NMR and Stereochemistry - · PDF fileNMR Spectroscopy Proximity of Protons – 2D...
Transcript of NMR and Stereochemistry - · PDF fileNMR Spectroscopy Proximity of Protons – 2D...
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NMR and StereochemistryChem 4010/5326:
Organic Spectroscopic Analysis
© 2015 Andrew Harned
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General flow for solving structuresMolecular weight/formula (MS)
Functional groups (IR, NMR)
Carbon connectivities (substructures) (NMR)
Positions of functional groups within framework (gross structure)
(2D NMR, coupling constants)
Stereochemical issues
C10H20OExact Mass: 156.1514
Molecular Weight: 156.2652
How can thisbe solved???
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Relative Stereochemistry(Diastereomers)
Can be determined with many of the tools we have already discussed, along with some new ones
Bifulco, G.; Dambruoso, P.; Gomex-Paloma, L.; Riccio, R. Chem. Rev. 2007, 107, 3744.
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NMR SpectroscopyStrategies for determining relative stereochemistry
Chemical Shifts– Diastereotopic protons will have different chemical shifts, this will
only tell you that diastereomers are present, cannot necessarily tell which is which by inspection only by comparison to known structures
– Spatial orientation may place certain protons in shielding/deshielding portions of functional groups
Coupling Constants– In acyclic systems, usually cannot tell which is which by
inspection– Often must convert to rigid/cyclic structure
Both require some knowledge of 3D structure –> Make model(s)
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– Through space interactions between nuclei, whether or not they are directly coupled– Magnitude decreases as inverse of sixth power of distance
NMR SpectroscopyProximity of Protons
– Strongly irradiate one, get larger # in excited state– The others then shift to lower state to compensate and peak increases in intensity– Subtracting the normal spectrum from the NOE
spectrum helps with interpretation– Useful for determining stereochemistry– Need rigid system
Nuclear Overhauser Effect (nOe)
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NMR SpectroscopyProximity of Protons
Nuclear Overhauser Effect (nOe)• nOe Difference: Subtract original spectrum from the irradiated spectrum – This leaves only the enhanced protons
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NMR SpectroscopyProximity of Protons
• nOe Difference: Subtract original spectrum from the irradiated spectrumNuclear Overhauser Effect (nOe)
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NMR SpectroscopyProximity of Protons
• nOe Difference: Subtract original spectrum from the irradiated spectrumNuclear Overhauser Effect (nOe)
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NMR SpectroscopyProximity of Protons
– 2D experimentsNOESY: Nuclear Overhauser Effect SpectroscopyROESY: Rotating-frame Overhauser Effect
Spectroscopy– Look like COSY, but cross-peaks are for through space interactions
• cross peaks not observed past ~5 Å
NOESY vs. ROESY
Theo
retic
al m
axim
um N
OE
– For MW <~600 NOE is always positive– For MW 700–1200 NOE goes through zero– For MW >1200 NOE is negative– ROE is always positive, but works best for MW 700–1200– If given choice for small molecules, run NOESY
Figure from: http://www.columbia.edu/cu/chemistry/groups/nmr/NOE.htm
Nuclear Overhauser Effect (nOe)
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NMR SpectroscopyProximity of Protons
J. Org. Chem. 2008, 73, 2898
Nuclear Overhauser Effect (nOe)
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1,3-Diol StereochemistryDerivatization as Acetonide
Rychnovsky, S. D.; Rogers, B. N.; Richardson, T. I. Acc. Chem. Res. 1998, 31, 9–17
– 1,3-Diols are very common motifs in natural products– Determining the relative stereochemistry can be difficult because many are on acyclic or macrocyclic carbon chains with unknown conformations– Rychnovsky reasoned that converting the 1,3-diols to an acetonide would make the system rigid– Furthermore it was expected that syn-diols would prefer a chair conformation, while anti-diols would prefer a twist-boat conformation– These two would then lead to differences in the 13C NMR spectrum
13C NMR Analysis of acetonide carbons
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1,3-Diol StereochemistryDerivatization as Acetonide
Chart adapted from: Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron Lett. 1990, 31, 945–948axial M
e
equatorial Me
13C NMR Analysis of acetonide carbons
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1,3-Diol StereochemistryDerivatization as Acetonide
Evans, D. A.; Rieger, D. L.; Gage, J. R.Tetrahedron Lett. 1990, 31, 7099–7100.
– Acetonides of polyproprionate polyols display similar chemical shift patterns
13C NMR Analysis of acetonide carbons
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Case StudyMacrolactins, Part 1
– The macrolactins were isolated from a deep sea bacterium and displayed interesting biological activity; gross structure determined, but stereochemistry unknown
Rychnovsky, S. D.; Skalitzky, D. J.; Pathirana, C.; Jensen, P. R.; Fenical, W. J. Am. Chem. Soc. 1992, 114, 671–677
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Absolute Stereochemistry(Enantiomers)
Seco, J. M.; Quinoa, E.; Riguera, R. Chem. Rev. 2004, 104, 17.
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NMR SpectroscopyEnantiomer Determination
– Several different methods available
– Two main strategies:1) chiral solvating agent – chiral solvent or additive (e.g. shift reagent)
– no covalent linkage– very small differences in δ between the two enantiomers– many times requires both enantiomers of substrate;
not always available2) chiral derivatizing agent – chiral auxiliary
– covalent linkage– diastereomeric derivatives made using two enantiomers of
auxiliary– does not require both enantiomers of substrate
Determination of Absolute Configuration
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NMR SpectroscopyEnantiomer Determination
The sign (+ or –) of ΔδL1 and ΔδL2 allows for determination of configuration of A
– Two main derivitizing agents (both enantiomers needed)
– These are the most common, others available but will not discuss, see review (same principles)
Chiral Derivatizing Agents
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NMR SpectroscopyEnantiomer Determination
1) Polar or bulky group to fix a particular conformation2) A functional group to allow for attachment of substrate3) A group able to produce an efficient and space-oriented anisotropic effect
– Shields/deshields L1 and L2 in each diastereomer
Chiral Derivatizing Agents
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NMR SpectroscopyEnantiomer Determination
– Working conformational model, actual conformation may vary– Ph of (R)–MTPA shields L2
– Ph of (S)–MTPA shields L1
Mosher Analysis with MTPA
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NMR SpectroscopyEnantiomer Determination
– Original method used 19F due to limitations in instruments– Modified method uses 1H or 13C
Majority of examples with alcohols, but has been used with other groups (see review)
Modified Mosher Analysis
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NMR SpectroscopyEnantiomer Determination
– Example
Modified Mosher Analysis
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NMR SpectroscopyEnantiomer Determination
– Example
Modified Mosher Analysis
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NMR SpectroscopyEnantiomer Determination
– Example
Modified Mosher Analysis
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NMR SpectroscopyEnantiomer Determination
– Conformational model will break down on occasionModified Mosher Analysis
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NMR SpectroscopyEnantiomer Determination
– Sometimes need to make derivativeModified Mosher Analysis
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NMR SpectroscopyEnantiomer Determination
– Diols possible as wellModified Mosher Analysis
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Case StudyMacrolactins, Part 2
Rychnovsky, S. D.; Skalitzky, D. J.; Pathirana, C.; Jensen, P. R.; Fenical, W. J. Am. Chem. Soc. 1992, 114, 671–677
Authentic samples of each fragmentwere made and subjected to full Mosher analysis and then compared to degraded material
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Absolute Stereochemistry
(a bit of UV)
Crews, P.; Rodríguez, J.; Jaspars, M. Organic Structure Analysis; Oxford University Press: New York, 1998; pp 349–371.
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Electromagnetic spectrum
Taken from: http://www4.nau.edu/microanalysis/Microprobe/Xray-Spectrum.html
Increasing Energy & Frequency
Increasing Wavelength
Different effects observed in different areas
• UV – electronic transitions• IR – bond vibrations• Microwaves – rotational motion• Radiowaves – nuclear spin transitions
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Overview of methods
Taken from: Crews, P.; Rodriguez, J.; Jaspars, M. Organic Structure Analysis; Oxford University Press: New York, 1998, p 5.
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Intro to UV-Vis• UV range: 200–400 nm• Visible range: 400–800 nm• Below 200 nm strongly absorbed by air (O2 & CO2) or solvents;
must use vacuum techniques to determine (commercial instruments available)
• Observe electronic transitions: excitation of an electron from bonding or nonbonding orbital to antibonding orbital
• Four types of transitions:
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Intro to UV-VisUseful Terminology:
• λmax – wavelength where maximum absorbance is observed• Bathochromic (Red) shift – increasing λmax • Hypsochromic (Blue) shift – decreasing λmax • Molar extinction coefficient (ε) – gives an indication of the peak
intensity at λmax (how strongly it absorbs the light)
Beer-Lambert Law:
See Pretsch and Lambert for tables
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Chiral ChromophoresBy using plane polarized light with UV wavelengths we can obtain information about the stereochemistry of chiral molecules.• Recall that chiral, molecules will rotate plane polarized light
Measuring [α] or [Φ] over a range of wavelengths results in a optical rotatory dispersion (ORD) plot – S-shaped curve
Plain curve – chiral compound with no chromophoreCotton effect (CE) occurs with compounds containing a chromophore
+ CE: peak is at higher λ than trough– CE: peak is at lower λ than trough
Zero crossover occurs at λmax
Opposite enantiomers display opposite ORD curves of identical magnitude
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Chiral ChromophoresIf circularly polarized light is used instead, a circular dichroism (CD) plot is obtained instead
Left- and right-handed circularly polarized light is differentially absorbed by chiral molecules and yields elliptically polarized light
Plotting [θ] or Δε vs. wavelength gives CD plot – Gaussian curve
• can be positive or negative• can be easier to interpret when more than one
chromophore is present
Sounds like an easy way to determine
stereochemistry.But...
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The Catch
Rules have been established to interpret the signs of the ORD and CD spectra for carbonyl-containing molecules.
Allow for determining constitution, conformation, or configuration...But you need to know two of these
So in order to determine the absolute configuration of a molecule you need to know its structure (including any relative
stereochemistry) and know its conformation
Nonrigid molecules, need not apply
Often need to have a known molecule of similar composition/stereochemistry for comparison
How do you interpret the data!!!
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The Octant RuleDeveloped from rigid cyclohexanones, but
has been extended to other systems
1) Substituents in back lower right and back upper left make + contribution2) Substituents in back lower left and back upper right make – contribution3) Substituents in any of the planes dividing the octants make no contribution
Begin by trisecting carbonyl with three planes
Review: Kirk, D. N. Tetrahedron 1986, 42, 777–818.
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The Octant Rule
Konopelski, J. P.; Sundararaman, P.; Barth, G.; Djerassi, C. J. Am. Chem. Soc. 1980, 102, 2737–2745
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The Octant Rule
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The Octant Rule
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The Exciton Chirality MethodWhat if the molecule of interest does not have a ketone or
another molecule with which to compare?
If two chromophores are located near each other, the excited state is delocalized between the two – splitting the excited state. This is known as exciton coupling or Davydov splitting.
Excitations of the two split energy levels generates CEs of mutually opposite signs.
The signs of the first and second CE will tell the spatial relationship between the chromophores.
Often requires making a derivative to install the chromophores.
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The Exciton Chirality Method
Lin, Y.-Y.; Risk, M.; Ray, S. M.; Van Engen, D.; Clardy, J.; Golik, J.; James, J. C.; Nakanishi, K. J.
Am. Chem. Soc. 1981, 103, 6773–6775.
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The Exciton Chirality Method
MacMillan, J. B.; Xiong-Zhou, G.; Skepper, C. K.; Molinski, T. F. J. Org. Chem. 2008, 73, 3699–3706.
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The Exciton Chirality MethodDo not necessarily need two aromatics
One partner can be an allylic or homoallylic olefin
Harada, N.; Iwabuchi, J.; Yokota, Y.; Uda, H.; Nakanishi, K. J. Am. Chem. Soc. 1981, 103, 5590–5591.
230 nm: benzoate π→π*
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The Exciton Chirality Method
Andersson, T.; Berova, N.; Nakanishi, K.; Carter, G. T. Org. Lett. 2000, 2, 919–922.
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The Exciton Chirality Method
Superchi, S.; Casarini, D.; Summa, C.; Rosini, C. J. Org. Chem. 2004, 69, 1685–1694.
Configurations of Functional Groups1-Aryl-1,2-diols
Skowronek, P.; Gawronski, J. Tetrahedron Lett. 2000, 41, 2975–2977.
Allylic Amines
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The Exciton Chirality MethodConfigurations of Functional Groups
Chiral Sulfoxides
Gawronski, J.; Grajewski, J.; Drabowicz, J.; Mikolajczyk, M. J. Org. Chem. 2003, 68, 9821–9822.
Three possible rotamers!
Major from modeling
ArS
R
O
(S)
ArS
R
O
(R)
or