Chapter 13 ... E. McMurry Chapter 13 SttDtitiStructure Determination: Nuclear Magnetic Resonance Spectroscopy Paul D. Adams • University of Arkansas

John E. McMurry

www.cengage.com/chemistry/mcmurry

Chapter 13St t D t i tiStructure Determination:

Nuclear Magnetic gResonance Spectroscopy

Paul D. Adams • University of ArkansasRevisions by Dr. Daniel Holmes – MSU

The Use of NMR Spectroscopy

Used to map carbon-hydrogen framework of molecules

Used to determine relative location of atoms within a molecule

Most helpful spectroscopic technique in organic h i tchemistry

Depends on very strong magnetic fields Earth’s magnetic field is ~0.00006 Tesla Refrigerator magnet is ~0.005 Tesla

MRI f 1 5 3 0 T l MRI range from 1.5 – 3.0 Tesla Largest NMR Magnet at MSU is 21.2 Tesla



Otto Stern, USA: Nobel Prize in Physics 1943, "for his contribution to the development of molecular ray method and his discovery of the magneticdevelopment of molecular ray method and his discovery of the magnetic moment of the proton"

Isidor I. Rabi, USA: Nobel Prize in Physics 1944, "for his resonance method for recording the magnetic properties of atomic nuclei"

Felix Bloch, USA and Edward M. Purcell, USA: Nobel Prize in Physics 1952, "for their discovery of new methods for nuclear magnetic precision measurements and discoveries in connection therewith"

S C 1991 f Richard R. Ernst, Switzerland: Nobel Prize in Chemistry 1991, "for his contributions to the development of the methodology of high resolution nuclear magnetic resonance (NMR) spectroscopy

Kurt Wüthrich Switzerland: Nobel Prize in Chemistry 2002 "for his Kurt Wüthrich, Switzerland: Nobel Prize in Chemistry 2002, for his development of nuclear magnetic resonance spectroscopy for determining the three-dimensional structure of biological macromolecules in solution"

Paul C. Lauterbur, USA and Peter Mansfield, United Kingdom: Nobel Prize gin Physiology or Medicine 2003, "for their discoveries concerning magnetic resonance imaging"

Why This Chapter?

NMR is the most valuable spectroscopic technique used for structure determination Through-bonds and through-space

More advanced NMR techniques are used in biological chemistry to study protein structure

d f ldiand folding

Hadjuk et al. J. Am. Chem. Soc. 2000, 122, 7898

13.1 Nuclear Magnetic Resonance Spectroscopy 1H or 13C nuclear spins (or any NMR active nucleus like

15N 31P 29Si 2H 11B) ill li ll l t i t

Spectroscopy

15N,31P,29Si,2H, or 11B) will align parallel to or against an external magnetic field

Parallel orientation is lower in energy making this spin state more populated

At 21 2 T (900 MHz) the excess population is only At 21.2 T (900 MHz), the excess population is only 0.014%, which means there are only 140 spins out of a million aligned with the field

13.1 Nuclear Magnetic Resonance Spectroscopy Radio energy of exactly correct frequency (resonance)

l i t fli i t ti ll l t t

Spectroscopy

causes nuclei to flip into anti-parallel state Energy needed is related to molecular environment

(proportional to field strength, B)(p p g , ) Frequency of transition: =-B0

13.2 The Nature of NMR Absorptions

Electrons in bonds shield nuclei from magnetic field

Absorptions

Different signals appear for nuclei in different environments

The NMR Measurement

The sample is dissolved in a solvent that does not have a signal itself (CDCl ) and placed in a long thin tubea signal itself (CDCl3) and placed in a long thin tube

The tube is placed within the magnet

The NMR Measurement

A radiofrequency pulse (10-15 s) is transmitted to the sample nuclear spins ‘flip’ to higher energy state if insample, nuclear spins flip to higher energy state if in resonance with pulse Nuclei relax back to equilibrium, which is detected as

i i lt ill ti i th NMR bmicroscopic voltage oscillations in the NMR probe The oscillations decay over time (Free Induction Decay or

FID) Pulses repeated many times and data summed to get

improved Signal compared to the Noise Fourtier Transform is used to convert the FID to a

spectrum with frequency vs. intensity

13.3 Chemical Shifts

The relative energy of resonance of a particular nucleus resulting from its local environment is called chemical shiftfrom its local environment is called chemical shift Beff = Bapplied – Blocal

The more electron density around the nucleus, the greater the shielding of that nucleus (Blocal is larger)g ( local g )

Shielded nuclei appear to the right of the NMR spectrum and are called upfield

Deshielded nuclei appear to the left and are called downfield�

13.3 Chemical Shifts

Nuclei that absorb on upfield side are strongly shielded.Chart calibrated versus a reference point set as 0 tetramethylsilane Chart calibrated versus a reference point, set as 0, tetramethylsilane [TMS]

Any difference in the electron density about a nucleus will mean a difference in chemical shift Electronegative atoms (e.g. Cl, O, N) will deshield a neighboring

nucleus

Measuring Chemical Shift

Numeric value of chemical shift: difference between strength of magnetic field at which the observed nucleusstrength of magnetic field at which the observed nucleus resonates and field strength for resonance of a reference (TMS) Difference is very small but can be accuratelyDifference is very small but can be accurately

measured Taken as a ratio to the total field and multiplied by

106 so the shift is in parts per million (ppm)0 so t e s t s pa ts pe o (pp ) Resonances normally occur downfield of TMS, to the

left on the chart Calibrated on relative scale in delta () scaleCalibrated on relative scale in delta () scale

Independent of instrument’s field strength 500.0005 MHz and 300.0003 MHz both equal 1 ppm

13.4 13C NMR Spectroscopy: Signal Averaging and FT-NMR Carbon-13: only carbon isotope with a nuclear spin

N t l b d 1 1% f C’ i l l

Signal Averaging and FT-NMR

Natural abundance 1.1% of C’s in molecules Sample is thus very dilute in this isotope

Sample is measured using repeated accumulation ofSample is measured using repeated accumulation of data and averaging of signals, incorporating pulse and the operation of Fourier transform (FT NMR)All signals are obtained simultaneously using a All signals are obtained simultaneously using a broadband excitation pulse

Frequent repeated pulses give many sets of data that d t d iare averaged to reduce noise

Fourier-transform of averaged pulsed data gives spectrum (see Figure 13-6)p ( g )

13.4 13C NMR Spectroscopy: Signal Averaging and FT-NMRSignal Averaging and FT-NMR

13.5 Characteristics of 13C NMR Spectroscopy Is not quantitative when run using standard

conditions

Spectroscopy

conditions Provides a count of the different types of

environments of carbon atoms in a molecule Look for any type of symmetry (e.g. a symmetry

plane, a rotation axis) in the molecule you are investigatingg g

Any carbons that are related by symmetry will give rise to one resonance

13.5 Predict Number of 13C ResonancesResonances


7 unique carbons 5 niq e carbons7 unique carbons 5 unique carbons



7 unique carbons 4 unique carbons



C60: Buckminsterfullerene601 carbon resonance at 143 ppm

0 proton resonances!

13.5 Characteristics of 13C NMR Spectroscopy Provides a count of the different types of environments of

carbon atoms in a molecule

Spectroscopy

carbon atoms in a molecule 13C resonances are 0 to 220 ppm downfield from TMS

(Figure 13-7) Chemical shift affected by electronegativity of nearby Chemical shift affected by electronegativity of nearby

atoms O, N, halogen decrease electron density and shielding

(“deshield”) moving signal downfield to the left( deshield ), moving signal downfield to the left. sp3 C signal with no electronegative group is around 0

to 9; sp3 C signal with electronegative resonates between 5 to 110; sp2 C: 110 to 220 5 to 110; sp C: 110 to 220

C(=O) at low field, 160 to 220

Characteristics of 13C NMR Spectroscopy (Continued) 13C chemical shift regions

Spectroscopy (Continued)

Characteristics of 13C NMR Spectroscopy (Continued) Spectrum of 2-butanone is illustrative- signal for


C=O carbons on left edge

Characteristics of 13C NMR Spectroscopy (Continued) Spectrum of para-bromoacetophenone is


illustrative- signal for C=O carbons on left edge

Characteristics of 13C NMR Spectroscopy (Continued) Spectrum of methyl propionate




2



4

2



41

2



41 3

2

13.6 DEPT 13C NMR Spectroscopy Improved pulsing and computational methods

Spectroscopy

give additional information DEPT-NMR (distortionless enhancement by

polarization transfer) Normal spectrum shows all C’s then:

Obtain spectrum of all C’s except quaternary (broad band decoupled)Ch l t bt i t i f ti Change pulses to obtain separate information for CH2, CH

Subtraction reveals each type (See Figure 13- Subtraction reveals each type (See Figure 13-10)

13.6 DEPT 13C NMR SpectroscopySpectroscopy

6-methyl-5-hepten-2-ol

CH’s

CH3’s

CH2’s

13.7 Uses of 13C NMR Spectroscopy Provides details of structure

E l d t i t ti i li i ti f 1 hl

Spectroscopy

Example: product orientation in elimination from 1-chloro-methyl cyclohexane

Difference in symmetry of products is directly observed in the spectrumspectrum

1-methylcyclohexene has five sp3 resonances ( 20-50) and two sp2 resonances 100-150

13.8 1H NMR Spectroscopy and Proton Equivalence Proton NMR is much more sensitive than 13C and the

active nucleus (1H) is essentially 100% of the natural

Proton Equivalence

active nucleus (1H) is essentially 100% of the natural abundance

Shows how many kinds of nonequivalent hydrogens are in da compound

Theoretical equivalence can be predicted by seeing if replacing each H with “X” gives the same or different p g goutcome

Equivalent H’s have the same signal while nonequivalent are differentare different There are degrees of nonequivalence

Nonequivalent H’s

If replacement of each H with “X” gives a different constitutional isomer,

Then the H’s are in constitutionally heterotopicenvironments and will have different chemical shifts – they are nonequivalent under all circumstancescircumstances

Equivalent H’s

Two H’s that are in identical environments (homotopic) have the same NMR signalhave the same NMR signal

Test by replacing each with X if they give the identical result, they are equivalent Protons are considered homotopic

Enantiotopic Distinctions

If H’s are in environments that are mirror images of each other they are enantiotopicother, they are enantiotopic

Replacement of each H with X produces a set of enantiomers

The H’s have the same NMR signal (in the absence of chiral materials)

Diastereotopic Distinctions

In a chiral molecule, paired hydrogens can have different environments and different shiftsenvironments and different shifts

Replacement of a pro-R hydrogen with X gives a different diastereomer than replacement of the pro-S hydrogen

Diastereotopic hydrogens are distinct chemically and Diastereotopic hydrogens are distinct chemically and spectroscopically

Homotopic, Enantiotopic, or Diastereotopic?Diastereotopic?


ti t ienantiotopic


di t t iti t i diastereotopicenantiotopic


di t t iti t i di t t idiastereotopicenantiotopic diastereotopic



diastereotopic



diastereotopic diastereotopic



diastereotopic diastereotopic homotopic

13.10 Integration of 1H NMR Absorptions: Proton Counting The relative intensity of a signal (integrated area) is

proportional to the number of protons causing the signal

Absorptions: Proton Counting

proportional to the number of protons causing the signal This information is used to deduce the structure For example in ethanol (CH3CH2OH), the signals have

the integrated ratio 3:2:1the integrated ratio 3:2:1 For narrow peaks, the heights are the same as the areas

and can be measured with a ruler

2,2-dimethylpropanoate

13.9 Chemical Shifts in 1H NMR Spectroscopy

Proton signals typically range from 0 to 10

Spectroscopy

Downfield signals are H’s attached to sp2 C electrons in alkenes and, especially, aromatics circulate when exposed

to an external magnetic field to further deshield the protons.

Upfield signals are H’s attached to sp3 C

Electronegative atoms attached to direct C cause downfield shift Electronegative atoms attached to direct C cause downfield shift

13.9 Chemical Shifts in 1H NMR SpectroscopySpectroscopy


1.0


1.01.8


1.01.8

6 16.1


6 3

1.01.8

6.3

6 16.1


6 37 2

1.01.8

6.37.2

6 16.1


6 37 2

1.01.8

6.37.2

6.8

6 16.1


6 37 2

1.01.8

6.37.2

6.8

6 16.1

3.8


13.11 Spin-Spin Splitting in 1H NMR Spectra Peaks are often split into multiple peaks due to

interactions between nonequivalent protons on adjacent

NMR Spectra

interactions between nonequivalent protons on adjacent carbons, called spin-spin splitting This is a through-bond interaction and transmitted via the

b di l tbonding electrons The splitting will be one more peak than the number of H’s

on the adjacent carbon (“n+1 rule”) The relative intensities are in proportion to a binomial

distribution (Pascal’s Triangle) and are due to interactions between nuclear spins that can have two possible p palignments with respect to the magnetic field

The set of peaks is a multiplet (2 = doublet, 3 = triplet, 4 = quartet)quartet)

Simple Spin-Spin Splitting

An adjacent CH3 group can have four different spin alignments as 1:3:3:1

This gives peaks in ratio of the adjacent H signalof the adjacent H signal

An adjacent CH2 gives a ratio of 1:2:1

The separation of peaks i lti l t i din a multiplet is measured and is a constant, in Hz J (coupling constant)

Rules for Spin-Spin Splitting

Equivalent protons do not split each other The signal of a proton with n equivalent

neighboring H’s is split into n + 1 peaksProtons that are farther than t o carbon atoms Protons that are farther than two carbon atoms apart do not split each other

13.12 More Complex Spin-Spin Splitting Patterns Spectra can be more complex due to overlapping

Splitting Patterns

signals, multiple nonequivalence Example: trans-cinnamaldehyde

13.12 More Complex Spin-Spin Splitting PatternsSplitting Patterns


H 6.1 ppm

J = 16 HzJ 16 Hz


H 6 1 ppmH 6.1 ppm

J = 16 Hz

J = 7 Hz


H 6 1 ppmH 6.1 ppm

J = 16 Hz

J = 7 Hz

13.13 Uses of 1H NMR Spectroscopy The technique is used

to identify likely

Spectroscopy

y yproducts in the laboratory quickly and easily

Example:Example: regiochemistry of hydroboration/oxidation of methylene-cyclohexanecyclohexane


to identify likely

Spectroscopy




to identify likely

Spectroscopy



Only that for cyclohexylmethanol is observed

XX

13.13 Uses of 1H NMR Spectroscopy Could we have used 13C to find the answer?

Spectroscopy

13.13 Uses of 1H NMR Spectroscopy Could we have used 13C to find the answer?

Spectroscopy

Not without running a DEPT (the CH3 would be distinctive)

Let’s Work Some Problems

Predict the splitting pattern



CHBr2CH3

CHBr2CH3CHBr2CH3





CH3OCH2CH2Br

CH3OCH2CH2Br

CH3OCH2CH2Br





ClCH2CH2CH2Cl

ClCH2CH2CH2Cl




Predict the splitting pattern(Red is split by Blue)(Red is split by Blue)




Predict the splitting pattern(Red is split by Blue)(Red is split by Blue)






How would you distinguish between these isomers?



The compound on the left has two vinylic protons with chemical shifts around 5-6 ppm; the one on the right will not.

The compound on the right will not have protons above 1.5 ppm.





The compound on the left diethyl ether has twoThe compound on the left, diethyl ether, has two proton resonances: a quartet and a triplet.

The compound on the right, methoxypropane,The compound on the right, methoxypropane, has at 4 proton resonances: a singlet, a triplet, a multiplet, and another triplet.


How would you distinguish between these isomers



Both compounds will have three proton resonances with the same splitting pattern: singlet, quartet, and a triplet. The CH2 group of the left compound, ethyl

acetate, will have a chemical shift around 4 ppm, while the CH group of right compound 2-while the CH2 group of right compound, 2-butanone, will be around 2.2 ppm.





Each compound will have 4 proton peaksf The left compound will have two methyl singlets

The right compound will have a methyl singletand a methyl doubletand a methyl doublet

Documents

Chapter 13 ... E. McMurry Chapter 13 SttDtitiStructure Determination: Nuclear Magnetic Resonance Spectroscopy Paul D. Adams • University of Arkansas