multidimensional nmr experiments - organic synthesis … · 02/12/2014 · multidimensional nmr...
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Multidimensional NMR Experiments
Chem 8361/4361:Interpretation of Organic Spectra
© 2009–2013 Andrew Harned & Regents of the University of Minnesota
2D NMR SpectroscopyGeneral Information
– More complicated experiments to set up than 1H and 13C– Changes in pulses (#, length, angles, mixing times, etc.)– Observe effects based on relationship of nuclei
**Can be homonuclear (same nuclei) (e.g. H–H) or heteronuclear (different nuclei) (e.g. H–C, H–P, etc.)**
– Will only go over the what the experiments tell you and how to interpret, and only for the most common and widely used for solving organic structures
– DEPT, H–H COSY, HMQC (HETCOR), HMBC, INADEQUATE (C–C COSY)
– There is a whole alphabet soup of other experiments (both 1D and 2D)
– EXSY, TOCSY, HOHAHA, INEPT, WATERGATE, and many more
http://www.chem.ox.ac.uk/spectroscopy/nmr/acropage.htm
2D NMR SpectroscopyNumber of Protons on Carbon
DEPT (Distortionless Enhancement by Polarisation Transfer
– Used to be known as APT (Attached Proton Test)– DEPT is 1H-detected; APT is 13C-detected
– Tells you how many protons are attached to a particular carbon– negative peaks = CH2
– positive peaks = CH and CH3 (distinguishable with further processing)– “missing” peaks = carbons w/o protons
– With a little help from IR and chemical shift of 1H and 13C, can get a rough idea of molecular weight
2D NMR SpectroscopyNumber of Protons on Carbon
DEPT (Distortionless Enhancement by Polarisation Transfer
1
1 = Carbon spectrum
2
2 = ↓ CH2 ↑ CH, CH3
3
3 = ↑ CH
135ºpulse
90ºpulse
– Tells you which protons are coupled to one another– Very useful when peaks are overlapping in 1H NMR and you are unable to calculate coupling constants, or when there are a lot of similar coupling constants– Cross peaks are coupled to each other
– Newer method is DQF (Double Quantum Filtered)-COSY– same information, but looks “cleaner”
2D NMR SpectroscopyWho is Talking to Who?
1H–1H COSY (Correlation Spectroscopy)
C C C
H
1 bond H–H coupling
H
2D NMR SpectroscopyWho is Talking to Who?
1H–1H COSY (Correlation Spectroscopy)
1H1H
4H2H 2H 1H
3H3H
2H
– Overlapping protons and a lot of similar coupling constants
Raffinose–a trisaccharide
2D NMR SpectroscopyWho is Talking to Who?
1H–1H COSY (Correlation Spectroscopy)
Raffinose–a trisaccharide
2D NMR SpectroscopyWho is Talking to Who?
1H–1H COSY (Correlation Spectroscopy)
4H
1H
1H2H2H1H
3H3H
2H
2D NMR SpectroscopyWho is Talking to Who?
1H–1H COSY (Correlation Spectroscopy)– DQF-COSY: Double Quantum Filtered COSY – cleans up the spectrum by reducing noncoupled systems (e.g. CH3 singlets)
CH2
CH2
H3C CH3
HO
Ipsenol
2D NMR SpectroscopyWho is Talking to Who?
1H–1H COSY (Correlation Spectroscopy)– DQF-COSY: Double Quantum Filtered COSY – cleans up the spectrum by reducing noncoupled systems (e.g. CH3 singlets)
CH2
CH2
H3C CH3
HO
Ipsenol
2D NMR SpectroscopyWho is Talking to Who?
1H–1H COSY (Correlation Spectroscopy)
C6H10O2
2D NMR SpectroscopyWho is Talking to Who?
1H–1H COSY (Correlation Spectroscopy)
O
O
– Tells you which protons are coupled to one another– Very useful when peaks are overlapping in 1H NMR and you are unable to calculate coupling constants, or when there are a lot of similar coupling constants– Cross peaks are coupled to each other
Recall...1H–1H COSY
C C C
H
H
2 & 3 bond H–H coupling
H
– Tells you which protons are coupled to one another– Very useful when peaks are overlapping in 1H NMR and you are unable to calculate coupling constants, or when there are a lot of similar coupling constants– Cross peaks are coupled to each other
Recall...1H–1H COSY
C C C
H
H
2 & 3 bond H–H coupling
H
4H
1H
1H
2H2H1H
3H
3H
2H
This can still causeambiguities!
2D NMR SpectroscopyWho is Talking to Who?
1H–1H TOCSY (Total Correlation Spectroscopy)
– Tells you which protons are in the same spin system (a continuous chain of spin-spin coupled protons)– Magnetization from HA is transferred to HB, which then transfers to HC and on down the line
– Can be run as either a 1D or 2D experiment– Running as a 1D experiment greatly simplifies spectra with severe signal overlap– Related experiment (HOHAHA) gives essentially the same information– Can also observe one-bond 1H–13C couplings (HMQC-TOCSY, hetero-TOCSY, HEHAHA) - will not discuss
C C C
HA HB
C C
HC HD HE
1D TOCSYSpin System Identification
1H–1H TOCSY (Total Correlation Spectroscopy)– Irradiate at frequency of proton of interest– Wait a period of time (typically 20 to 400 ms) and then collect1D spectrum– Only observe protons to which magnetization has been transferred– Short periods of time (20 ms) will only give rise to “single step” transfers; longer periods of time allow magnetization to propagate further
α- and β-lactose
1D TOCSYSpin System Identification
O
H4
O
H3
HO
H2
H1
OHH5
OH
OHO
HO
H
H
HO
H
HOHH
OH
β-lactose4.67 ppm
H6,H6'
1D TOCSY
Claridge, T. D. W. High-Resolution NMR Techniques in Organic Chemistry, 2nd Ed., Elsevier, 2009.
O
HN
OO
HN
OO
N3
OO
OO
O
OO
O2A B,C D
12
34
56
1D TOCSY
Claridge, T. D. W. High-Resolution NMR Techniques in Organic Chemistry, 2nd Ed., Elsevier, 2009.
O
HN
O
O
HN
O
O
N3
O
O
O
O
O
O
O
O
2
A
B,C
D
1
234
5
6
2D TOCSYSpin System Identification
1H–1H TOCSY (Total Correlation Spectroscopy)– Cross peaks are in the same spin system
O
OHHO
N3O
O
12
3 4
56
COSY TOCSY
Claridge, T. D. W. High-Resolution NMR Techniques in Organic Chemistry, 2nd Ed., Elsevier, 2009.
N
N
23
45
6
7
8
9 10
1112
13
17
19
2925
23
2D TOCSY– Cross peaks are in the same spin system
Claridge, T. D. W. High-Resolution NMR Techniques in Organic Chemistry, 2nd Ed., Elsevier, 2009.
Intermediate in biomimetic synthesis of manzamine
N
N
23
45
6
7
8
9 10
1112
13
17
19
2925
23
2D TOCSY– Cross peaks are in the same spin system
Claridge, T. D. W. High-Resolution NMR Techniques in Organic Chemistry, 2nd Ed., Elsevier, 2009.
Intermediate in biomimetic synthesis of manzamine
N
N
23
45
6
7
8
9 10
1112
13
17
19
2925
23
2D TOCSY– Cross peaks are in the same spin system
Claridge, T. D. W. High-Resolution NMR Techniques in Organic Chemistry, 2nd Ed., Elsevier, 2009.
Intermediate in biomimetic synthesis of manzamine
New DevelopmentsDeconvolution via MDEC
MDEC (Multi Frequency Homonuclear Decoupling)– Conceptually the same as the homonuclear decoupling experiment mentioned earlier, but allows multiple frequencies to be decoupledat the same time
J. Am. Chem. Soc. 2009, 131, 15994–15995
(a) 1H NMR(b) irr @ H-1(c) irr @ H-1/H-7(d) irr @ H-1/H-3a/H-7
H-2 (dddd)
H-2 (app dt)
H-2 (dd, J = 3.3, 12.2 Hz)
H2
H
Me
H1
OHH3b
H3a MeMe
H7
123
7
OH
X
X
X
New DevelopmentsDeconvolution via MDEC
1D-TOCSY-MDEC
J. Am. Chem. Soc. 2009, 131, 15994–15995
123 4
O
O
Me
H
H
H
MeMe
H
6
(a) 1H NMR(b) 1D-TOCSY irr @ H-3(c) 1D-TOCSY irr @ H-3 with MDEC @ H-1b, H-2b, H-3
H-2aX
X
X
2D NMR SpectroscopyWho is Talking to Who?
1H–13C COSY– HETCOR (Heteronuclear Correlation)
– older experiment; 13C-detected– HMQC (Heteronuclear Multiple Quantum Correlation) and HSQC (Heteronuclear Single Quantum Correlation)
– newer experiments; 1H-detected; largely replaced HETCOR– Both give same information, experimentally very different– Peaks have one-bond coupling (i.e. attached directly)– Compliments DEPT– Particularly useful for diastereotopic protons
C C C
H
1 bond H–C coupling
2D NMR SpectroscopyWho is Talking to Who?
HMQC
C C C
H
1 bond H–C coupling
2D NMR SpectroscopyWho is Talking to Who?
HMQC
C C C
H
1 bond H–C coupling
DiastereotopicProtons
2D NMR SpectroscopyWho is Talking to Who?
HMQC
Can “see into” multiplets
H2C
O
CH3
H
HH3C
H3C
Caryophyllene Oxide
2D NMR SpectroscopyWho is Talking to Who?
HMQC
O
O
2D NMR SpectroscopyHO
Cl
2D NMR SpectroscopyHO
Cl
2D NMR SpectroscopyHO
Cl
2D NMR SpectroscopyWho is Talking to Who?
1H–13C COSY (Long Range)
– COLOC (Correlated spectroscopy for Long range Couplings)– older experiment; 13C-detected
– HMBC (Heteronuclear Multiple Bond Coherence)– newer experiment; 1H-detected; completely replaced COLOC
– Both give same information, experimentally very different– Peaks have two- or three-bond coupling– “Sees through” heteroatoms and quaternary carbons– Can be very complicated, but is very powerful
C C C
H
2 and 3 bond H–C couplings
H1
2 3C O C
H
H1
2 3C C C
H
HO
1
2 3
2D NMR SpectroscopyWho is Talking to Who?
HMQC
C C C
H
1 bond H–C coupling
2D NMR SpectroscopyWho is Talking to Who?
HMBC
C C C
H
2 and 3 bond H–C couplings
H1
2 3
2D NMR SpectroscopyWho is Talking to Who?
OCH3
OH
OH
OCH3
or
2D NMR SpectroscopyWho is Talking to Who?
OCH3
OH
OH
OCH3or
2D NMR SpectroscopyWho is Talking to Who?
OCH3
OH
OH
OCH3or
2D NMR SpectroscopyWho is Talking to Who?
OCH3
OH
OH
OCH3or
2D NMR SpectroscopyWho is Talking to Who?
OCH3
OH
OH
OCH3or
2D NMR SpectroscopyWho is Talking to Who?
13C–13C COSY
– INADEQUATE (Incredible Natural Abundance Double Quantum Transfer Experiment)– tells what carbons are attached to each other– if you know what type of carbon it is (C, C=O, CH, CH2, CH3, etc.) from DEPT, you can almost write down the entire gross structure by running two NMR experiments
– BUT it is 13C–13C coupling– probability of one 13C is 0.01– two next to each other 0.01x0.01 = 0.0001 (~1 molecule in 10,000)
– Need lots of sample and instrument time to overcome– In our facility: 80% v/v, overnight, 500 MHz = nothing
C C C
1 bond C–C coupling
ON
2D NMR SpectroscopyWho is Talking to Who?
INADEQUATE
C C C
1 bond C–C coupling
2D NMR SpectroscopyWho is Talking to Who?
INADEQUATE– Cross peaks show up as doublets = JCC – Diagonal is midway between the two doublets
5 4 1 9 103 11 2 15 126,714
2D NMR Spectroscopy
OH
CH C CH CH2 C CH2
CH3,CH3,CH2,CH3
2D NMR Spectroscopy
2D NMR Spectroscopy
C C,CH
2D NMR Spectroscopy
C CCH CH CH2 CH2 CH3CH3 x2
O
Br
WhichIsomer?
2D NMR Spectroscopy
O
Br
2D NMR Spectroscopy
O
Br