Chemistry 125: Lecture 62 March 28, 2011 NMR Spectroscopy Decoupling 13 C NMR and Double Labeling...
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Transcript of Chemistry 125: Lecture 62 March 28, 2011 NMR Spectroscopy Decoupling 13 C NMR and Double Labeling...
Chemistry 125: Lecture 62March 28, 2011
NMR SpectroscopyDecoupling
13C NMR and Double LabelingCorrelation and 2D NMR
Electrophilic Aromatic Substitution This
For copyright notice see final page of this
file
Proton Decoupling
13C H
100 MHz25 MHz
(in frame rotating at 100 MHz)
C13 NMR spectrum
while irradiating H
(100 MHz)
H average
H up H down
Decoupling Power determines the rate of this precession.
Pulse (25MHz) to observe C13
or
If it is fast enough, the 13C doublet
collapses.
40 db (inverse log measure of rf power)
CH2
CHCH3
C
CH2
CHCDCl3
Observe 13C while decoupling 1H at various powers.
1 db (inverse log measure of rf power)
CH2
CHCH3
C
CH2
CH
CDCl3
Observe 13C while decoupling 1H at various powers.
NOE(Nuclear Overhauser
Enhancement)
RF excitation of a nucleus strengthens the
signal from nearby nuclei.
Bad for integration
Good for determining structure(see below)
Proton-Decoupled 13C NMR Assignments forthe Artificial Sweetner Neotame Monohydrate
Prof. Eric Munson, Kansas Univ.
One peak per carbon, pretty
well spread out
Why no 13C-13C splitting?
Only 1-4% of 13Cs have an adjacent 13C
in the same molecule.
C=O CaromC-X
e-neg
Calkane
7
Double Labeling
Introduction:Lanosterol Biogenesis
Cf. Frames 6-13 of Lecture 52and e.g. J&F, Sec. 12.13 pp. 554-562
Squalene
+
+
+
+
+
HO
HH
H
CH3
HH
CH3
H+
CH3H3C
H3C CH3
CH3
CH3
CH3H3C
Lanosterol(source of cholesterol
& steroid hormones)
Squalene
+
+
+
+
+
HO
HH
H
CH3
HH
CH3
H+
CH3H3C
H3C CH3
CH3
CH3
CH3H3C
Lanosterol(source of cholesterol
& steroid hormones)
3°
3°
3°
3°3°
Cute StoryIs it True?
(“Wait for NMR”)
HO
HH
CH3H3C
H3C CH3
CH3
CH3
CH3H3C
Squalene
Lanosterol
13C Label
Single Label Enrichment
Enriched Peaks
(100x stronger than natural-abundance peaks)
HO
HH
CH3H3C
H3C CH3
CH3
CH3
CH3H3C
Squalene
Lanosterol
13C Label
Single Label Enrichment
Enriched Peaks
Proves that they entered as a unit.
The dilute double label experiment enhances the same 12 13C peaks as the single label experiments, but only 8 of them show spin-spin splitting (because their C-C bond stays intact). HO
HH
CH3H3C
H3C CH3
CH3
CH3
CH3H3C
13C Double Label
Squalene
DILUTE !
Double-Doublet (proton decoupled)13C-13C splitting (neighboring 13Cs)
Power of Correlation
both labeled, but notin the same molecule
Few single precursor molecules have any C13 label, but thosethat are labeled have two C13s.
These are both labeled, in the same molecule
Strongly confirms the rearrangement scheme.
1H to 1HCorrelation by NOE
(through-spacemagnetic interaction)
protonsin proteinpolymer
proximity(< 6Å) of
With Molecular Mechanics Constraints gives 3-D Structure (without crystal!)
NH at d7.25
is within 6Å of NHs at d8.9, 8.3, 8.25, 7.7
Narrow range; mostly HN-C=O protons
Identify NH withamino acid by
coupling throughCH to R
H
HO
NHR O
NHR
Less-congested, off-diagonal peaks appear when “tickling” one signal on the diagonal enhances another.
diago
nal s
hows n
ormal
spec
trum
heav
ily co
nges
ed by
overl
appin
g sign
als
1H vs. 1H Correlation
in TIME
0.3 sec 40°C
d(ppm)
Note: ppm scale is slanted and "wackbards". The protons in methyls C and D are near + charge (see resonance structures), thus deshielded from lack of electron density, and appear furthest to right, i.e. at highest d.
(Range of peaks is 150 Hz in 60 MHz spectrometer = 2.5 ppm.)
+
+
+
++
+ +
+
C A
D B
B C
Methide Shift: 1-2 (as shown)
“2-Dimensional”NMR
H3C CH3
H3C
CH3
CH3
H3C CH3
H3C
CH3
CH3
CH3
+
A B
C D
A D
or 1-Anywhere?
Electrophilic Aromatic Substitution
H
HH
H
H
H
D2SO4
H
HH
H
D
H
e.g. J&F Sec. 14.4
H
HH
H
H
H
D
A/D via intermediate +
D2SO4
C6D6etc.
Observable!
Or other electrophiles in place of D+
e.g. NO2+, Br+, HOSO2 , R+, R-C=O R-C=O+HOSO2
+
In electrophilic addition to alkenes, a nucleophile would add in the next step, but here it is easier to lose H+ and recover aromatic stabilization.
+
+
+
SHMo2 (Simple Hückel Molecular Orbital Program)
Benzene Pentadienyl
Cation addition converts ring to chain (destroys aromaticity).
H
HH
H
H
H
D+
H
HH
H
H
H
D
+
Locus ofodd electron in
radical,
+ charge(LUMO)in cation.
- charge (HOMO)in anion,
SOMO(nonbonding)
Cf.
e.g. J&F, Sec. 14.4b
+
LUMO
X
NO2
++
+ +
H
O2N
X
+++
+
H
O2N
X
+
+ +
H
Substituent Effects on Rate (e.g. sec. 14.9-14.10)
X
O2N
X
O2N
X X
NO2
+ +NO2
+
(from HONO2/H2SO4)
X Relative Rate (overall)
H [1] Cl 0.03 NO2 6 10-8
CH3 25 OH 1000
(CH3)3N+ 1 10-8
donation / withdrawal
p (or ) e-donation eases formation of cation intermediates
p (or ) e-withdrawal retards formation of cation intermediates
HO H+
Note: +NO2 is O=C=O with an extra proton in the center
productsintermediates
Cf. J&F, Table 14.2
4 py (or px) electrons
Why is -NO2 e-Withdrawing when -OH is e-Donating?
-NO2 6 10-8p e-withdrawal retards formation of cation intermediates
-OH 1000 p e-donation eases
N
O O
O
H
pO-1
0
High HOMO; Good Overlap with Phenyl
(able to donate, but not willing)
Low OMO;Good Overlapwith Phenyl
HOMO as high as pO;
OH is a Donor
NO2 is a Acceptor
but No Overlap with Phenyl
NO2 isallylic
(willing, but not able)
(willing and able to accept)
Low LUMO;Good Overlapwith Phenyl pC
C=C
Substituent Effects on Orientation (e.g. J&F, Sec. 14.9-14.10)
X
NO2
+
(from HONO2/H2SO4)
X- Relative Rate (per replaceable H)
H- [1] [1] [1] Cl- 0.0008 0.03 0.13
O2N- 9 10-80.6 10-8 0.03 10-8
H3C- 1 39 46 (CH3)3C- 4 6 72
DirectingActivating
Deactivating
Act
Deact
Deact
s p
(CH3)3N- 3 10-8 0.6 10-8 + _
ortho meta para
EtOC=O 0.006 0.0006
- 0.003
o/p
m
o/p
“e-donating”
“e-withdrawing”
(steric hindrance)?
X
NO2
++
+ +
H
O2N
X
+++
+
H
O2N
X
+
+ +
H intermediates
Activate the ElectrophileHalogenation (e.g. J&F, Sec. 14.4f)
“Cl+”
H
d+
d-
+29 +38
AlCl3 “Lewis acid” catalyst
AlCl5Cl2 vs.
LUMOsSurface Potentials
(Al, like B, has an empty valence AO)
AlCl4 leaving group
Cf. [Br2]2
for rate of addition to
alkene
Activate the Nucleophile
H
OH
C
O
O
OH
H
NH2
100 atm125°C
Self-Igniting Rocket Fuel(1944)
N
O
O
+
Salicylic AcidKolbe (1860)
OH
C
O
OH
H+
Aspirin
loweredHOMO
raisedHOMO
C
O
H3C
Acetylation of anilinemakes its nitration
controllable.
Charles Friedel(1832-1890)
James Mason Crafts(1839-1917)
AlCl3/C-Electrophile: The Friedel-Crafts Reaction
Par
is (W
urtz
- M
édic
ine)
Cor
nell
MIT
MITP
aris
(Fri
edel
- M
ines
)
Pres
iden
t
AlCl3/C-Electrophile: The Friedel-Crafts Reaction
1877
End of Lecture 62March 28, 2011
Copyright © J. M. McBride 2011. Some rights reserved. Except for cited third-party materials, and those used by visiting speakers, all content is licensed under a Creative Commons License (Attribution-NonCommercial-ShareAlike 3.0). Use of this content constitutes your acceptance of the noted license and the terms and conditions of use.
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