topic 12 addition to π - uci sites · carey & sundberg advanced organic chemistry. part a:...
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Topic 12: Addition to π*
Tetrahedral intermediates
Read: F. A. Carey & R. J. Sundberg Advanced Organic Chemistry, Part A: Structure and Mechanisms. 5th Ed. Ch. 7I. Fleming Molecular Orbitals and Organic Chemical Reactions, 5.1.3.1, 5.1.4, 5.2.1
Professor David L. Van VrankenChemistry 201: Organic Reaction Mechanisms I
Nu .. Nu
-..
Addition of Nucleophiles to Simple C=C Bonds is Not Common
■ Addition to C=C much slower than addition to C=O
Felkin, H. et. al. Tetrahedron Lett. 1969, 707.
Bartlett, P. D.; Tauber, S. J.; Weber, W. P. J. Am. Chem. Soc. 1969, 91, 6362.
■ Directed addition: 5-membered T.S. confers an entropic advantage
■ Requires 2° or 3 ° alkyllithiums + ether or amine additives
O O Li
Li1°
but...Li
Li
Fast if: • 2° & 3° R-Li • H2C=CH2 • cat. R3N • ROR solvent
always fast
E Nu
π*CC
π*CN
π*CO
MO lowerLUMO
more charge
Why is C=O more electrophilic than C=C?There are two reasons...
Oδ+ δ−
2 equiv.i-PrLiLi LiEt2O
OEt2
OEt2-30 °C
OLi Li
2 equiv.i-PrLi
Li
OHO
Li
OLi
Li
Addition of Nucleophiles to C=O
■ The C=O bond is polarized
Burgi, H. B.; Dunitz, J. D. Acc. Chem. Res. 1983, 16, 153.
(Crystal structures confirm attack trajectory)
■ Electronegative atoms distort the HOMO and LUMO
Dipole Moment:µ = ∆q × dist. = 2.7 D suggests ± 0.23 charges
■ "Coefficients" describe the relative size of p orbitals in π and π*■ The coefficient is bigger on carbon in π*C=O
■ The Bürgi-Dunitz Angle = Preferred Nu—C — O angle = 109°
HF/STO-3G
1.22 Å
O O.... .. -
+
C O
E
C Oπco
π*co
Nu..
π: electronegative atom gets larger coeff.
π*: electropositive atom gets larger coeff.
C ORR
109°Me2N
R O
N-C-O distortions = 109 ° = maximum overlapX-ray
Nu
The Felkin-Anh Analysis*
■ Chiral centers adjacent to carbonyls control the stereoselectivity of Nu addition(The selectivity is usually modest.)
■ Strong nucleophiles = early, reactant-like transition states (= Felkin,Cram)■ Nucleophiles attack opposite side of large groups (= Dauben)
■ Nucleophile attacks on the opposite side of electronegative groups
Compare Two Newmans: here’s how
■ Forming bond eclipses small rather than medium group
Nguyên, T. A. Topics Curr. Chem. 1980, 88, 145. Chérest, M.; Felkin, H. Tetrahedron Lett. 1968, 2205
■ Attack from Bürgi-Dunitz angle (= Anh)
JACS 1956, 2579
*His last name is Nguyen, not Anh
S
Med
BIG
Med
S
BIG
better TS
vs.Nu
O
RNu
O
RMe Me
Cost = 5.5 kcal/mol
Med
s
OMe
Nu
OMeO-
sMedR forming bond
donates into σ*
σ*
Me
O
Me
Ph
MeMe
PhEt2O35 °C
OHHPh
MeMe
HHO
74 : 26
LiAlH4
Nu
O
R
Med S
BIG
Cram modelnot quite right
Chelation Control and Lewis Acids
■ Gives opposite of Felkin-Anh (= Cram's chelate model)
■ Good chelating metals: TiX4, ZnX2, MgX2, LiXMengel, A.; Reiser, O. “Around and beyond Cram's Rule.” Chem. Rev. 1999, 99, 1191.
Carey & Sundberg Advanced Organic Chemistry. Part A: Structure and Mechanism, 4th Ed. Table 4.9, p. 236.
■ Lewis Acidity Scales■ Lewis Acids: Increase δ+ and lower LUMO, thus chlelated form is more reactive than un-chelated.
■ Bad solvents for chelation control: DMSO, DMF, ROH, DME, THF(compete with substrate for chelation to metal)
■ Siloxy groups are poor for chelation: RO >> R3SiO
BCl3 1.00
AlCl3 0.91
BF3 0.76AlEt3 0.63
SnCl4 0.61
-6.6
-25.6
+4.1-10.1
+10.0
O OL.A.+ L.A.
L.A. ∆H LUMO lowering
H H
∆δ(H-3)1.35
1.23
1.170.63
0.87
TiCl4OBF3+ OO
OR
Ti-Cl Cl
Cl Cl-2
++
O
C7H15
OBnR1
C7H15
OBn -O Bu
Et2O-20 °C
99 : <1
MgBuMgBr
BrMgBu
RMgBr =BuMgBr or ROMgBr
XBr-2
+
+
O
C7H15
OBn
MgX
Br
+Bu
-2
Donor Effects on C=O Reactivity
■ Donation slows addition of nucleophiles
Guthrie, J. P. JACS 1978, 100, 5892
■ Rates of HO— addition to C=O
■ Evidence for Donation = Rotational Barriers
Carey & Sundberg "8.4 Reactivity of Carbonyl Compounds Toward Addition"Advanced Organic Chemistry. Part A: Structure and Mechanism, 4th Ed.
O
X
.. -
+
O
X
O
X
.. -
+..
: : : : : :
EMO
nO
πC=O*
π
π*
O
R
RO..
new π*
old π*
recall:
O
H
O
CH3
O
OR
O
NR2
> > >
krel (OH-) 1011
O
H H> O
O->
109 107 104 1 <1
O
Me OMe
O -
Me OMe
+
OO
Me
120 °
Costs ~12 kcal/mol
to twist
pO π*O
Me NMe
pN is more nucleophilic than pO
O -
Me NMe
+H H
Costs ~20 kcal/mol
to twist
O
Cl
O
OR
O
NR2
>>> > O
O->
1011 100 10-2 ??
Overall Hydrolysis Rates:
Effects of Ring Size on C=O Reactivity
■ Electronic and strain effects
C&S A, 5th Ed. Table 7.4
■ Relative rates for carbonyl addition
Proposed model: pyramidalization relieves eclipsing
NaBH4 in i-PrOHO
krel
O OO
20 10 1 0.5
Ph H
O
12,400
H
H
HH
H
H H
H
O
H
H
HH
HO
H
OH
H H
H
OH
H
many confs.always ≥1 eclipse
best conf.= 2 eclipse
many confs.always ≥1 eclipse
no eclipse
H2OR
O-
R+e- deficient
+H H
OHOH
O
H H
Keq 2300
O
CH3 H
1
O
H3C CH3
0.008
σC-H = donor
O
F3C CF2
1,200,000
O
CH3O
Me
0.6
F
OR
OHHO
ROFF FF
lubiprostone
HO OH
cyclopropanonehydrate
cyclopropanone
Owants 120°instead of 60° OEtHO
commerciallyavailable
Effects of Charge and Electronegativity
■ Formal charge is more important than electronegativity
Borch, R. F.; Hassid, A. I. "New Method for Methylation of Amines" JOC 1972, 37, 1673.
■ Borch reductive amination
ONON
BCN
HHH
Si
H
EtEtEt
X
<+
< <+
--reacts w/
BH
HHH -
E π*C=N+
π*C=N< +
RNH2
NaCNBH3
H2O
O+ aq. MeOH
pH 5
NHR
HNR+
5 fastelementary steps
HB
CN
H H-
+
HNR
HB
NC
HH-
+
fast
O
HB
CN
H H-
slow
Substitution through Addition-Elimination
■ Stable TIM with Weinreb's amide
■ Easier to add to π* than σ*
■ Unstable Tetrahedral Intermediate (TIM)
L.p. on O-Li pushes out the L.G.
Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
O
ClNu.. -
never
O
XNu +..
X
O -Nu....
.. O
Nu+ ..-
σ*c-x
π*c=oTIM
X
PhLi PhLi
OMe
O
Ph
O
Ph
OLi
Phevenfaster
OMe
O
Ph
Li: Li+
N
O
N
O
Me
OMe OMeLi
Me
PhPh
O
stable
PhLi H2O
workup
Why Are Acid Chlorides Reactive?
■ Relative reactivity toward Nu:
■ The order is not because of electronegativity: Br (3.0) < Cl (3.2) < F (4.0)
p
s
HF/STO-3G■ C-X bond lengths:
Conclusion: acid chlorides are reactive b/c of poor l.p donation
■ Long bonds = poor overlap nX -> π*
O
Br
O
Cl> >> O
F
O
Br
O
Cl> >> O
F
1.88 Å 1.73 Å 1.34 Å
O
F..
O
F
-
+O
Cl..
important not
H
H F>..+
H
H H+
cationstability: >>
H
H CF3+
F
H F>..+
:
a 3rd fluorinedoesn't stabilize
Nucleophilic Acyl Transfer Catalysis
■ Rebek “three-phase test” distinguishes nucleophilic catalysis from base catalysis.
■ 4-DMAP catalyzes acyl transfer G. Hoefle, W. Steglich, Vorbrueggen, H Angew. Chem., Int. Ed. Engl. 1978, 17, 569.
Rebek, J., Jr. "Mechanistic Studies Using Solid Supports: The Three Phase Test" Tetrahedron1979, 35, 723.
"…grinding the polymer-bound acylating agent and polymer-bound amine in a mortar, with or without solvent, failed to induce direct reaction between the solid phases."
10 mol% DMAP leads to 104 rate acceleration in the acylation of 3° alcohols.
Used in conjunction w/ stoichiometric bases.
■ The key residue in the ribosome looks like DMAP, but is just a base.
NN
HO
O
O
O+
O
O
10 mol% DMAPEt3N
CH2Cl2
O
N+
Nvia
O
NHProtein
proteintranslation
NNH2N
NN ribosome
:
A2486
H2NProtein
O
O-tRNA+
role?
O -
O-tRNANH
HProtein+
NN NH2
N Nribosome
:via
R
O
O
NO2
N NH
R NH2
H2O / dioxane
R
OHNO2
R NH
O
O
N+
via
NHR
O
O -
NR H
H+ N si:
NOTsimply a base
mech?
LUMO Lowering Catalysis
Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 4232.
■ Organocatalytic D-A(rapid equilibrium for iminium ion formation)
■ Knoevenagel Condensation – It looks like addition of an enolate to a C=O, but not the use of a 2° amine.
Jones Org. React. (1967), 204Crowell & Peck JACS (1953),1075
OEt
O OO
R H+
NH
OEt
O O
CHR
OEt
OH O
NR
H OEt
O O
N
H
AcOH
R+
PhO
PhN*R
R*+
fast D-A Ph
CHO
Ph
+rapid
up to 93% e.e.
NH
NOMe
Me
Me
Bn
R*2NH =
5 mol% R*2NH
*R2Nrapid
Conjugate Addition Reactions
■ LUMO coefficients predict 1,4
■ Effects of conjugation and E.N. on LUMO Read: Fleming 1.1C&S A 1.6
■ Charge predicts 1,2 Best for 1,2 C=O additionWorst Nu for 1,4 addition
F- or Cs+ -OR
0.62 -0.42 -0.53LUMO coeff. 0.60 0.38 0.17 0.28c2 ∝ e- pop. 0.36
High, localized charge
Best Nu for 1,4 addition
HOMO
EMO
LUMOconjugation
2000Nobelprize
O
π*
π
EMO
R-LUMO
calculate,predict,
or memorize
O
MO
+.62 -.43-.53 +.60
Nu.
HF/STO-3G coeff.
:
.
O - O -+ +
6x higher+0.21+1.25
O O- NR2R3PRS
..- ..