT

the covalent component cannot be neglected!(13C‐6Li/7Li coupling)

Gawley, R. E. In Stereochemical Aspects of Organolithium Compounds; Verlag Helvetica Chimica Acta: 2010, p 93

Central chirality (η1) Planar chirality (η3)

Chiral organolithiums

First report on a chiral organolithium (Letsinger, 1950)

Letsinger, R. L. J. Am. Chem. Soc. 1950, 72, 4842

Demonstrates the ability of the C‐Li bond to retain its configuration!

Still, W. C.; Sreekumar, C. J. Am. Chem. Soc. 1980, 102, 1201

net inversion or net retention

net retention

A configurationally stable organolithium (Still, 1980)

How to assess the configurational stability of a chiral organolithium?

Electrophilic quenching

Dynamic NMRHoffmann test(and variants)


Ashweek, N. J.; Brandt, P.; Coldham, I.; Dufour, S.; Gawley, R. E.; Klein, R.; Sanchez‐Jimenez, G. J. Am. Chem. Soc. 2005, 127, 449

Conceptually simple

Amenable to kinetic studies ( ΔG‡enantiomerization)

Requires a route to the enantioenriched organolithium precursor

Ashweek, N. J.; Brandt, P.; Coldham, I.; Dufour, S.; Gawley, R. E.; Klein, R.; Sanchez‐Jimenez, G. J. Am. Chem. Soc. 2005, 127, 449


Reich, H. J.; Dykstra, R. R. Angew. Chem. Int. Ed. Engl. 1993, 32, 1469

Examples

To determine the enantiomerization barrier of chiral organolithiums,the exchange of diastereotopic groups is analyzed by dynamic NMR

Hoffmann, R. W.; Dress, R. K.; Ruhland, T.; Wenzel, A. Chem. Ber. 1995, 128, 861

Examples

Marshall, J. A.; Gung, B. W.; Grachan, M. L. In Modern Allene Chemistry; Wiley‐VCH Verlag GmbH: 2008, p 493Neef, G.; Eder, U.; Seeger, A. Tetrahedron Lett. 1980, 21, 903

Reich, H. J.; Holladay, J. E.; Walker, T. G.; Thompson, J. L. J. Am. Chem. Soc. 1999, 121, 9769

Allenyllithiums

Mechanisms of enantiomerization:

Electrophilic quenching: Dynamic NMR:

The Hoffmann test: a serendipitous discovery

Hoffmann, R. W.; Lanz, J. W.; Metternich, R. Liebigs Ann. Chem. 1988, 161

1988 – study of the stereoselective addition of allenylmetal reagents to aldehydes

The allenyltitanium reagentis configurationally stableon the reaction timescale

The Hoffmann test

Hirsch, R.; Hoffmann, R. W. Chem. Ber. 1992, 125, 975

1992 – formal report on the test

Experiment 1:

Experiment 2:

Examples

Hoffmann, R. W.; Rühl, T.; Chemla, F.; Zahneisen, T. Liebigs Ann. Chem. 1992, 719Hoffmann, R. W.; Rühl, T.; Harbach, J. Liebigs Ann. Chem. 1992, 725

Configurationallylabile

Configurationallystable

(Weinreb amide)

Energy diagrams

Basu, A.; Thayumanavan, S. Angew. Chem. Int. Ed. 2002, 41, 716

Experiment 1 (racemic E)

Experiment 2 (enantiopure E)



Curtin‐Hammett

non‐Curtin‐Hammett

ΔΔG‡ dependent ΔΔG‡ dependent

ΔΔG‡ dependent ΔGo dependent (1:1)

s factor and level of conversion


If s is not in the optimal range between 1.5 and 3,a different electrophile should be chosen

Experiment 2 must go to completion! Use an excess of the electrophile Long reaction times are needed when s is high

( decomposition of SM and products)

s should be < 3

A comparison of the A/B ratios for Experiment 1 and 2 is

inconclusive if s < 1.5

When s is too small…

Hoffmann, R. W.; Rühl, T.; Harbach, J. Liebigs Ann. Chem. 1992, 1992, 725

s = 1.2 no conclusion can be drawn;change electrophile!

Enantiopurity of the electrophile


A moderate excess of E (1‐5 equiv)

of slightly degraded ee(> 95%)

is tolerated

A product ratio of 1:1 can be reached in Experiment 2

only if the electrophile is enantiomerically pure

(1 equiv of E)

(2 equiv of E)

(5 equiv of E)

Side reactions


1. Both enantiomers of the organometallic reagent are consumed at the same rate Experiment 1: decreased yield Experiment 2: decreased yield and 1:1 dr

Yieldin Exp. 2

drin Exp. 2

The deviation from the ideal 1:1 dr is not significant if the extent of the side reaction and the s factor are small

Side reactions


2. The enantiomers of the organometallic reagent are consumed at different rates (s*) Experiment 1: decreased yield Experiment 2: increased or decreased yield relative to Experiment 1 and = or 1:1 dr

Yieldin Exp. 2

drin Exp. 2

Side reactions that occur to an extent of less than 10%will not jeopardize the test

s* = 5

RLi tested with the Hoffmann test

Hoffmann, R. W. In Stereochemical Aspects of Organolithium Compounds; Verlag Helvetica Chimica Acta: 2010, p 165

Allylmetal reagents

Hoffmann, R. W.; Polachowski, A. Chem.Eur. J. 1998, 4, 1724

To summarize…

The substrate is used as a racemate

The resulting diastereomers only have to be identified as such (NMR, GC, HPLC) – itis not necessary to assign the relative configuration

When more than 2 diastereomers are generated (e.g., E = aldehyde), their relativeconfiguration must be assigned

Large s factors, incomplete conversion, insufficient enantiopurity of theelectrophile, and side reactions may lead to inconclusive results

Not suitable to quantify ΔG‡enantiomerization

Variants have been developed

The “poor man’s Hoffmann test” (Beak, 1996)

Basu, A.; Gallagher, D. J.; Beak, P. J. Org. Chem. 1996, 61, 5718

Experiment 1:

Experiment 2:

The er reflects ΔΔG‡ if RLi is configurationally labile,the population of the diastereomeric complexes if RLi is configurationally stable

er Exp1 er Exp2 for stable RLi

er Exp1 = er Exp2 for labile RLi (ambiguous)

Does not require an enantioenriched electrophile – an achiral electrophile is used Requires a chiral ligand for RLi

The er reflects ΔΔG‡

Energy diagrams

Experiment 1 (excess E)



Curtin‐Hammett

ΔGo dependent:er reflects

the population

non‐Curtin‐Hammett

ΔΔG‡ dependent:er reflects s



The test cannot establish configurational lability unambiguously:

identical er in the two experiments can be the result of equivalence of the activation energies (s 1)

Basu, A.; Gallagher, D. J.; Beak, P. J. Org. Chem. 1996, 61, 5718Beak, P.; Basu, A.; Gallagher, D. J.; Park, Y. S.; Thayumanavan, S. Acc. Chem. Res. 1996, 29, 552

Experiment 2 (substoichiometric E)

Examples

Could beconfigurationally

labile


Basu, A.; Gallagher, D. J.; Beak, P. J. Org. Chem. 1996, 61, 5718Thayumanavan, S.; Basu, A.; Beak, P. J. Am. Chem. Soc. 1997, 119, 8209

Examples


Nakamura, S.; Nakagawa, R.; Watanabe, Y.; Toru, T. J. Am. Chem. Soc. 2000, 122, 11340

Group exercise: more on allenylithiums

The configurational stability of an allenyllithium reagent was determined using a different variant of the Hoffmann test: Experiment 1: deficiency of enantiopure reagent Experiment 2: excess of enantiopure reagent

How does this test work? What conclusions can be drawn on the stability of the allenyllithium reagent?

Group exercise: more on allenylithiums

Experiment 1: deficiency of enantiopure reagent

Experiment 2: excess of enantiopure reagent

At low conversions, dr s

when a racemic organolithiumreacts with an enantiopure electrophile

Same as Experiment 2 in the Hoffmann test:dr = 1:1 for a stable RLidr = s for a labile RLi

The allenyllithium isconfigurationally labileover the timescale

of addition to camphor

Bejjani, J.; Botuha, C.; Chemla, F.; Ferreira, F.; Magnus, S.; Pérez‐Luna, A. Organometallics 2012, 31, 4876

Configurational stability of organolithiums: timescale

10 kcal/mol: t1/2 = 0.03 s at –78 ºC

15 kcal/mol: t1/2 = 3 h at –78 ºC, 0.01 s at 25 ºC

20 kcal/mol: t1/2 = 145 years at –78 ºC, 53 s at 25 ºC

Coldham, I.; Sheikh, N. S. In Stereochemical Aspects of Organolithium Compounds; Verlag Helvetica Chimica Acta: 2010, p 253Clayden, J. Organolithiums: Selectivity for Synthesis; Pergamon: 2002

“Configurationally stable” is a term which has a meaning only when it is associated with a temperature and a timescale

Barriers have been determined quantitativelyonly for a few classes of organolithiums

Configurational stability of organolithiums: summary

Benzylic organolithiums: low barriers (8‐10 kcal/mol)

α‐heteroatom substituted organolithiums: higher barriers

Chelation and bulky groups increase the barrier

Cyclic α‐amino, cyclopropyl, oxiranyl, aziridinyl organolithiums: stable (> 20 kcal/mol)

Coldham, I.; Sheikh, N. S. In Stereochemical Aspects of Organolithium Compounds; Verlag Helvetica Chimica Acta: 2010, p 253Clayden, J. Organolithiums: Selectivity for Synthesis; Pergamon: 2002

Preparation of chiral organolithiums

Dynamic resolutions: kinetic vs thermodynamic control

Dynamic Kinetic Resolution (DKR)ΔΔG‡ dependent

Dynamic Thermodynamic Resolution (DTR)ΔGo dependent

Benzylic organolithiums

Not an asymmetric deprotonation

DKR or DTR?

The organolithium isconfigurationally labile

over the timescale of the experiment, butconfigurationally stable

over the timescale of reaction with TMSCl DTR

Gallagher, D. J.; Du, H.; Long, S. A.; Beak, P. J. Am. Chem. Soc. 1996, 118, 11391

Benzylic organolithiums

Thayumanavan, S.; Basu, A.; Beak, P. J. Am. Chem. Soc. 1997, 119, 8209Kimachi, T.; Takemoto, Y. J. Org. Chem. 2001, 66, 2700

The organolithium isconfigurationally labile

over the timescale of the experiment, andconfigurationally labile

over the timescale of reaction with E DKR

DKR or DTR? Poor man’s Hoffmann test: inconclusive Hoffmann test: labile racemic stannane enantioenriched product

Diarylmethanes

DKR or DTR?No experiments were performed

to assess the configurational stability of theintermediate organolithium

Prat, L.; Dupas, G.; Duflos, J.; Quéguiner, G.; Bourguignon, J.; Levacher, V. Tetrahedron Lett. 2001, 42, 4515Kuo, S.‐C.; Chen, F.; Hou, D.; Kim‐Meade, A.; Bernard, C.; Liu, J.; Levy, S.; Wu, G. G. J. Org. Chem. 2003, 68, 4984

α-Oxygen

Zschage, O.; Hoppe, D. Tetrahedron 1992, 48, 5657Paulsen, H.; Hoppe, D. Tetrahedron 1992, 48, 5667

invertive

configurationally labileone diastereomeric organolithium crystallizes Crystallization‐Induced Dynamic Resolution

α-Nitrogen

Weisenburger, G. A.; Faibish, N. C.; Pippel, D. J.; Beak, P. J. Am. Chem. Soc. 1999, 121, 9522Johnson, T. A.; Curtis, M. D.; Beak, P. J. Am. Chem. Soc. 2001, 123, 1004

configurationally stableover the timescale of the experiment

Asymmetric deprotonation

configurationally labileat ‐25 oC

configurationally stableat ‐78 oC DTR

α-Sulfur and Selenium

DKR or DTR?Hoffmann test: labile

DKR

DKR or DTR?Poor man’s Hoffmann test: stable

Synthesis of axially chiral olefins

DTR

Nakamura, S.; Nakagawa, R.; Watanabe, Y.; Toru, T. J. Am. Chem. Soc. 2000, 122, 11340Nakamura, S.; Aoki, T.; Ogura, T.; Wang, L.; Toru, T. J. Org. Chem. 2004, 69, 8916

Conclusion

Chiral organolithium reagents have had a significant impact on stereoselectivesynthesis

Assessment of the configurational stability of an organolithium reagent isfundamental for the rational design of stereoselective processes

NMR spectroscopy and the Hoffmann test have provided information on theconfigurational stability of several classes of chiral organolithiums

Several parameters affect the configurational stability: solvent, temperature,substituents, intramolecular coordination – a systematic structure‐activityrelationship has not been developed

Bibliography

Gawley, R. E. Stereochemical Aspects of Organolithium Compounds(Topics in Stereochemistry, Vol. 26); Verlag Helvetica Chimica Acta: 2010

Clayden, J. Organolithiums: Selectivity for Synthesis; Pergamon: 2002

Ōki, M. Applications of Dynamic NMR Spectroscopy to Organic Chemistry; VerlagHelvetica Chimica Acta: 1985

Basu, A.; Thayumanavan, S. Angew. Chem. Int. Ed. 2002, 41, 716

Beak, P.; Basu, A.; Gallagher, D. J.; Park, Y. S.; Thayumanavan, S. Acc. Chem. Res. 1996, 29, 552


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