HyperconjugationHyperconjugation Alan B. Northrup MacMillan Group Meeting September 17, 2003 Review...
Transcript of HyperconjugationHyperconjugation Alan B. Northrup MacMillan Group Meeting September 17, 2003 Review...
Hyperconjugation
Alan B. Northrup
MacMillan Group Meeting
September 17, 2003
Review of the Basics:Kirby, A.J. "Stereoelectronic Effects," in Oxford Chemistry Primers, New York, 1996, Vol. 36, pp. 3-33.
A semi-quantitative approach to frontier orbital size and application to pericyclic reactions:
Fleming, I. Frontier Orbitals and Organic Chemical Reactions, Wiley; New York, 1998.
Anomeric Effect in Detail:
Kirby, A.J. The Anomeric Effect and Related Stereoelectronic Effects at Oxygen, Springer-Verlag; New York, 1983.
Graczyk, P.P.; Mikolajczyk, M. "Anomeric Effect: Origin and Consequences," in Topics in Stereochemistry, 1994, Vol. 21, p 159.
s s*
s p
What is Hyperconjugation?
n A Resonance View:
MeMe
H
H H
H
MeMe
H H
n Frontier Molecular Orbital Depiction:
HH
Me
Me
H
HOMO
LUMOsC-H
p
∆E
Estab
Overlap = S
Estab aS2
∆E
n Physical Evidence for Hyperconjugation's Existance:
Adamantane
110° 1.530 Å
[SbF5–F–SbF5]–
Adamantyl Cation X-Ray Struture
100.6°
1.431 Å
1.608 Å
Laube, T., et al. Angew. Chem. Int. Ed. 1986, 25, 349
s p
Why is Hyperconjugation Stabilizing?n Remember the H2 Molecule:
n Hyperconjugation Revisited:
HH
Me
Me
H
HOMO
LUMOsC-H
p
∆E
Estab
Overlap = S
Estab aS2
∆E
H1s H1s
H H
distance
Ener
gy
H H
H H
H H
The FMO View:
Stabilization of the highest energy electrons stabilizes the entire system
One Central Postulate of FMO Theory
Conjugation vs. Hyperconjugation
n Butadiene shows a strong preference for planarity
HHH
H HH
H
HH
∆G = +4 kcal/mol
n Sterics alone cannot account for this large conformational bias
HHH
H
p p*
planar non-planar
planar: non-planar:
p p*no
p
p*
p
p*
Estab aS2
∆E
n Conjugation and Hyperconjugation are essentialy the same phenomenon
orbitals are orthogonal
MO Diagram:MO Diagram:
Positive, Neutral and Negative Hyperconjugationn The literature is full of different descriptors for hyperconjugation
MeMe
H
H H
H
MeMe
H H
"positive hyperconjugation"
MeO2SOMe MeO2S
"negative hyperconjugation"
O
N HMe
Me
O
N HMe
Me
"neutral hyperconjugation"
n Slight, but significant differences in MO diagrams
s p
HH
Me
Me
H
HOMO
LUMO
sC-H
p
n p*
HOMOLUMO
nlp
p*
p
s s*
HOMO
LUMO
nlp-
s*
s
n "Hyperconjugation" will be used to refer to any of the above
OMe
Ranking Electron-Donating Abilityn Energies from PES provide a somewhat intuitive order for e- pairs on the same atom:
n C-X bonds, where X is electronegative lower both s and s* orbitals, making them worse donors
RRR
> >HR
R
R R >
sp3 carbanion sp2 carbanion p-bond
R
Rsp3-sp3 s-bond
decreasing donating ability
>R
sp3-sp2 s-bond
Csp3 Csp3
sC-C
s*C-CC-C bond: C-F bond:
Csp3
Fsp3
sC-F
s*C-F
Incr
easin
g Do
nor S
treng
th C–C
C–H
C–N
C–O
C–F
n Lone pair energies follow a similar trend
HP
HH
HN
HH
HS
H
HO
HH Cl> > > >
Ranking Electron-Accepting Abilityn Lower-lying LUMOs are better able to accept electron density
n C-X bonds, where X is electronegative lower both s and s* orbitals, making them better acceptors
>R R >
sp2 p*
R
Rsp3-sp3 s*
decreasing accepting ability
>R
sp3-sp2 s*
Csp3 Csp3
sC-C
s*C-CC-C bond: C-F bond:
Csp3
Fsp3
sC-F
s*C-F
Incr
easin
g Ac
cept
or S
treng
th
C–C
C–H
C–N
C–O
C–F
n A brief note on overlap:
R R
sp p*
>
atomic orbital
s*C-F
s*C-O
s*C-N
s*C-C
s*C-H
syn = = good! anti = = bad!
HH
Conformational Effects of Hyperconjugation: Single Bondsn Staggered vs. Ecipsed Ethane Conformers
n Conformational Preferences of Esters
H
H
HH
H
HH
HH HH
H
Staggered Eclipsed
∆G = +3 kcal/mols s*
HOMO
LUMO
sC-H
s*C-H
sC-H
H
HH
H
Pophristic, V.; Goodman, L. "Hyperconjugation not steric repulsion leads to the staggered structure of ethane." Nature, 2001, 411, 565-568.See also: Angew. Chem. Int Ed. 2003, 4183-4194 for one paper against and one paper for the above explanation
therefore, each interaction ≈ 1 kcal/mol
n The Gauche Effect
H
Cl
HO
Me
Example: MOM-Cl
Cl
H
HO
Me
∆G = +2 kcal/mol
HO
H
Example: H2O2
HO
H
n s*C-Cl
H
O
OMe H
O
OMe
∆G = +4.8 kcal/mol
difference: n s*C-O
H
O
Ot-Bu H
O
Ot-Bu
90:10 syn:anti
difference: n s*C-O
Blom, Gunthard Chem. Phys. Lett. 1981, 84, 267 Oki, M.; Nakanishi, H Bull. Chem. Soc. Jpn. 1970, 43, 2558
Structural Effects of Hyperconjugation: Double Bonds
n IR Stretching Frequencies can Indicate the Degree of Hyperconjugation
NNDH3C
NND
H3C
n s*
nlp
s*
s
nN-D = 2317 cm-1 nN-D = 2188 cm-1
nN-N = 1559 cm-1 nN-N = 1565 cm-1
n The Following can be Rationalized with Hyperconjugation
Craig, N. C., et al. J. Am. Chem. Soc. 1979, 101, 2408
1715 cm-1 1745 cm-1 1788 cm-1 1813 cm-1
O O O O
n Position of this Equilibrium Deteremined by an n to s* Hyperconjugative Interaction
O
O
O
O
OMeO O OMe
>20:1
Vankatataman, H; Cha, J.K. Tet. Lett. 1989, 30, 3509
The Anomeric Effect: What is it?
n Anomeric Effect refers to the tendency of anomeric substituens to prefer an axial configuration
OMe
OMe
∆G = –0.6 kcal/mol
O O
OMe
OMe
∆G = +0.6 kcal/mol
n Electron-Withdrawing Groups Increase the Magnitude of the Anomeric Effect
Anomeric Effect is worth ca. 1.2 kcal/mol
O O
Cl
Cl
∆G = +1.8 kcal/molAnomeric Effect ≈ 2.8 kcal/mol
O O
X
X
OBz
OBz
BzO
BzOBzOBzO
favored for X=F, Cl, Br, OAc
n Hyperconjugation Explains this Effect:
O O
OMeOMe
n s*no overlap possible
axial anomer: equitorial anomer:
nlp
s*
s
The Anomeric Effect: Consequencesn Spiroketal Conformations are Controled via the Anomeric Effect
OO O O O
O >20:1
n Rate of Acetal Hydrolysis can be Impacted Considerably
HO
O
OH O
O
O
O
OO
O
NH
Me
H
H
OH
HO Me
Me
Me
Me
Me
H
H
H
n Azaspiracid Stereochemistry at all 5 Anomeric Centers is Predicted by the Anomeric Effect
O O OArH
H
O O OArH
H
k1
k2
O OOH
k2
k1
≈ 200
JCS Chem. Comm. 1979, 1079
OO
OO
n s*
k1 slow
k2 fast
O
R
The exo-Anomeric Effectn The exo-Anomeric Effect Concerns the Conformation of an O-Glycosidic Linkage (cf. Gauche Effect)
O
OR
O
H
n s*
nlp
s*
s
n While Important to Sugar Chemists, only Rarely Exploited in Synthesis:
Gupta, R.C.; Slawin, A.M.Z.; Stoodly, R.J.; Williams, D.J.; J.C.S. Chem. Comm. 1986, 1116.
13% nOe
O
H
OTMS
H
CH2OAc
AcO
AcO
AcO
endo Cycloaddition from Top Face
O
AcOH2C OAc
O
OAc
OAc
OTMS
O
O
O
O
O
O
H
HOR*
OTMS
8:1 dr
H
The Anomeric Effect: It's not just for Oxygen Anymore
n Similar Effects are Noticed with Nitrogen
n Hyperconjugation has Large effects on Even C-H Bonds
n Anomeric Effect in Orthoamides can Cause Strange Reactivity:
NN
Nt-Bu
t-Bu
t-Bu NN
Nt-Bu
t-Bu
t-Bu
∆G = –0.35 kcal/mol
Katritzky, A.R. J.C.S. B 1970, 135
NN
N
Me
Me Me
MeSolution Structure (NMR):
Anderson, J. E.; Roberts, J.D. J. Am. Chem. Soc. 1967, 96, 4186
N
N
H10H6 H4
IR: "Bohlmann Bands"2700 to 2800 cm-1
for H4, H6, and H10
Disappear when protonated
Bohlmann, Ber. 1958, 91, 2157
1H NMR: Extra Electron Density Causes Shielding
H10 is furthest upfield
H4 and H6 upfield by almost 1ppm of remaining protons
Only off by 0.5 ppm when acid is added
N NN N
NN
Illustrated proton d = 2.3 ppm
HBF4
110 °C, 1 dayN N
N
BF4–
H2+
Erhardt, J.M; Wuest, J.D. J. Am. Chem. Soc. 1980, 102, 6363
The Anomeric Effect: It's not just for Oxygen Anymoren Dithianes Allow the Study of this Effect for Sulfur
n Carbon is not the only atom through which this effect may be transmitted!
SS S
S
R
R
R ∆G (kcal/mol)
SCH3SPh
CO2MeCOPhCO2HNMe2
1.642.022.102.46>2.65
≈ 0
OMe
BH2Cl•MeS OBMe
Cl
HB-Cl bond = 1.890 Å
X-Ray Structure
lit. range: 1.72-1.877 Å
Shiner, C.S.; Garner, C.M.; Haltiwanger, R.C. J. Am. Chem. Soc. 1985, 107, 7167
n Anomeric Effect Through Phosphorous can be Significant for Phosphite Reactiviy
(EtO)3P: + 2 EtOSPhpentane
–78 °CP(OEt)5 + PhSSPh
OP
OO + 2 EtOSPh
r.t. N.R.
P(OEt)5
OH
OHOH O
PO
OOEt
OEt
OP
O O
no donation possible
OEtSPh
The Role of Hyperconjugation in the Transition State: Theory
n The SN2 Reaction TS looks like a 3c-4e– Bond:
H
H H BrII– CH3Br+ I CH3
n MO Diagram for a 3c-4e– Bond:
2
1
Basis Set:
bonding
nonbonding
antibonding
Prediction: Substituents with Low-Lying LUMOs will Accelerate the Sn2 by Stabilizing Electron Density from Nucleophile and Leaving Group through Hyperconjugation
Theoretical Support for the following Arguments: Houk, K. N., et al. Science, 1986, 231, 1109
Transition State Hyperconjugation Explains Substituent Effects in the SN2 Reaction
n Here's the Rate Data on the SN2 Reaction:
I– + R ClAcetone
I R
Entry R krel a-LUMO
1234567
n-BucylcohexylPhCO2CH2
AllylBenzylNCCH2
PhCOCH2
1.0<0.0001
59.179
1953,070
105,000
s*C-C
s*C-C
s*C-O
p*C-C
p*C-C
p*C-N
p*C-O
sterics are still important
n Data fits the Following ModelConant, J.B.; Kinner, W.R.; Hussey, R.E. J. Am. Chem. Soc. 1925, 47, 488
Cl
I–
TS HOMO
p*
p
Hyperconjugation in Carbonyl Addition Reactionsn The Carbonyl Addition Reaction
n Origin of Diastereoselectivity Subject of Much Debate (See NAP Group Meeting)
HHO
Nu
p*
OHH
NuNu
HO HH
Felkin Model Predicts Ketones Well, Fails for Aldehydes:
RL
H RMORRL
H RMRO
Nu
destabilizinginteraction
R
O
RL
RMNu
RRL
RM
Nu OH
Nu
favored disfavored
H
O
RL
RMNu
HRL
RM
Nu OH
RL
H RMOH
RL
H RMHO
Nu
destabilizinginteraction
Nu
favoreddisfavored
predicts wrong product!
Ahn and Eisenstein add the Dunitz-Burgi Trajectory and the "Antiperiplanar Effect":
RL
H RMOR
RL
H RMRO
Nu
destabilizinginteraction
Nu
favored disfavored
rationalized stereochemistry for aldehydes and ketones
The "Antiperiplanar Effect":Hyperconjugation in Actionn Polar Substituents act as RL in the Felkin-Ahn Model:
n Transition State Hyperconjugation, or How SMe can act Larger than i-Pr
TS HOMO
s*C-R
sC-R
Me
MeSMe
O
PhLiBH(s-Bu)3
Me
MeSMe
OH
Ph
Me
MeSMe
OH
Ph
96:4 syn:anti
Shimagaki Tet. Lett. 1984, 25, 4775
RL
H RMOR
Nu
favoredSMe
H i-PrOR
favored
H–
RL
H RMOR
nNu
p*C-O
s*C-R L Predicts Better Acceptor at RL leads to better selectivity
n Sterics Predicts the Opposite Trend:
RH
O
Me
Me
Me
OLi
OMeR
OH
Me Me MeOMe
O R= c-C6H11 9:1 syn:antiR= Ph >200:1 syn:anti
H
Transition State Hyperconjugation in C=O Additions: Cieplak
n A Much Maligned Theory:
n Cieplak: Transition State is stabilized by an interaction between a filled substrate orbital and TS s* orbital
"Structures are stabilized by stabilizing their highest energy filled states. This is one of the fundamental assumptions in frontier molecular orbital theory. The Cieplak hypothesis is nonsense."
—Prof. David A. EvansChem 206 Lecture Notes
s*TS
R
H ROR
s*TS
sC-R
sC-R
Cieplak, A.S. J. Am. Chem. Soc. 1981, 103, 4540
n Cieplak and Felkin-Ahn Both Usually Predict Same Sense of Diastereoselection
t-Bu
O
H
s*C-H
sTS
Felkin-Ahn: Axial Attack Favored
t-Bu
Os*C-C
sTSt-Bu
O
sC-H
s*TS
Cieplak: Axial Attack Favored
t-Bu
O
sC-C
s*TS
favored disfavored favored disfavored
Transition State Hyperconjugation in C=O Additions: Cieplakn Examples consistent with Cieplak but not Felkin-Ahn
n le Noble Has Many Examples with 2-Adamantanones:
O
RR
Nu
RR
RR
HO Nu Nu OH
R=EWG, Shaded bond's s*, better acceptor, F-A predicts anti
syn anti
R=EWG, Shaded bond's, worse donor, Cieplak predicts syn
R Nu syn:anti
CO2Me
CH2OMe
CH2=CH2
Et
LAHMeLi
NaBH4MeLi
LAHMeLi
NaBH4MeLi
87:13>90:10
40:6034:66
35:6527:73
20:8017:83
Chem. Rev. 1999, 99, 1387-1467
O
R
Nu
R R
HO Nu Nu OH
syn anti
Same argument as above
R Nu syn:anti
CO2Me
F
TMS
SnMe3
NaBH4MeLi
NaBH4MeLi
NaBH4MeLi
NaBH4MeLi
57:4355:45
62:3870:30
50:5049:51
48:5248:52
Breakdown of the Cieplak Model: Is it Simply Electrostatics?n Critics of Cieplak Cite Role of Electrostatics in pro-Cieplak Examples:
n Die-Hard Proponents of Cieplak Have a Hard Time Explaining This Houk Example:
O
CO2MeCO2Me
Nu
d
d++
is syn product due to simple electrostatic attraction?
O
EtEt
Nud
d --
is anti product due to simple electrostatic repulsion?
O
EWG
O
EWG
Cieplak Prediction: Equatorial EWG should lower shaded bonds' donor strength, leading to more axial attack for A than B
A B
Diastereomer EWG axial:eq.N.A.
AB
AB
H
OAcOAc
ClCl
60:40
71:2983:17
71:2988:12
n Houk Invokes an Electrostatic Argument to Explain B's Enhanced axial selectivity
Houk, K.N., et al. J. Am. Chem. Soc. 1991, 113, 5018
O
EWG
d+
Nu
Axial Approach TrajectoryO
EWG
Equitorial Approach Trajectory
d- Nu
unfavorable
favorable
The b-Silicon Effect: Hyperconjugation Yet Againn A Silicon b to a Leaving Group Greatly Enhances Ionization
n Late Transition State for Rate-Determining Ionization (Endothermic)
t-Bu
OTFA
Xsolvent
t-Bu
X
TFA
t-Bu TFA–X
kSi
kH= 2.4 x 1012 bridged intermediates ruled out
by Deuterium isotope effects
Lambert et al. Acc. Chem. Res. 1999, 32, 183
Rxn Coordinate
Ener
gy
TS
sm
cation
t-Bu
SiR3
hyperconjugationstabilizes cation
sC-Si
p
n Why is C-Si so much better a donor than C-H? Look at the bonds!
Csp3
Sisp3
BDE ≈ 72 kcal/molCsp3H1s
BDE ≈ 102 kcal/mol
C–H
good overlap
C–Si
worse overlap
C–Si bond has a much higher HOMO
Nucleophillic Olefin Addition Reactions: Homo-Raising Hyperconjugationn Nucleophillic olefins constitute a key class of reagents
n Hyperconjugation Raises the p HOMO of the alkene by donation to the p*
HMe
Me
OHO
TMSO
HMe
BL2 O
HMe
NMe2
Me
O
HMe
O
Me
O
HMe
HO
HMe
Me
OMe
OC
" "
H
s or n p*
s or n
p*
p
N.B.: The p orbital is raised in energyMagnitude of HOMO-raising is related to amount of donationto the p*
Enamines: A Case Study in Hyperconjugationn Like amides there is restricted rotation about the C-N bond
n E-Enamines prefer a near Gauche-Out conformation While Z-Enamines prefer Orthogonal In
-90 -60 -30 0 30 60 90
Lone Pair Torsion Angle
Rela
tive E
nerg
y (
kca
l/m
ol)
N,N-Dimethylvinylamine
(E)-1-Dimethylaminopropene
(Z)-1-Dimethylaminopropene
0
2
4
6
8
Me
N Me
0°
+90°
Weston, J.W.; Albrecht, H. J.C.S. Perkin 2, 1997, 1003
q
Me2N Me2N
Me
Me2N Me
"orthoganol in""gauche out"
"orthogonal out""gauche in"
Me
N MeR
NR
Me
Me
NR
Gauche Out
Me
Me
Orthogonal OutOrthogonal In Gauche In
NR
Me
Me
align electron-density on N with p-bondalign electron-density on N with p*
Consequences of Enamine Conformation on Reactivity
n Hyperconjugation not only stabilizes "gauche out" but also makes it more reactive:
n Following MO Diagrams Illustrate the Difference
sC-N
p*
p
Me
N Me
gauche out
Me2N
Me12
13C NMR:C1: 127.4 ppmC2: 86.3 ppm
1H NMR:H1: 5.76 ppmH2: 4.10 ppm∆d = 1.66 ppm∆d = 41.1 ppm
Me
Me
N Me
Me2N Me
1 2
13C NMR:C1: 132.1 ppmC2: 93.4 ppm
1H NMR:H1: 5.30 ppmH2: 4.30 ppm
∆d = 1.00 ppm∆d = 38.7 ppm
Lambert, J.B. et al. J. Am. Chem. Soc. 1980, 102, 6659
orthogonal in
Orthogonal In: 2 sC-N to p*:
nN
p*
p
Gauche Out: 1 nN to p* and 1 sC-N to p*
More hyperconjugation, higher p HOMOalkene more reactive
Less hyperconjugation, lower p HOMOalkene less reactive
Mechanism of Enamine Hydrolysis: Implications for Aldol Chemistryn Two Competing Ideas for Enamine Hydrolysis
NMe Me
H+
H+
NMe Me
NMe Me
H
C-protonation
H
N-protonation
intermol.
H+ transferN
Me Me
H
as above O
Me
NMe Me
HHO
O
Me+ NHMe2
+ NHMe2
n Hyperconjugation makes N protonation difficult
Me Me
N
Me 1:1 AcOH:NaOAc pH=5Me Me
N
Me–OAc 80 °C
Me Me
N
–OAcMe
C-protonationequilibration
Me Me
N
Me 12N HCl or 12N HClO4
Me Me
N
Me
H
X–
9:1 d.r.
5h
1:4 d.r.
stable
rt or 80 °CN-protonation
Bathélémy, M.; Bessiere, Y. Tetrahedron 1976, 32, 1665
Enamines in the Aldol Reaction: Computational Considerationsn The Enamine Aldol Rection
n Computed Properties of the Transition State
NMe2 O
H Me
H+ NMe Me
H2O
H
O
H MeMe
A surprisingly late transition state:
O OH
"Normal" Bond LengthsC–C 1.544 Å
C–N 1.492 Å
C–O 1.470 Å
n What a Late Transition State Means for the Aldol
ONMe
Me
…not this!
ONMe
Me
TS looks more like this…
n Protonation only increases product devel in TS
n Non-basic enamine N in TS (Hyperconjugation)
n C-N Conformation locked in "gauche out"
Proline-Catalyzed Aldol Rection Transition States
n The Direct Aldehyde-Aldehyde Aldol Reaction
H
O
MeH
O
Me
10 mol% L-Proline
DMF, +4 °C
O
HMe
Me
OH 80% yield4:1 anti:syn
99% ee (anti)
n Barbas-List Transition State
H
N
O O
OMe
Et
H
n Jorgenson's Transition State
H
N
O O
OMe
Et
H
n MacMillan's Transition State
H
N
O O
OMe
Et
H
n First Model
n Correctly Predicts Stereochemistry
n Bifurcated H-bond
n Rigid 5-6 system
n Intimate Involvement of Chirality
n Second Model
n Correctly Predicts Stereochemistry
n Removes Bifurcated H-bond
n 9-membered Ring (8 planar centers)
n Intimate Involvement of Chirality
n Third Model
n Correctly Predicts Stereochemistry
n Removes Bifurcated H-bond
n Rigid 6 membered system
n No Intimate Involvement of Chirality
n Disregards Hyperconjugationn Imporves Hyperconjugation
Hyperconjugation Conclusions
n s* s s*n p* s p*
It's a simple, but powerful theory.