John E. McMurry www.cengage.com/chemistry/mcmurry Chapter 13 Structure t Determination: ti Nuclear Magnetic Resonance Spectroscopy Revisions by Dr. Daniel Holmes MSU Paul D. Adams University of Arkansas
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 chemistry Depends on very strong magnetic fields Earth s magnetic field is ~0.00006 Tesla Refrigerator magnet is ~0.005 Tesla MRI range from 1.5 30T 3.0 Tesla Largest NMR Magnet at MSU is 21.2 Tesla
The Use of NMR Spectroscopy
The Use of NMR Spectroscopy Otto Stern, USA: Nobel Prize in Physics 1943, "for his contribution to the development 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" 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 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 in 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 and dfolding Hadjuk et al. J. Am. Chem. Soc. 2000, 122, 7898
13.1 Nuclear Magnetic Resonance Spectroscopy 1 H or 13 C nuclear spins (or any NMR active nucleus like 15 N, 31 P, 29 Si, 2 H, or 11 B) will align parallel l to or against an external magnetic field Parallel orientation is lower in energy making this spin state more populated At 21.22 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) causes nuclei to flip into anti-parallel l state t Energy needed is related to molecular environment (proportional p to field strength, B) ) Frequency of transition: =- B 0
13.2 The Nature of NMR Absorptions Electrons in bonds shield nuclei from magnetic field 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 3 ) 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 in resonance with pulse Nuclei relax back to equilibrium, which is detected as microscopic i 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 shift B eff = B applied B local The more electron density around the nucleus, the greater the shielding of that nucleus (B local is larger) 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 [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 nucleus resonates and field strength for resonance of a reference (TMS) Difference is very small but can be accurately measured Taken as a ratio to the total field and multiplied by 10 6 so the shift is in parts per million (ppm) Resonances normally occur downfield of TMS, to the left on the chart Calibrated 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 13 C NMR Spectroscopy: Signal Averaging and FT-NMR Carbon-13: only carbon isotope with a nuclear spin Natural abundance 1.1% 1% of C s in molecules l Sample is thus very dilute in this isotope Sample 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 broadband excitation pulse Frequent repeated pulses give many sets of data that are averaged dto reduce noise Fourier-transform of averaged pulsed data gives spectrum (see Figure 13-6)
13.4 13 C NMR Spectroscopy: Signal Averaging and FT-NMR
13.5 Characteristics of 13 C NMR Spectroscopy Is not quantitative when run using standard 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 investigating g Any carbons that are related by symmetry will give rise to one resonance
13.5 Predict Number of 13 C Resonances
13.5 Predict Number of 13 C Resonances 7 unique carbons 5 unique carbons
13.5 Predict Number of 13 C Resonances
13.5 Predict Number of 13 C Resonances 7 unique carbons 4 unique carbons
13.5 Predict Number of 13 C Resonances
13.5 Predict Number of 13 C Resonances C 60 : Buckminsterfullerene 60 1 carbon resonance at 143 ppm 0 proton resonances!
13.5 Characteristics of 13 C NMR Spectroscopy Provides a count of the different types of environments of carbon atoms in a molecule 13 C resonances are 0 to 220 ppm downfield from TMS (Figure 13-7) Chemical shift affected by electronegativity of nearby atoms O, N, halogen decrease electron density and shielding ( deshield ) ), moving signal downfield to the left. sp 3 C signal with no electronegative group is around 0 to 9; sp 3 C signal with electronegative resonates between 5 to 110; sp 2 C: 110 to 220 C(=O) at low field, 160 to 220
Characteristics of 13 C NMR Spectroscopy (Continued) 13 C chemical shift regions
Characteristics of 13 C NMR Spectroscopy (Continued) Spectrum of 2-butanone is illustrative- signal for C=O carbons on left edge
Characteristics of 13 C NMR Spectroscopy (Continued) Spectrum of para-bromoacetophenone is illustrative- signal for C=O carbons on left edge
Characteristics of 13 C NMR Spectroscopy (Continued) Spectrum of methyl propionate
Characteristics of 13 C NMR Spectroscopy (Continued) Spectrum of methyl propionate 2
Characteristics of 13 C NMR Spectroscopy (Continued) Spectrum of methyl propionate 4 2
Characteristics of 13 C NMR Spectroscopy (Continued) Spectrum of methyl propionate 1 4 2
Characteristics of 13 C NMR Spectroscopy (Continued) Spectrum of methyl propionate 1 3 4 2
13.6 DEPT 13 C NMR Spectroscopy Improved pulsing and computational methods 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) Change pulses to obtain separate information for CH 2, CH Subtraction reveals each type (See Figure 13-10)
13.6 DEPT 13 C NMR Spectroscopy 6-methyl-5-hepten-2-ol CH s CH 3 s CH 2 s
13.7 Uses of 13 C NMR Spectroscopy Provides details of structure Example: product orientation ti in elimination i from 1-chloromethyl cyclohexane Difference in symmetry of products is directly observed in the spectrum 1-methylcyclohexene has five sp 3 resonances ( 20-50) and two sp 2 resonances 100-150
13.8 1 H NMR Spectroscopy and Proton Equivalence Proton NMR is much more sensitive than 13 C and the active nucleus ( 1 H) is essentially 100% of the natural abundance Shows how many kinds of nonequivalent hydrogens are in a compound Theoretical equivalence can be predicted by seeing if replacing each H with X gives the same or different outcome Equivalent H s have the same signal while nonequivalent are 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 heterotopic environments and will have different chemical shifts they are nonequivalent under all circumstances
Equivalent H s Two H s that are in identical environments (homotopic) have 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 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 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 spectroscopically
Homotopic, Enantiotopic, or Diastereotopic?
Homotopic, Enantiotopic, or Diastereotopic? enantiotopic t i
Homotopic, Enantiotopic, or Diastereotopic? enantiotopic t i diastereotopic t i
Homotopic, Enantiotopic, or Diastereotopic? enantiotopic t i diastereotopic t i diastereotopic t i
Homotopic, Enantiotopic, or Diastereotopic? enantiotopic t i diastereotopic t i diastereotopic t i diastereotopic
Homotopic, Enantiotopic, or Diastereotopic? enantiotopic t i diastereotopic t i diastereotopic t i diastereotopic diastereotopic
Homotopic, Enantiotopic, or Diastereotopic? enantiotopic t i diastereotopic t i diastereotopic t i diastereotopic diastereotopic homotopic
13.10 Integration of 1 H NMR Absorptions: Proton Counting The relative intensity of a signal (integrated area) is proportional to the number of protons causing the signal This information is used to deduce the structure For example in ethanol (CH 3 CH 2 OH), the signals have the 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 1 H NMR Spectroscopy Proton signals typically range from 0 to 10 Downfield signals are H s attached to sp 2 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 sp 3 C Electronegative atoms attached to direct C cause downfield shift
13.9 Chemical Shifts in 1 H NMR Spectroscopy
13.9 Chemical Shifts in 1 H NMR Spectroscopy 1.0
13.9 Chemical Shifts in 1 H NMR Spectroscopy 1.8 1.0
13.9 Chemical Shifts in 1 H NMR Spectroscopy 1.8 1.0 61 6.1
13.9 Chemical Shifts in 1 H NMR Spectroscopy 63 6.3 1.8 1.0 61 6.1
13.9 Chemical Shifts in 1 H NMR Spectroscopy 72 7.2 63 6.3 1.8 1.0 61 6.1
13.9 Chemical Shifts in 1 H NMR Spectroscopy 72 7.2 63 6.3 1.8 1.0 6.8 61 6.1
13.9 Chemical Shifts in 1 H NMR Spectroscopy 72 7.2 63 6.3 1.8 1.0 6.8 61 6.1 3.8
13.9 Chemical Shifts in 1 H NMR Spectroscopy
13.11 Spin-Spin Splitting in 1 H NMR Spectra Peaks are often split into multiple peaks due to interactions between nonequivalent protons on adjacent carbons, called spin-spin splitting This is a through-bond interaction and transmitted via the bonding 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 alignments with respect to the magnetic field The set of peaks is a multiplet (2 = doublet, 3 = triplet, 4 = quartet)
Simple Spin-Spin Splitting An adjacent CH 3 group can have four different spin alignments as 1:3:3:1 This gives peaks in ratio of the adjacent H signal An adjacent CH 2 gives a ratio of 1:2:1 The separation of peaks in a multiplet l t 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 peaks 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 signals, multiple nonequivalence Example: trans-cinnamaldehyde
13.12 More Complex Spin-Spin Splitting Patterns
13.12 More Complex Spin-Spin Splitting Patterns H 6.1 ppm J = 16 Hz
13.12 More Complex Spin-Spin Splitting Patterns H 6.1 ppm J = 16 Hz J = 7 Hz
13.12 More Complex Spin-Spin Splitting Patterns H 6.1 ppm J = 16 Hz J = 7 Hz
13.13 Uses of 1 H NMR Spectroscopy The technique is used to identify likely products in the laboratory quickly and easily Example: regiochemistry of hydroboration/oxidation of methylene- cyclohexane
13.13 Uses of 1 H NMR Spectroscopy The technique is used to identify likely products in the laboratory quickly and easily Example: regiochemistry of hydroboration/oxidation of methylene- cyclohexane
13.13 Uses of 1 H NMR Spectroscopy The technique is used to identify likely products in the laboratory quickly and easily Example: regiochemistry of hydroboration/oxidation of methylene- cyclohexane Only that for cyclohexylmethanol is observed X
13.13 Uses of 1 H NMR Spectroscopy Could we have used 13 C to find the answer?
13.13 Uses of 1 H NMR Spectroscopy Could we have used 13 C to find the answer? Not without running a DEPT (the CH 3 would be distinctive)
Let s Work Some Problems Predict the splitting pattern
Let s Work Some Problems Predict the splitting pattern CHBr 2 CH 3 CHBr 2 CH 3
Let s Work Some Problems Predict the splitting pattern
Let s Work Some Problems Predict the splitting pattern CH 3 OCH 2 CH 2 Br CH 3 OCH 2 CH 2 Br CH 3 OCH 2 CH 2 Br
Let s Work Some Problems Predict the splitting pattern
Let s Work Some Problems Predict the splitting pattern ClCH 2 CH 2 CH 2 Cl ClCH 2 CH 2 CH 2 Cl
Let s Work Some Problems Predict the splitting pattern
Let s Work Some Problems Predict the splitting pattern (Red is split by Blue)
Let s Work Some Problems Predict the splitting pattern
Let s Work Some Problems Predict the splitting pattern (Red is split by Blue)
Let s Work Some Problems Predict the splitting pattern
Let s Work Some Problems Predict the splitting pattern
Let s Work Some Problems How would you distinguish between these isomers?
Let s Work Some Problems 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.
Let s Work Some Problems How would you distinguish between these isomers?
Let s Work Some Problems How would you distinguish between these isomers? The compound on the left, diethyl ether, has two proton resonances: a quartet and a triplet. The compound on the right, methoxypropane, has at 4 proton resonances: a singlet, a triplet, a multiplet, and another triplet.
Let s Work Some Problems How would you distinguish between these isomers
Let s Work Some Problems 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 CH 2 group of the left compound, ethyl acetate, will have a chemical shift around 4 ppm, while the CH 2 group of right compound, 2- butanone, will be around 2.2 ppm.
Let s Work Some Problems How would you distinguish between these isomers?
Let s Work Some Problems How would you distinguish between these isomers? Each compound will have 4 proton peaks The left compound will have two methyl singlets The right compound will have a methyl singlet and a methyl doublet