Cieplak Effect:Fact or Fiction? - School of Chemical … · Cieplak Effect:Fact or Fiction? ... •The theory that the C-H bond is a better electron donor then the C-C bond is

Cieplak Effect:Fact or Fiction?Kimberly M. Hilby

SED Group Meeting

01/31/2017

1

Overview of Presentation

• Introduction

• Theory behind Cieplak Effect

• Key Experiments/ Criticism

• Criticism of theory

• Modern day applications

• Conclusion

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A Curious Trend

Boone, J. R.; Ashby, E.C Top. Stereochem. 1979, 11, 53Wigfield, D.C. Tetrahedron 1979, 35, 449-462 3

% of Axial Attack % of Axial Attack

NaBH4, 2-propanol 87 75

LiBH4, THF 93 71

LiAlH4, Et2O 92 82

LiAl(OMe)3H, THF 56 37

L-Selectride 3 -

Felkin’s Theory of Torsional Strain

Cherest, M.; Felkin, H. Tetrahedron Lett. 1968, 2205-2208Dale, G. Tetrahedron 1966, 22, 3373-3382

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Equatorial Attack Axial Attack

• Model agrees with Felkin-Ahn where most electronegative atom will be opposite of entering nucleophile

Torsional Strain- Repulsion due to two filled molecular orbitals interacting with each other

Steric Strain- Two bulky non-bonding groups interact together and repel each other

Criticism of Torsional/Felkin Model• One of the most important parts of the theory is that the molecule becomes flattened in the transition state

and that these small difference in orbital interactions will be preserved in the transition state to create a energy difference between axial and equatorial attack

Lectard, A.; Lichanot, A; Metras, F.; Gaultier,J. Hauw, C.J. J. Mol. Struc. 1973, 18, 403Cieplak,A.S. J. Am. Chem. Soc. 1981,103, 4540-4552 5

• Angle used <O-C1-C2-Heq is usually used to show deviation from the perfect chair and in crystal structures is shown to range from 2.5˚- 12.7˚

• Argued that the orbitals would be able to optimized decreasing the energy between the transition states

• Model also was argued to not take into account nucleophile structure, counterion, solvent influences and heteroatoms contained within the system

Andrzej Stanislaw Cieplak

Cieplak, A.J. Chem. Rev. 1999, 99, 1265-1336 6

• Born in Warsaw, Poland in 1948

• Went to the University of Warsaw in 1968-1971 for his undergraduate degree- was arrested during this time for representing pro-democracy chemistry students

• Earned his Ph.D. at the Institute of Organic Chemistry of the Polish Academy of Sciences under Marian Kocor in 1976

• Became a Research Associate at Harvard in 1978 and in 1981 he published paper about the criticisms behind Felkin theory of torsional strain

• Moved to Fordham as an Assistant Professor in 1983-1990

• Had multiple visiting professorships

Counter-Theory: The Cieplak Effect

Reprinted (2017) with permission from (Cieplak,A.S. J. Am. Chem. Soc. 1981,103, 4540-4552). Copyright (1981) American Chemical Society.

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Axial Attack Equatorial Attack • In the transition state a nucleophile will add so that the most electron donating bond will be able to donate into the σ*

C-Nuc of the newly forming bond

• In cyclohexanone, C-H bond is more electron donating then the C-C so axial approach will be more favorable

Microscopic Reversibility

• Cieplak argues that that the same orbital interactions that assist a reaction in one direction will assist it in other direction

• If the hydride was to be extruded, in the transition state you would get donation from the σC-Hax into the anti-bonding of the σC-H which would weaken the bond and lower the energy that would need to extrude it

• In the opposite direction, this donation would donate into the anti-bonding of the σC-H lowering the energy of the transition state

8Cieplak,A.S. J. Am. Chem. Soc. 1981,103, 4540-4552

Hyperconjugation

• The Cieplak effect is counterintuitive to FMO theory- Proposes that electron density hyperconjugates into anti-bonding orbital in the transition state

Reprinted (2017) with permission from (Coxon, J.M.; Houk, K.N.; Luibrand, R.T. J. Org. Chem. 1995, 60, 418-427). Copyright

(1995) American Chemical Society."9

• Hyperconjugation into this orbital will create a stabilizing effect and will lower the transition state for this addition

C-H vs. C-C ability to Electron Donate• The theory that the C-H bond is a better electron donor then the C-C bond is based off the Baker-

Nathan effect.

• Baker-Nathan Effect was theorized in 1935- when studying the Menschutkin reaction(shown below)

• Based off of previous work down by Ingold they expected that the rate would increase with more saturated carbon substituents (R= t-Bu>i-Pr>Et>Me)

• When they ran the study they found Me>Et>i-Pr>t-Bu- to rationalize this they said that the C-H was less localized and can more readily electron donate into the system

• This effect has its roots in hyperconjugation but is not really invoked anymore

Baker, J.W.; Nathan, W.S. J. Chem. Soc. 1935,1840-184410

le Noble’s Experiment Design

Kaselj,M.; Chung,W.S.; le Noble, W.J. Chem. Rev. 1999, 99, 1387-1413 11

• Adamantanes were used to probe the Cieplak effect ,were considered a good model system because of the structural rigidity of the system that would lead to low distortion along the carbonyl

• Also would avoid C-H vs. C-C electron donating argument• This system is also considered isoelectric so there would be no steric bias for addition to one face

over the other

• EDG would give Cis alcohol if the Cieplak effect is occurring

• EWG would give trans alcohol if the Cieplakeffect is occuring

Preliminary Le Noble Results

Cheung,C.K.; Tseng, L.T.; Lin,M.-H.; Srivastava,S.; le Noble, W.J. J.Am. Chem. Soc. 1986, 108, 1598-1605Xie, M.; Noble, W.J. J. Org. Chem. 1988, 54,3836-3839 12

Alcohol

5-Substituent(R) Nucleophile Conditions %trans %cis

C6H5 LiAlH4 Et2O, Rt 56 44

C6H5 LiAl(Ot-Bu)3H Et2O, Rt 49 51

t-Bu LiAlH4 Et2O, Rt 50 50

t-Bu LiAl(Ot-Bu)3H Et2O, Rt 42 58

F NaBH4 Me2CHOH, Rt 62 38

OH NaBH4 Me2CHOH, 0˚C 43 57

CF3 NaBH4 Me2CHOH, 0˚C 59 41

TMS NaBH4 i-C3H7OH, rt 45 55

SnMe3 NaBH4 i-C3H7OH, rt 43.5 56.5

SnMe3 MeLi Ether, 0˚C 36.5 63.5



Alcohol














Alcohol














Alcohol














Alcohol












Interesting results in le Noble’s Work

• Way to fluorinate every hydrogen on Adamantanone. If Cieplak’s model held they should have gotten a higher amount of E

• Author explains it is because the vicinal bond is more electron poor then the incipient bond and Felkin-Ahn addition model becomes dominate

Kaselj, M.; Adcock, J.L; Luo, H.; Zhang, H.; Zhang, H.; Li, H.; le Noble, W.J. J. Am. Chem. Soc. 1995, 117, 7088-7091Adock, J.L; Luo, H. J. Org. Chem. 1992, 57, 4297 17

le Noble Results Continued

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Alcohol

Substrate Nucleophile Conditions %trans %cis

NaBH4 D2O, rt

87 13

NaBH4 D2O, rt

96 4

NaBH4 MeOH, 0˚C

88 12

• Cieplak and le Noble that azaadamatones gave the best evidence for the Cieplak effect because of there high facial selectivity

Kaselj, M.; Gonikberg, E.M.; le Noble, W. J. J. Org. Chem. 1998, 63, 3218-3223

Le Noble’s 5-Azaadamantanone Experiment• The 5-Azaadamantanone with a 96:4 (syn:anti) was supposed to be one of the best example to

date of the Cieplak effect.

Reprinted (2017) with permission from (Coxon, J.M.; Houk, K.N.; Luibrand, R.T. J. Org. Chem. 1995, 60, 418-427). Copyright (1995) American Chemical Society." 19

• Calculation by the Houk group hypothesize that pyramidalization of the carbonyl occurs because ring anti to N donates more so into carbonyl which causes better overlap orbital

• Trans reduction of azaadamantanone favored because of less torsional strain

Cis reduction of Azaadamantanone is less favored because of torsional strain

Other Non-Carbonyl Additions

• le Noble also studied addition into Methyleneadamantanes

Srivastava, S.; le Noble, W.J. J. Am. Chem. Soc. 1987, 109, 5874-5875 20

Results from Non-Carbonyl Additions

Srivastava, S.; le Noble, W.J. J. Am. Chem. Soc. 1987, 109, 5874-587521

Product Ratio

substituent on R reagent %(cis) %(trans)

F :CCl2 60 40

HCl >99 trace

COOMe HCl 72 28

B2H6 41 59

CH2CH3 B2H6 62 38

• Results gave more evidence towards the Cieplak Effect

• Moved past the normal Carbonyl addition reaction and showed that this effect could be applied to broader systems

Mehta Experiments

• Mehta experimented with 7-Norboranones and used different hydride sources to addition into them and get their selectivity

• Chosen because of unbiased ketone and easily functionalized

Mehta, G.; Khan, F. A. J. Am. Chem. Soc. 1990, 112, 6140-6142 22

Mehta Experiment Results

Trans:Cis Distribution

Substrate NaBH4 LiAlH4 (t-BuO)3LiAlH MeLi

84:16 87:13 77:23 >90:<10

36:64 35:65 34:66 27:73

20:80 21:79 29:71 17:83

Mehta, G.; Khan, F. A. J. Am. Chem. Soc. 1990, 112, 6140-6142 23

Mehta explanation for vinyl groups• One explanation for why the vinyl groups give opposite selectivity then what would be expected

because of donation of the vinyl group into the σC-H into the antibonding

Mehta, G.; Khan, F. A. J. Am. Chem. Soc. 1990, 112, 6140-614224

Houk’s Criticism of Mehta’s Model

Reprinted (2017) with permission from (. Paddon-Row, M.N.; Wu, Y.D.; Houk, K.N. J. Am. Chem. Soc. 1992, 114, 10638-10639). Copyright (1992) American Chemical Society

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• When R=EWG then C2 and C3 become more positive causing syn addition

• When R=EWG then C2 and C3 become more positive causing syn addition

Further Criticism of Mehta’s Model

Reprinted (2017) with permission from (. Paddon-Row, M.N.; Wu, Y.D.; Houk, K.N. J. Am. Chem. Soc. 1992, 114, 10638-10639). Copyright (1992) American Chemical Society 26

• Houk modeled incoming hydride addition when R=Ketone and was pointed into the system

• In this system, structure 4 was the more stable of the two

• Houk modeled incoming hydride addition when R=Ketone and was away from the system

• In this system, structure 6 was the one observed but is calculated to have a higher energy

Back to the beginning:A Curious Trend

Boone, J. R.; Ashby, E.C Top. Stereochem. 1979, 11, 53Wigfield, D.C. Tetrahedron 1979, 35, 449-462 27

% of Axial Attack % of Axial Attack

NaBH4, 2-propanol 87 75

LiBH4, THF 93 71

LiAlH4, Et2O 92 82

LiAl(OMe)3H, THF 56 37

L-Selctride 3 -

Houk’s support for the Torsional Model

"Reprinted (2017) with permission from (Wu, Y.; Houk, K.N. J. Am. Chem. Soc. 1987, 109, 908-910 ). Copyright (1987) American Chemical Society." 28

• Houk made truncated transition states for axial attack on the cyclohexanone- shows the flattening of the molecule and how this would minimize the torsional interactions

• After computing the transition state- significant steric strain would be introduced because the CCO-Cα would rotate introducing torsional strain within that transition structure

Further Computational Studies Done

Reprinted (2017) with permission from (Mukherjee,D.; Wu, Y.D.; Fronczek, F.R.; Houk, K.N J. Am. Chem. Soc. 1988, 110, 3328 ). Copyright (1988) American Chemical Society.

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• Cyclohexanone which flattens during addition- axial attack is predicted by both Cieplak and Felin-Ahn/Felkin torsional theory

• Benzocycloheptenone by the Cieplak effect was predicted to give axial attack and in Felkin’s Model was predicted to be predominant because of more favorable staggering

• Computational model predicted predominantly equatorial attack and upon reduction with LiH- got a 60:40(equatorial attack: axial attack)

Felkin-Ahn Model

Reprinted (2017) with permission from (Coxon, J.M.; Houk, K.N.; Luibrand, R.T. J. Org. Chem. 1995, 60, 418-427). Copyright (1995) American Chemical Society."

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• EWG group will make axial attack more likely because will lower the σ*• EDG will make raise equatorial attack because with raise the σ*

• In the absence of steric effects, the lower σ* of the vicinal bond will be antiperiplanar to the π*C-

O cause a lowering of energy• Interaction makes it more energetically favorable

to be attacked- will also extend orbital more axially

Cieplak’s Response• Cieplak in 1989 responded that Houk’s model did show that torsional effects were coming into

play but also stated that these models did not give evidence for Felkin’s theory

• Claimed that it showed that the model would allow hyperconjugation into the orbitals

• Also that in the equatorial attack there would be severe interaction between C-O and C-C which also isn’t predicted in Felkin’s Model

Cieplak, A.S.; Tait, B.D.; Johnson, C.R. J. Am. Chem. Soc. 1989, 111, 8447-8462 31

Electrostatic Effects vs the Cieplak Effect• Many of the critics of the Cieplak effect claim that instead of being caused by hyperconjugation,

electrostatic effects are actually showing the observed trends

• These EDG or EWG groups bias the molecule in such away to cause a certain addition to be lower energy

Reprinted (2017) with permission from (Coxon, J.M.; Houk, K.N.; Luibrand, R.T. J. Org. Chem. 1995, 60, 418-427). Copyright (1995) American Chemical Society." 32

Meyers Model• Using unsaturated lactams, found that selectivity was indicative of the Cieplak effect

Meyers, A.I.; Wallace, R.H. J. Org. Chem. 1989, 54, 2509-2510 33

Fault with Model• When Meyer switched group from Me to CF2CF3 found opposite selectivity as Cieplak effect

would predict

• Came up with counter theory that the Cieplak effect is not in effect at all but instead the selectivity has to do with perturbation of the π-system in enolate or C=C by the nitrogen lone pair

Meyers, A.I.; Wallace, R.H. J. Org. Chem. 1989, 54, 2509-251034

Modern day invoking of Cieplak Effect

• Found high ee in the reduction below in a very unbiased system

Turner et. al. ACS Catalysis 2016, 6, 3753-3759 35

• Turner group used enzymes to synthesized piperidines and Pyrrolidines

• Explained that this was most likely because of the hydride wanting to add anti-periplanar to the axial hydrogen

• Result is especially interesting because when you use the other enantiomer of enzyme get only a 38% ee

Modern Day invoking of Cieplak Effect• Towards the synthesis of the Core of Briarane Diterpenoid the Cieplak effect was invoked to

explain the selectivity in one step

• The nucleophilic attack was said to happen antiperiplanar the more electron rich C-Me bond

Moon, N.G.; Harned, A.M. J. Org. Chem. 2015, 80, 2218-2221 36

Through the years….

https://archive.org/stream/EvansD.A.MyersA.G.HarvardOrganicChemistryLectureNotes20062007/EvansD.A.MyersA.G.HarvardOrganicChemistryLectureNotes2006-

2007_djvu.txt37

Andrzej Stanislaw Cieplak William J. le Noble Goverdhan Mehta

Supporters

Professor Dave Evans, a critic of the theory, once said while talking about the subject “The Cieplak hypothesis is nonsense… Just because a hypothesis correlates a set of observations doesn’t make the hypothesis correct”

Critics

Ken Houk William Adcock Benjamin Gung

https://archive.org/stream/EvansD.A.MyersA.G.HarvardOrganicChemistryLectureNotes20062007/EvansD.A.MyersA.G.HarvardOrganicChemistryLectureNotes2006-2007_djvu.txt

I open it to the group. Do you think that the Cieplak is a real effect that should be invoked?

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Cieplak Effect:Fact or Fiction? - School of Chemical … · Cieplak Effect:Fact or Fiction? ... •The theory that the C-H bond is a better electron donor then the C-C bond is