NMR and Stereochemistry - · PDF fileNMR Spectroscopy Proximity of Protons – 2D experiments NOESY: Nuclear Overhauser Effect Spectroscopy ROESY: Rotating-frame Overhauser Effect

NMR and StereochemistryChem 4010/5326:

Organic Spectroscopic Analysis

© 2015 Andrew Harned

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???

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.

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)

– 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)


Nuclear Overhauser Effect (nOe)• nOe Difference: Subtract original spectrum from the irradiated spectrum – This leaves only the enhanced protons


• nOe Difference: Subtract original spectrum from the irradiated spectrumNuclear Overhauser Effect (nOe)


• nOe Difference: Subtract original spectrum from the irradiated spectrumNuclear Overhauser Effect (nOe)


– 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



J. Org. Chem. 2008, 73, 2898


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


Chart adapted from: Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron Lett. 1990, 31, 945–948axial M

e

equatorial Me



Evans, D. A.; Rieger, D. L.; Gage, J. R.Tetrahedron Lett. 1990, 31, 7099–7100.

– Acetonides of polyproprionate polyols display similar chemical shift patterns


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

Absolute Stereochemistry(Enantiomers)

Seco, J. M.; Quinoa, E.; Riguera, R. Chem. Rev. 2004, 104, 17.

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


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


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


– Working conformational model, actual conformation may vary– Ph of (R)–MTPA shields L2

– Ph of (S)–MTPA shields L1

Mosher Analysis with MTPA


– 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


– Example



– Example



– Example



– Conformational model will break down on occasionModified Mosher Analysis


– Sometimes need to make derivativeModified Mosher Analysis


– Diols possible as wellModified Mosher Analysis

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

Absolute Stereochemistry

(a bit of UV)

Crews, P.; Rodríguez, J.; Jaspars, M. Organic Structure Analysis; Oxford University Press: New York, 1998; pp 349–371.

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

Overview of methods

Taken from: Crews, P.; Rodriguez, J.; Jaspars, M. Organic Structure Analysis; Oxford University Press: New York, 1998, p 5.

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:

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

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

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...

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!!!

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.

The Octant Rule

Konopelski, J. P.; Sundararaman, P.; Barth, G.; Djerassi, C. J. Am. Chem. Soc. 1980, 102, 2737–2745

The Octant Rule

The Octant Rule

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.

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.


MacMillan, J. B.; Xiong-Zhou, G.; Skepper, C. K.; Molinski, T. F. J. Org. Chem. 2008, 73, 3699–3706.

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*


Andersson, T.; Berova, N.; Nakanishi, K.; Carter, G. T. Org. Lett. 2000, 2, 919–922.


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

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

Documents

NMR and Stereochemistry - · PDF fileNMR Spectroscopy Proximity of Protons – 2D experiments NOESY: Nuclear Overhauser Effect Spectroscopy ROESY: Rotating-frame Overhauser Effect