6-CMR-1.1

© Copyright Hans J. Reich 2010

6. Carbon-13 Nuclear Magnetic Resonance Spectroscopy

6-CMR-1 Measuring 13C NMR Spectra 6-CMR-2 Referencing 13C NMR Spectra6-CMR-3 Origin of Chemical Shifts6-CMR-4 13C Chemical Shift Effects on sp3 Carbons6-CMR-5 Alkane 13C Shifts - Calculation using Shift increments6-CMR-6 13C Chemical Shift Effects on sp2 and sp Carbons6-CMR-7 One-Bond Carbon-Proton Coupling (1JC-H)6-CMR-8 Two- and Three-Bond Carbon-Proton Coupling (2JC-H, 3JC-H)6-CMR-9 Long Range C-H Couplings6-CMR-10 Assignment of Carbon-13 NMR Signals

_________________________________________

6.1 Measuring 13C NMR Spectra

13C6 I = ½ Natural abundance: 1.1% 12C6 I = 0 Natural abundance: 98.9%

Spectrometer Frequency:

1H 100.0 200.0 300.0 360.0 500.0 600.0 MHz13C 25.14 50.28 75.4 90.5 125.7 150.8 MHz

Sensitivity

The low natural abundance of 13C has three principal consequences:

1. It is much harder to obtain 13C than 1H NMR spectra. Whereas an 1H spectrum on 1 mg of a typicalorganic compound can usually be obtained in 15-30 minutes of spectrometer time, it might take several hoursto obtain a much lower quality 13C spectrum on the same sample. Thus, unless your compound does nothave useful 1H signals, you will usually measure many more 1H than 13C NMR spectra.

Inherent sensitivity: 1.59% (1H = 100). Sens. = ((C/(H)3

Actual sensitivity: 0.017% (1/5700)

2. The effects of 13C nuclei on spectra of other nuclei (e.g., 1H, 19F, 31P) are very minor. Each protonsignal is surrounded by 13C satellites separated by 1JC-H (typically 120-150 Hz), each with an intensity of 0.5%of the central peak. The central peak arises from the 98.9% of 12C which is NMR transparent. The 13Csatellites can be readily detected for sharp peaks.

3. Coupling between carbons (JCC) is not usually observed, because two adjacent 13C nuclei occur inonly 1.1% of the carbons. There are thus 13C satellites on the carbon peaks (each about 0.5% of the intensityof the main peak), in the same way that there are 13C satellites on proton spectra. The couplings can bemeasured directly with some difficulty by accumulating many scans on a very concentrated sample, but abetter way is to use one of the multi-pulse 2D experiments (e.g., INADEQUATE) which nulls the central peaksdue to adjacent 12C atoms. Even so, large samples and long acquisition times are required.

6-CMR-1.2

Se130.96 (JSe-C = 102.8 Hz)

132.67 (JSe-C = 11.5 Hz)

129.01 (JSe-C = 2.7 Hz)

126.97 (JSe-C < 2 Hz)

25.1 MHz 13C NMR Spectrum in CDCl3

133 132 131 130 129 128 127 126 125ppm

C4

C3

C1

C2

Decoupling

Most 13C NMR spectra are very complex. The methyl carbon of an ethoxy group will appear as a largequartet, with each line further split into triplets. Even in fairly simple molecules each carbon may be coupledto a number of different protons. In complicated molecules, these multiplets overlap badly, and may beimpossible to analyze.

1JCH = 100-250 Hz2,3JCH . 2-10 Hz

To simplify 13C spectra, we usually use some form of broadband decoupling (noise decoupling) to removethe effect of proton couplings. This also dramatically increases signal intensity, since now all carbons appearas singlets (assuming absence of other spin 1/2 nuclei like 31P or 19F). The increase is actually greater by afactor of 2-3 than would be predicted on the basis of simply combining the 13C multiplet intensities becausethe Nuclear Overhauser Effect causes additional increases in signal intensity. More about this in Section 8.

Figure 6-1.1. 13C NMR spectrum of diphenyl selenide in CDCl 3.

6-CMR-1.3

Figure 6-1.1 shows the fully coupled and decoupled 13C NMR spectra of diphenyl selenide. Althoughthe large 1JC-H splittings are easy to identify, the fine structure of the individual multiplets is not first order (e.g.,only the para carbon has an approximately centrosymmetric pattern, the others do not). This is because weare looking at the X part of an AA'BB'CX pattern (ABC are protons, X is carbon). Since the AA' and BB’parts are strongly coupled, we see the usual complex effects of "virtual coupling" on the X resonance (seeSection 5-15, 5-16). When noise {1H} decoupling is applied, the spectrum becomes much more intense, andonly 4 lines remain, one for each carbon.

In this compound we have a second magnetically active nucleus (77Se, natural abundance 7.5%, I =1/2), so each of the 13C peaks has 77Se satellites, although coupling between C-4 and the selenium is toosmall to detect (the satellites are under the main peak).

Attached Proton Tests

The disadvantage of obtaining fully decoupled spectra is that all information about how many protonsare coupled to each carbon is lost. Since information about the number and position of C, CH, CH2 and CH3

carbons is valuable in making structure and spectral assignments, several types of experiments to determine13C multiplicities have been developed (undecoupled spectra are not usually used because of extensivesignal overlap and poor signal-to-noise).

Single Frequency Off-Resonance Decoupling (SFORD).

This is the oldest method for determining attached protons, and has been largely replaced by moreefficient methods. In this technique powerful single frequency proton decoupling is applied 500-2000 Hzupfield or downfield of the proton chemical shifts in the sample. All C-H couplings are reduced in proportionto:

1. The distance (*) from the decoupler frequency to the proton position,2. The power of the decoupler.Typical experiments would reduce the normal one-bond couplings of 125-250 Hz to perhaps 12-20 Hz,

and the longer range couplings to <1 Hz. The spectrum now appears as a series of singlets, doublets, tripletsand quartet depending on whether the carbon is quaternary, or has one, two or three protons attached. Fig. 6-2 illustrates the effect of decoupler offset on the 13C NMR spectrum of methanol.

Figure 6-1.2. Methyl carbon quartet of methanol obtained for various offsets of the decoupler frequency fromthe 1H chemical shift of methanol (from Wehrli and Wirthlin).

6-CMR-1.4

Some difficulties with this technique are:1. Sensitivity is not very good.2. Multiplets are not always clean.3. For complex molecules, some regions of the spectrum can become hopelessly crowded.

6-CMR-1.5

90 80 70 60 50 40 30 20 10 0ppm

APT4.0 msecdelay (1/2J)

7.5 msecdelay (1/J)

APT

Normal

CO2H

OH

O

13C NMR of Triterpene

Spectral Editing

There are a number of multipulse experiments which group the signals in a 13C NMR spectrumaccording to the number of attached protons.

J-Modulated Spectra. This is the most primitive form of spectral editing. By placing a suitable delaytime between the pulse and the beginning of the acquisition, spectra are obtained in which C and CH2 groupsare positive, and CH and CH3 are negative.

In this experiment, after the pulse there is a short delay, during which the decoupler is turned off, andthe 13C NMR spectrum becomes modulated by the CH coupling frequency. After the delay the decoupler isturned on, and the FID is recorded. If the delay is 1/J then the quaternary and CH2 carbons are positive, andthe CH and CH3 signals are negative. If the delay is 1/2J all peaks except quaternary are nulled. More on thisexperiment in Sect 8-Tech-9.1.

1/40

6-CMR-1.6

120 100 80 60 40 20ppm

CD

Cl 3

Normal

DEPT-135

DEPT-90

OH

Note absenceof quaternary carbons

Small amountof "leakage"

CH only

CH, CH3 positiveCH2 negative

DEPT (Distortionless Enhancement of Polarization Transfer): The DEPT technique has proven superiorto others in providing information on attached protons reliably, efficiently and with high selectivity. It is aproton-carbon polarization transfer method, so DEPT spectra are actually more sensitive than normalacquisitions. A set of spectra with pulse delays adjusted for B/2 (DEPT-90) and 3B/4 (DEPT-135) are taken. The DEPT-90 spectrum shows only CH carbons, the DEPT-135 shows positive CH3 and CH, and negativeCH2 signals. It is important to understand that the appearance of positive and negative signals can bereversed by phasing, so it is necessary to have some way of determining whether the spectrum has beenphased for CH2 positive or negative. Quaternary carbons are invisible (Fig. 6-1.3).

"Leakage" can occur in DEPT-90 spectra because 1JC-H varies as a function of environment, and thetechnique assumes that all 1JC-H are identical. This can result in small peaks for CH2 and CH3 signals, whichshould have zero intensity. For similar reasons the C-H of terminal acetylenes (C/C-H) will show anomalousintensities in DEPT spectra (either nulled or very small in DEPT-90, or present in DEPT-135) because the C-H coupling is much larger (around 250 Hz) than the normal value of 125 Hz for which the DEPT experiment isusually parameterized.

Figure 6-1.3. The normal 13C NMR spectrum and a typical set of DEPT spectra of an alkyne. Note theabsence of the quaternary alkyne carbons in the DEPT spectra, and the presence of small peaks for the CH2

and CH3 signals in the DEPT-90 spectrum, which, in principle, should have only CH signals.

1/38

6-CMR-2.1

6.2 Referencing C-13 NMR Spectra

Tetramethylsilane (TMS) is the primary reference for C-13 spectra. The relatively low sensitivity of C-13NMR requires the addition of substantial amounts of TMS, so it is common to use solvent peaks as asecondary reference. Below are listed chemical shifts of several common solvents used in NMRspectroscopy. Note that isotope shifts are quite large in C-13 NMR, so separate values are reported for thedeuterated and protonated solvents (from Levy, J. Magn. Res. 1972, 6, 143; Reich unpublished work).

Compound (solvent) Protio compound (*) Per-deutero compound (*)

Cyclohexane 27.51 26.06Acetone 30.43 29.22Dimethyl Sulfoxide 40.48 39.56Dichloromethane 54.02 53.61Dioxane 67.40Tetrahydrofuran 68.12 26.30Ether 66.23 15.58Chloroform 77.17 76.91Carbon tetrachloride 95.99Benzene 128.53 127.96Acetic Acid (*CO) 178.27Carbon Disulfide 192.8Carbon Disulfide external 193.7 9/32

6-CMR-3.1

electronicenergylevels

HOMO

LUMO

ΔE

90°

Molecular orbital symmetryrequirement for σp

LUMO

HOMO:

6.3 Origin of Chemical Shifts

There are three principal effects which control NMR chemical shifts: diamagnetic, paramagnetic andneighboring group anisotropy:

Fd Diamagnetic term - electron circulation within an s orbital causes shifts to low frequency (upfield,shielding) of the local nucleus. This term dominates proton chemical shifts, it changes in a more or lesspredictable way with electron density and hybridization so that chemists feel comfortable in rationalizing manyof the effects observed.

Fn Neighboring group anisotropy - diamagnetic circulation causes local magnetic fields, which willhave an effect on neighboring nuclei. These effects are on the order of at most a few ppm, and are constant(same size in ppm) independent of the nucleus which is being affected. Thus, anisotropy effects areimportant in proton NMR, where they are significant when compared with other effects, but are usuallyinsignificant for nuclei (such as 13C) that have shift ranges of hundreds of ppm.

Fp Paramagnetic term - circulation of electrons between ground and excited states of p orbitalsinduced by the external magnetic field causes large high-frequency (downfield, deshielding) shifts of nearbynuclei. Although the forces exerted on electrons by the magnetic field are small compared to the energydifferences between ground and exited states, the shifts are very large, and even minuscule amount ofparamagnetic circulation cause very large chemical shifts. All nuclei heavier than 1H (with the possibleexception of 6Li and 7Li) have Fp as the principal chemical shift effect.

The Paramagnetic Term: It is fortunate that Fp often responds in the same way to electron densityeffect as does Fd, since this results in parallel 1H and 13C chemical shift features. However, a qualitativedescription of the relationship between * and molecular features must consider two factors which affect Fp

and Fd quite differently and may cause very counterintuitive behavior: the 1/)E dependence, and orbitalsymmetry effects.

(1) Since we are dealing with promotion of electrons from ground to excited states, the energyseparation between filled and empty orbitals (HOMO-LUMO separation) has an important effect, i.e. low-lyingunoccupied molecular orbitals of the correct symmetry (see (2) below) result in large paramagnetic (high-frequency) shifts.

Fp % E(1/)E) where )E is the energy separation.

(2) The orbital symmetry relationship between the orbitals determines whether circulation between anypair of filled and empty orbitals can occur. Since the closest pair of filled and empty orbitals is the HOMO andLUMO, we restrict our consideration to these. In order for paramagnetic electron circulation(mixing betweenground and excited states) to occur, the HOMO and LUMO orbitals must have the same symmetry after a 90°rotation. Thus if the HOMO and LUMO are p-orbitals which are perpendicular to each other, Fp will be large. An especially striking example is provided by the N-protonation of pyridine (Breitmeier, Spohn Tetrahedron1973, 29, 1145). The C-3,5 and C-4 shifts move to high frequency, as expected from the increase in positive

6-CMR-3.2

NSi:

N

tBu

tBu

NSi:

N

tBu

tBu

δ22 = -2.1

δ33 = -4.5

δ11 = 350.7δSi = 114.7(in solution)

NC:

N

Me

Me

NC:

N

tBu

tBu

δ22 = 82

δ33 = 177

δ11 = 370δC = 213.7

NC H

N

Me

Me

+

δ 135.0in solution solid state

charge at nitrogen. On the other hand, the C-2,6 shifts move to low frequency. The latter are close to the N-lone pair (the HOMO in the Figure above) which has a proper symmetry relationship with the B* orbitals of thearomatic ring, and are thus most affected by the reduction of paramagnetic electron circulation on protonationat nitrogen. The 15N chemical shift also moves to lower frequency on protonation.

A very similar example of these chemical shift effects is provided by the comparison between methyllithiumand phenyllithium. Here the C-Li bond plays the same role as the N-lone pair in pyridine. The conversion ofCH4 to CH3Li causes a low-frequency shift, whereas the conversion of C6H5-H to C6H5-Li causes a large high-frequency shift of the ipso carbon.

The individual vector components of the chemical shift can provide additional insights into the effect. The three components of the 13C chemical shift tensors of the carbene below, measured by solid state NMRtechniques (Arduengo et. al J. Am. Chem. Soc. 1994, 116, 6361) are shown. The *11 component whichdominates the strong high frequency chemical shift of the carbene carbon (213.7 ppm in solution) is the oneperpendicular to the sp2 lone pair on carbon and the empty p orbital, a situation very similar to that in PhLiabove. The chemical shifts for all heavy nuclei are dominated by the paramagnetic term. The threecomponents of the 29Si (I = ½) chemical shift of the silylene below (R. West, G. Buffy, M. Haaf, T. Mueller, B.Gehrhus, M. F. Lappert J. Am. Chem. Soc. 1998, 120, 1637) show a similar pattern.

CH3Li

-13.2 ppmLi

199.7 ppm

The downfield shift of C-1 in PhLiis the result of a favorableHOMO-LUMO symmetry

relationship and a small ΔE.

Li

HOMO

LUMO

:

CH4

-2.1 ppm H

128.5 ppm

Δδ -11.2 Δδ +71.2

6-CMR-3.3

0 -2020406080100120140160180200220δ

AlkanesR3C-O-

C=C

XC

OC

OC

NC

C

C C

C N

0 -2020406080100

77.2

CDCl3

73.2

HC≡CH

50.2

MeOHMe3N

47.6

O

39.7 27.8

MeCl

25.210.3

MeBr

Me-Me

5.9 0.0

Me4Si

-2.1

CH4

MeI

-20.0-13.2

MeLi

55.6

+NMe4

88.0

HOCH=CH2

δ

-2.9

H

HC C O

2.5

100120140160180200220

211.7

CH2=C=CH2

206.2

O

169.9

OMe

128.5 123.2

CH2=CH2

117.7

NC-Me

158.2

H2C=N-Me

149.0

HOCH=CH2

δ

127.2194.0

H

HO

O

C

-101030507090

210 190 170 150 130 110

CH3CH2OH

58.264.6

Me2CHOH

69.6

Me3COH

H

O

121.7

O=C=NMe

156.7

C -≡N

+-Me

H H

NMeMe +

167.9199.6

73.9

CH2=C=CH2

18.2

N

H

CO3H-

160

⊕

177.0164.9

NH2H

O

Li

102.6

23.1

CH2=N2

61.2

Me2O

6.5

MeSH

113.9

HC(OEt)3

170.8

P≡C-Me

The C-13 Chemical Shift Scale. The vast majority of 13C chemical shifts fall in the range of 0-220 ppm(Me4Si = 0.0). A rough grouping can be made according to the hybridization of the carbon atom, with sp3

carbons at lowest frequency (0-70 ppm); sp carbons of the acetylene type at 70-100 ppm, sp2 carbons(bonded to C and H) at 100-150 ppm, sp2 carbons of carbonyl groups at 160-220 ppm, and sp carbons of theallene type at 210-220 ppm. The chemical shift ranges given in the graph below are not the complete range,since unusual combinations of substituents can lead to shifts outside the ranges given.

An important point to note is that sp2 carbons of the double bond type cannot be distinguished fromthose of the aromatic type. This is in contrast to the situation with proton NMR, where the distinction betweenprotons bonded to vinyl carbons and aromatic carbons can usually be made easily. Some specific chemicalshifts of parent members of the various functional groups are given below. The chemical shifts of more highlysubstituted compounds will generally be to higher frequency.

6-CMR-3.4

6-CMR-4.1

6.4 13C Chemical Shift Effects on sp3 Carbons Reich Chem 605

Changes in 13C chemical shifts are usually discussed in terms of substituent perturbations ()*) on thechemical shifts of simpler model compounds. The effects are largest for substituent changes at the carbonitself (" effects) but sizable substituent effects are seen at the $, (, and sometimes even the * position. Thesubstituent effects of a number of common functional groups are summarized below. Roughly speaking, the "-effects are strongly dependent on electronegativity of the substituent, the $-effects are all to higher frequency,and fairly similar in size, and (-effects are all to lower frequency (except for organometallic substituents) and arein part the result of steric interactions.

)* (H 6 X) Positive )* are to high frequency (Downfield)

" $ (X (H-C 6 X-C) (H-CC 6 X-CC) (H-CCC 6 X-CCC)

CH3- +9.4 ("C) +9.5 ($C) -2.4CH3CH2- +18.8 ("C+$C) +7.0 ($+() -2.1CH2=CH- +20.4 +6.3 -2.9

HC/C- +4.5 +5.2 -3.5HO2C- +20.8 +2.7 -2.3N/C- +3.6 +2.0 -3.1H2N- +29.1 +11.8 -4.5O2N- +64.5 +3.1 -4.7HO- +49.4 ("O) +11.2 ($O) -4.7

CH3O- +58.7 ("O+$C) +6.5 ($O+(C) -6.0HS- +11.4 ("S) +12.1 ($S) -2.7

CH3S- +20.9 ("S+$C) +6.4 ($S+(C) -3.0F- +70.1 +7.4 -6.7

Cl- +31.3 +10.2 -4.6Br- +20.0 +10.4 -3.3

I- -6.1 +11.1 -0.8(CH3)3Sn- -1.7 ("Sn+3$C) +4.1 +0.9

Li- -1.4 +6.9 +5.4

1. "-Substituent Effects

The "-effect results from the replacement of a directly bonded H by an X group (*C-H 6 *C-X). Theprincipal factor influencing most "-substituent effects is the electronegativity of the attached atom. Thus, forelectronegative atoms we see strong high-frequency shifts (e.g., CH3OH * 48.8), for electropositivesubstituents, low-frequency shifts. For complex groups we must consider $ and ( interactions as well (e.g., X =OCH2CH3 is "O + $C + (C). As molecules get more crowded, both the " and $ shifts become smaller (branchingeffects).

Me-H -2.6Me-F 75.2 Me-O-Me 61.2 Me|4C 31.5Me-Cl 24.6 Me-S-Me 18.2 Me|4Si 0.0Me-Br 10.2 Me-Se-Me 10.4 Me|4Ge -1.9Me-I -20.2 Me-Te-Me -21.5 Me|4Sn -9.1

Me|4Pb -3.1

6-CMR-4.2

H CH3 I CH3

-24.0

CI4-292.4-2.1

CBr4

-29.4

CCl498.6

Te(CH3)2

-21.5Ph

I

I-25.8

-13.8

-0.8

-0.9

-0.6

-0.1

+0.1

H -0.7

-0.7

-12.9

-12.9

-0.7

-0.7

12.7

21.4

19.2

19.2

21.4

12.7

79.0

79.0

Δδ:(from octane)

H

68.7

84.218.6

29.0

28.9

31.8

22.9

13.6

22.7

32.1

29.4

29.4

32.1

22.7

13.6

Δδ:(from octane)

δ: δ:

+1.8

-0.4

-0.5

-0.2

0

0

13.6

22.7

32.1

29.4

29.4

32.1

22.7

13.6

-0.1

+2.9

+2.8

-0.1

+0.5

0

+0.3-2.3

-2.9

0

-0.4

-0.1

-0.4

+0.1

+2.7

+2.7

+0.1

-0.4

+0.3+0.2-2.8

-2.8

+0.2

+0.3

Δδ:(from octane)δ:

27.9 -2.4 -1.6

26.5 +6.3 +15.1-2.9 +2.3 23.2 +7.0

28.5 -0.1 -0.4+8.3

+6.8+3.0 +9.0-6.2-3.2 +0.6

-4.8 +1.0

Δδ:

Δδ:

Δδ:

Δδ:

Δδ:

-1.7

+3.0

-5.6

Heavy-Atom "-Effect: The correlation with electronegativity works well for first, and to some extent,second row atoms, but there is a "heavy atom" effect which runs counter to electronegativity. Thus iodine--bearing carbons of all types are strongly shifted to lower frequency. Similarly for C-Te signals.

"-Effect of Triple Bonds: Triple bonds (X = acetylene, nitrile) as substituents also cause unexpectedlylarge low-frequency shifts (e.g., CH3-CN * 0.3, CH3C/CH at -1.9, compare with CH3CH=CH2 at 18.7). Thelarge diamagnetic circulation in the triple bond may be responsible for these shifts. Below is a comparison of thechemical shifts of octane versus 1-octyne and 4-octyne.

"-Effect of Double Bonds. Unlike the situation with proton NMR, where double bonds cause relativelylarge shifts of allylic protons, the 13C shifts of carbons directly attached to double bonds are changed relativelylittle. Terminal vinyl groups or trans double bonds cause small high-frequency shifts, cis-substituted ones causelow-frequency shifts. The latter effect is a manifestation of the (-effect (see below).

Cycloalkenes sometimes show larger double bond substituent effects, but the size and even direction iserratic, as can be seen from the 3,4,5,6 and 7-membered ring examples below..

6-CMR-4.3

26.5

O

27.9 +14.1

O

+11.7Δδ: Δδ:

O

O O16.3Δδ: +28.9

+41.6

C

X

C

X

This carbon shift will be to lower frequency (upfield)

H H

The γ-effect:X can be C, O, N, halogen, S, etc

17.6 12.1

OH

17.725.6

OCH3

12.5

OCH3

8.817.6

137.5

12.9

132.2

NNHTs

17.125.3

NOH

14.721.5

NOH

25.731.9

H

82.575.8

110.1141.3

H

80.382.1

109.4140.3

15.918.6

Carbonyl substituents, on the other hand, do cause significant high-frequency shifts.

2. $-Substituent Effects

Replacement of H on an adjacent atom by an X group (*C-C-H 6 *C-C-X) is a $-substituent effect. Almostall substituents cause substantial high-frequency $-shifts (usually ~9 ppm, smaller if crowded), and these arenot very dependent on the electronegativity of the perturbing substituent. As for the "-effect, we have toconsider simultaneous (-shifts (e.g., X = CH2-CH3 is a $C + (C interaction). The origins of $ shifts are not wellunderstood.

3. (-Substituent Effects

A gamma effect is defined as the replacement of an H by X on the second atom (*C-C-C-H 6 *C-C-C-X). The (-effect is seen for virtually all X-substituents, provided the (-carbon has an attached hydrogen. There is astrong proximity component (syn (-effect, (-gauche effect) , which results in a dependence on stereochemistry. Syn (-effects are to low-frequency ()* is negative). The effect is largely independent of the nature of theintervening groups. For X = CH3, the effect is upfield by ~6 ppm if X and *C are close in space (gauche oreclipsed). For acyclic systems, the (C-effect is approximately -2 ppm, reflecting the fraction of the gaucheconformation. The (-effect is extensively used for stereochemical assignments. If a (-atom is close to a carbonin one isomer, and remote in another, then that carbon will be upfield in the first isomer, as illustrated below (fora theoretical analysis see: Kleinpeter, E.; Seidl, P. R. J. Phys. Org. Chem. 2005, 18, 272).

The effect is valuable for distinguishing E and Z isomers of alkenes, especially trisubstituted ones, whereother techniques (such as 3JHH) are not available. A CH3 (or other carbon group) which is cis to a substituentwill be to lower frequency (upfield) of the isomer in which the carbon substituent is cis to a hydrogen The effectsare very similar across C=N double bonds.

6-CMR-4.4

135.5

48.8

25.5

12.5

132.425.9

14.4

137.821.8Si

CH3

H

-7.3

39.0

31.1

23.2Si

H

CH3-4.4

37.5

30.7

25.1 Si

CH3

CH3

H

15.6

-7.0Si

CH3

H

CH3

17.3

-2.3

O 12.9 O

17.6

N N

58.4

N N

56.0

N N

54.9 Cl

22.5

Cl

18.2

S SO

20.428.8

S

32.1 29.4

O OS

S22.0

S

O

S13.7

N26.3 N+

O-

21.1SS

30.9

SS

27.0H

28.0

35.5

22.1

29.3

26.2

26.2

23.8

18.7

OH

F

H

H

H

H

F

87.331.821.5

47.8

91.533.525.3

47.3

26.927.427.9

48.7

H

CH332.636.0

27.7

48.0

OH

H

H

OH

68.733.420.9

48.1

70.936.025.6

47.2

CH3

H27.033.0

21.4

49.2

Stereochemical relationships in a variety of cyclic compounds can be deduced from the presence orabsence of (-gauche interactions.

Some substituents also cause anti (-effects, i.e. when X and the (-carbon are antiperiplanar. Alkylsubstituents show very small antiperiplanar (-shifts, but for X = O, N, or F significant effects are seen. Anti (-effects are almost always smaller than gauche (-effects and they can be either to lower or higher frequencydepending an a variety of structural factors. For example, if the perturbing substituent is at a quaternary centerin a cyclohexane (as in 1-methyl-1X-cyclohexanes) then the anti (-effects are to high frequency (downfield),whereas they are to lower frequency (upfield) when the substituent at C-1 is H (Schneider, Hoppen J. Org.Chem. 1978, 43, 3866).

6-CMR-4.5

OOR1

R2

HH

syn

antiOO

H

H

R2

R1

δ ~20

δ ~30

δ ~25

TBSO

OO

SPh

POMO

OO

SnBu3

30.02, 19.85

24.48, 24.44

OO

OO

30.13, 19.68

24.50, 24.26

OH

OOR1

H

HR2

Ph

OH OHsyn

anti

O

HOPh

MeH

O

HOPhMe

HO

HOPh

HH

HMe

H

H

HH

74.1

47.0

67.823.6

Ph

OH OH

70.946.7

64.723.3

Σ (C1 + C3) = 141.9

Σ (C1 + C3) = 135.6

Ph

O O

73.3

45.0

68.123.0

Ph

O O

70.5

40.4

64.322.4

Σ (C1 + C3) = 141.4

Σ (C1 + C3) = 134.8

B

Ph

B

Phγ-gauche interaction

Determination of Acyclic Syn-Anti Stereochemistry. The (-interactions present in axial substituents providethe basis for configurational assignment of syn and anti 1,3-diols using the methyl group chemical shifts of theiracetonide derivatives. In the syn isomers of the acetonides the 6-membered ring has a well-defined chairconformation, with both R-substituents equatorial. This places one of the acetonide methyl groups axial, theother equatorial, leading to a ca 10 ppm shift difference between the two methyls. The anti acetonides have atwist boat conformation, which places the two methyls in a very similar environment, and hence there is a verysmall chemical shift differences between them (Rychnovsky Tetrahedron Lett. 1990, 31, 945).

In addition to providing configurational information for systems with well-defined gauche/anti or cis/transrelationships as in the systems above, the generalized upfield shifts of all four of the atoms involved in gaucheinteractions can also be the basis for stereochemical assignments of diastereomeric pairs in acyclic systems.Thus syn and anti 1,3-diols show a well defined upfield shift for C-O carbons in the anti compared to the synisomer. The rationale for this behavior is that intramolecularly H-bonded conformations place a substituent in apseudo-axial orientation in the anti isomers, hence upfield shifts, whereas all substituents can be equatorial inthe syn isomer. Similar shift effects are found in boronic acid esters, where this conformational effect is morerigorously enforced. The effect is easily quantitated by summing the * values of the two C-O carbons - the onewith lower E will be the anti isomer (Hoffmann Tetrahedron Lett. 1985, 26, 1643; Chem. Ber. 1985, 218, 3980;for applications see: Pelter Tetrahedron 1993, 49, 3007).

The stereochemistry of aldol adducts ($ -hydroxy ketones and esters) can also be determined from 13Cchemical shifts by application of similar arguments (Heathcock, Pirrung, Sohn J. Org. Chem. 1979, 44, 4294).The stereochemistry of 1,2-diols can also be determined from analysis of 13C shifts using related arguments.

6-CMR-4.6

12.312.6

12.913.4

15.515.1

HO

OHδ(Δδ = 2.5)

(Δδ = 3.2)(Δδ 0.6 ppm)

(Δδ 0.8 ppm)

O O

20.6

29.5 32.2

22.6

28.731.8 31.8

Unavoidable δ-effect

22.6 27.2ε

α β γ

δ

A downfield ε-shift

16.1

-2.9

23.3

O40.8

O59.2

O72.8

NH

28.7

NH

38.2

N45.3

H

S

S18.2

S27.5

18.1

133.1

108.7

30.2

2.3

115.1 18.7

137.2

O NH

S26.5

23.3

32.8

130.8

68.6

26.7

47.1

25.7

31.7

31.2

19.323.1 29.7

Ring Size Effects

O NH

S27.0

25.4

23.0 69.5

27.7

24.9

47.5

27.3

25.2

29.9

27.826.6

127.4

4. *-Substituent Effects

Remote substituents effects across single bonds are small (* 0.2 ppm, , < 0.1 ppm) unless groups arejammed into each other, (e.g., cis 1,3-diaxial) in which case downfield shifts of several ppm are seen (for atheoretical analysis see: Kleinpeter, E.; Seidl, P. R. J. Phys. Org. Chem. 2005, 18, 272).

5. 3-Membered Rings

Cyclopropanes, cyclopropenes, epoxides, aziridines and other 3-membered rings tend to showpronounced upfield shifts. Cyclobutanes and four-membered heterocycles do not show similar effects.

6. Neighboring Group Anisotropy Effects

These effects, which play such an important role in 1H NMR spectroscopy, are usually overshadowed byother effects in heavier nuclei. This is because anisotropy effects are the same size (in ppm) for all nuclei. Avery striking 2 ppm shift in a proton NMR spectrum will be an (almost) insignificant 2 ppm shift for a carbon atthe same position in the molecule (e.g.; it is often trivial to distinguish vinyl from aromatic protons from theirchemical shift alone, this distinction cannot be made in the 13C spectrum).

6-CMR-5.1

CH3

CH3

CH3

CH2

CH315.6

5.9 15.69.7β

CH3

CHCH3

CH324.3

24.38.7β

CH3

C(CH3)2

CH331.5

31.57.2β

CH4-2.1 8.0α

5.9 10.2α

9.1 α 2.7 α16.1 25.2 27.9

CH3

CH2

CH315.6

15.6 CH2

CH2

CH313.2

24.39.4α

8.9 β16.1 25.2

CH3

-2.4 γ

13.2

CHCH3

CH2

CH311.5

29.94.9α

6.8 β31.8

CH3

-1.7 γ

22.08.8β'

C(CH3)2

CH2

CH38.7

30.40.5α

4.9 β36.7

CH3

-2.8 γ

28.96.9β'

C(CH3)2

CHCH3

CH315.9

32.91.5β'

1.4 α38.1

CH3

7.2 β

27.2-1.7γ

CH3

CH36.0 1.4α α

9.0 5.40.0 -6.4

ββ

γγ

-0.2 0.0δ δ

27.8

-2.1 + α + β + 3γ + 1°(2°) = -2.1 + 9.1 + 9.4 - 7.5 + 0 = 8.9

-2.1 + 2α + 3β + 2°(1°) + 2°(4°) = -2.1 + 18.2 + 28.2 + 0 - 7.5 = 36.8

-2.1 + 4α + β + 4°(2°) + 3[4°(1°)] = -2.1 + 36.4 + 9.4 - 8.4 - 4.5 = 30.8-2.1 + α + 3β + γ + 1°(4°) = -2.1 + 9.1 + 28.2 - 2.5 - 3.4 = 29.3

CH3

CH2

CCH3CH3

CH3

Calculated by Grant-ChaneyObserved

8.5

36.5

30.328.7

Error

+0.4

+0.3

+0.5+0.6

6.5 Alkane 13C Chemical Shift Calculations

Analysis of the 13C chemical shift of acyclic alkanes led to the first accurate method for the prediction ofchemical shifts. Grant-Chaney Calculations (J. Am. Chem. Soc. 1964, 86, 2984, plus later improvements) arebased on the observation that, in addition to ", $, (, and * effects, there are predictable branching effects, suchthat the " and $, effects, which are nearly constant for linear molecules, become progressively smaller whenthere are nearby tertiary and quaternary carbons. This is illustrated in the graphic below.

The Grant-Chaney system uses a constant set of "-, parameters, but then applies branching correctionswhich depend on the number of adjacent branched carbons. The method is quite flexible, and provides a basisfor accurately predicting chemical shifts of most alkanes, and can be extended to include other classes ofmolecules, using model systems close in structure to the molecule of interest.

*C = -2.1 + EniAi + branching corrections (in * from TMS)

Ai Branching Corrections (1°(3°) = a CH3 carbon (1°) with a CHR2 carbon (3°) attached to it).

" +9.1 1°(1°) 0 2°(1°) 0 3°(1°) 0 4°(1°) -1.5$ +9.4 1°(2°) 0 2°(2°) 0 3°(2°) -3.7 4°(2°) -8.4( -2.5 1°(3°) -1.1 2°(3°) -2.5 3°(3°) -9.5 4°(3°) -15.0* +0.3 1°(4°) -3.4 2°(4°) -7.5 3°(4°) -15.0 4°(4°) -25.0, +0.1

In this system, a primary carbon will have one branching correction, a secondary two, a tertiary three, and aquaternary carbon will have four branching corrections (although some may be zero).

6-CMR-5.2

αβ

γ αβ

γ

R

βγ

n iso

α β γ

n iso n isoR

CH3 + 9 + 6 +10 + 8 - 2

CO2- +21 +16 + 3 + 2 - 2

COOH +25 +20 + 5 + 3 - 2COOR +20 +17 + 3 + 2 - 2COCl +33 +28 + 2 - 2COR +30 +24 + 1 + 1 - 2CHO +31 0 - 2

C≡CH2 + 5 - + 6 - - 3

OH +48 +41 +10 + 8 - 5OR +58 +51 + 8 + 5 - 4OCOR +51 +45 + 6 + 5 - 3

C≡N + 4 + 1 + 3 + 3 - 3

R

CH=CH21 +21 - + 7 - - 2

Phenyl +23 +17 + 9 + 7 - 2

α β γ

n iso n isoR

NH2 +29 +24 +11 +10 - 5NH3

+ +26 +24 + 8 + 6 - 5NHR +37 +31 + 8 + 6 - 4NR2 +42 + 6 - 3NO2 +63 +57 + 4 + 4 - 5

SH +11 +11 +12 +11 - 4SR +20 + 7 - 3

F +68 +63 + 9 + 6 - 4Cl +31 +32 +11 +10 - 4Br +20 +18 +11 +10 - 3I - 6 + 4 +11 +12 - 1

11-Octene. 21-Octyne. 3n-, s-BuLi

SnMe3 - 2 - + 4 - -Li3 - 2 - 9 + 7 + 6 + 6

S(O)Me +42 - 1 - 3

Ph

CH2

CH

CH3

CH3

CH3

CH

CH3

CH3

24.6 + α-Ph-n (+23) = 47.6

23.3 + β-Ph-n (+9) = 32.3

Observed45.3

30.1

Model Calculated Error2.3

2.3

CO2CH3

CH

CH3

Br

CO2CH3

CH2

CH3

27.3 + α-Br-iso(+18) = 45.3

Observed

21.2

39.8

Model

9.0 + β-Br-iso(+10) = 19

Calculated

CO2CH3

CH

CH3

BrCH2

CH3

27.5 + α-COOR-iso(+17) = 44

21.2

39.8

19.1 + β-COOR-iso(+2) = 21

Br

5

2

4

0.2

Error

A less extensively parameterized but much more general scheme for the estimation of chemical shifts ofalkanes substituted by a variety of functional groups is given below. Instead of branching parameters, thissystem uses two types of " and $ parameters - those for the substituent at the end of the chain (n) and those inwhich the substituent is in the middle of it (iso). The smaller values of the iso versus the n " and $ parameterscorrespond to the branching corrections of the Grant-Chaney system. These parameters are not able to assistin estimation of shifts for quaternary carbons, and carbons attached to quaternary carbons. One would expectthis much simpler system to produce poorer results, and that is what is observed. It is permissible to mix Grant-Chaney and the n-iso systems in the same calculation, as long as the same effect is not counted twice

To use this system, the chemical shifts of an appropriate model system are corrected for the presence ofsubstituents by using the parameters in the table. For example, to estimate the C-2 chemical shift of 1-phenyl-2-methylpropane we use the C-2 shift of isobutane (23.3) and add the $-Ph-n increment (+9), giving 32.3(observed 30.1). Similarly, C-1 would use C-1 of isobutane (24.6) and "-Ph-n increment (+23) giving 47.6 (obs45.3). In this case the shifts are estimated with reasonable accuracy.

However, attempts to use this method to calculate the C-2 shift of methyl 2-bromopropionate are a little lesssuccessful. Using methyl propionate as a model, C-2 is in error by 5 ppm, whereas using bromoethane asmodel the error is 4 ppm.

6-CMR-5.3

Chemical Shift Effects Across Heteroatoms

H

N

CH2

CH2

CH2

CH2

CH2

CH3

H

42.7

34.6

27.1

32.3

23.2

14.2

9.7

-4.1

0.4

CH3

N

CH2

CH2

CH2

CH2

CH2

CH3

H

52.4

30.5

27.6

32.4

23.2

14.2

7.8

-2.2

0.0

CH3

N

CH2

CH2

CH2

CH2

CH2

CH3

CH3

60.1

28.3

27.6

32.3

23.2

14.3

36.7 45.6

β

γ

δ

β

γ

δ

7.8 β

DjerassiJACS-73-3711

CH3

O

H

CH3

O

CH3 60.0

49.3 60.010.7 β

8.0

CH3

O

CH2

CH3

68.0

15.0

57.9

α

-2.1 γ

Substituent Effects Across Heteroatoms. The Grant-Chaney $ and ( substituent parameters seem towork remarkably well even across heteroatoms like N (in amines) and O (in ethers).

6-CMR-5.4

HO

H

H

H

δcalc = -2.1 + 2α + 3β + 3γ + 5 δ + 2°(2°) + 2°(3°) = 35.836.7

28.3

δcalc = -2.1 + 3α + 1β + 1γ + 1δ + 2ε + 3°(1°) + 3°(1°) + 3°(2°) = 28.9δobs = 28.3, error = 0.6 ppm

From methane:

From methane:

Perturbation

28.323.3

δcalc = 23.3 + 1β + 1γ + 1δ + 2ε - 3°(1°) + 3°(2°) = 27.0

δobs = 36.7, error = 0.9 ppm

δobs = 28.3, error = 1.3 ppm

HO

CO2H

OH

OH

Estimate the marked carbon:

Model:31.3

OH

Base: 31.3βOH-iso 8.0γCH2 -2.5δCH2 0.3

37.136.8

Model:OH

OH

36.8

36.2Base: 36.2βvinyl-iso 6.2γCH2 -2.5δCH2 0.3

38.2

δ effect, but can ignore

2°(3°)OH -2.0

Perturbation:

If a parameter is missing,such as the βvinyl-iso needed here,try to estimate it:

16.1 22.3

βvinyl-iso = 22.3 - 16.1 = 6.2

16.3 32.7

αvinyl-iso = 32.7 - 16.3 = 16.4

36.8

Perturbation:

Perturbation:

δcalc

δcalc

δobs = 36.8, error = 0.3 ppm

δobs = 36.8, error = 1.4 ppm

13C Chemical Shift Calculations

1. For acyclic alkanes the Grant-Chaney Parameters are the most effective. They can be used either tocalculate shifts completely (from methane), or by a difference method (perturbation).

2. For more complicated systems, use model compounds as close as possible to the actual structures, andthen apply corrections for any structural differences using Grant-Chaney and other parameters (includingbranching corrections). If needed, a chemical shift parameter can be calculated by comparing two modelcompounds.

6-CMR-6.1

H

I

85.9(Δδ -37.4)

123.2

130.7(7.7)

I

H128.5

94.4(Δδ -34.1)

I

I11.2

153.3

Heavy Atom Effect - α-Effect of Iodine on sp2 Carbons

0.6

II

71.6

HH114.1

139.2

127.4

127.4

129.3

150.7

O

142.5

93.0

N158.6

91.7

O-Li+149.8

102.8

OSiMe3

Δδ from benzene (128.5)

EtOMeO

O

+35.5

-25.1

-2.1

-8.3

+4.9

+6.7

-2.7

+7.9

Δδ from 1,3-butadiene

CH3

-0.1

+0.7

-3.3

OCH3

-14.4

+1.0

-7.7

O Li+

-7.6

+1.7

-14.2

N(CH3)2

-15.6

+1.0

-11.5

0.1

0.0

+4.2

ONO2

-4.8

+0.9

+5.8

OH

-12.7

+1.4

-7.3

+26.9+31.4 +22.6 +9.1+8.9 +20.0+40.5

Δδ:

δ:

Δδ:

H

+6.0

-6.3

H

OEt

+15.0

-51.2

H

SEt

+0.9

+9.7

H

+8.7

+4.9

O

H

SiEt3

+13.7

+22.9

H

+12.8

-5.8

Δδ from acetylene (71.6)

Δδ:

H

-3.4

+12.0

6.6 13C Chemical Shift Effects on sp2 and sp Carbons

The carbons of double and triple bonds also show the ", $ and ( effects which have been wellestablished for saturated carbons. In addition, these carbons show large charge density effects resulting frompartial positive and negative charges in the B-system.

There are also heavy atom effects, seen mostly for carbons bonded to iodine.

1. Conjugation with B-Acceptors and B-Donors

Chemical shifts in B-polarized double and triple bonds follow charge densities in a reasonable way asqualitatively predicted by drawing resonance structures. Thus the $-carbon of ",$-unsaturated carbonylcompounds is downfield, whereas those of enol ethers and enamines is strongly upfield. The normal ", $, (effects discussed in Section 6.4 are seen here also.

Alkynes with first-row element substituents are also polarized in the same sense. However with secondand third row elements more complicated chemical shifts effects come into play.

6-CMR-6.2

δ Observed:

Charge (ρ):

Calc δ:(δ = 128.5+160ρ)

++ + +

207.2 175.0 155 128.5 108.5 102

+ 1/2 + 1/3 + 1/7 0 1/9 1/5

208.5 181.3 150.9 128.5 110.9 96.5

2. Strongly Charged Systems

Carbanions, carbonium ions. Must be very careful here. If charge is localized (F-charge, sp3 systems),effects are quite variable, and frequently the opposite of those in B-systems (e.g., C-1 of PhLi is at * 171.9,CH3Li * -13.2).

On the other hand, if charge is part of a B system, chemical shifts follow charge density rather well (160ppm/e). The various monocyclic aromatic anions and cations show a remarkably consistent set of chemicalshifts, which can be accurately predicted from the excess charge density at each carbon using the formulashown (Prog. Phys. Org. Chem 1976, 12, 229).

6-CMR-6.3

220 210 200 190 180 170 160 150

O204.1

H

O200.4

HO

O178.1

MeO

O170.7

Me2N

O169.6

MeO OMe

O156.5

Cl

O170.5O

198.6

O

O209.1

O219.6

O209.7

Me2N H

O162.6

Me2N H

S188.1

Me2N NMe2

O165.7

O=C=O124.2C=O

181.3

S=C=S192.8209.9

Se=C=Se

H

HCO

194.0

NaO

O180.4

O

O166.1

O

O197.5

H

O193.3

O206.3

O201.4

H

MeO

O166.0

O173.3

MeO

O219.6

O209.8

O209.7

O199.0

O O O

Θ = 0° Θ = 28° Θ = 50°

195.6 199.0 205.5 As the carbonyl is rotated out of conjugation, thechemical shift movesdownfield.

NC120.8

NC117.2

3. Carbonyl Groups

Carbonyl groups appear in two regions: ketones and aldehydes from 190-220 ppm, esters, acids amidesand related carbonyl functions between 150 and 175 ppm. The ketone region is quite distinctive, the onlyreasonably common function that appears around 200 ppm is the central carbon of allenes. There are moreinterferences in the acyl-X region, with occasional double bond and aromatic sp2 carbons, as well as C=Ncarbons appearing in the same range. Unfortunately, the various carboxylic acid derivatives do not havedistinct chemical shifts ranges, so that acids, esters, acid chlorides, amides, anhydrides are not readilydistinguished in the 13C NMR spectrum (this can often be done by examining the carbonyl stretch in the IRspectrum). Even carbonates, ureas, and carbamates are not well separated from the carboxylic acidderivatives.

There are several chemical shift effects of carbonyl groups which are large and consistent enough to beuseful for structure assignment.

Conjugation Effects. Conjugation to a double bond or aromatic ring causes upfield shifts (smaller *value) of 6-10 ppm for all types of carbonyl compounds. The effect is smaller for nitriles, but in the samedirection.

6-CMR-6.4

HO191.0

HO197.2

O

HHO

187.5

OMe

HO190.2

OMeO

206.3

O211.2 OH

O209.2

HOO206.5 F

Hydrogen Bonding Effects. Intramolecular hydrogen bonding causes substantial downfield (larger *value) shifts.

Most carbon signals are quite insensitive to solvent effects. Carbonyl groups are an exception – they movedownfield in protic solvents, an effect also attributed to hydrogen bonding.

6-CMR-6.5

Olefinic Carbon Shifts

(Roberts et al., J. Org. Chem. 1971, 36, 2757; F. W. Wehrli and T. Wirthlin, "Interpretation of C-13 NMR Spectra", Wiley, 1974, p. 41). Note that "' is beta to the carbon being calculated, $' is gamma.

C(-C$-C"-C=C-C"'-C$'-C(' *c(olefin) = 123.3 + EAi + corrections 8

Ai Corrections.

" 10.6 ","' (trans) 0$ 7.2 ","' (cis) -1.1( -1.5 "," -4.8"' -7.9 "',"' +2.5$' -1.8 $,$ +2.3(' +1.5

Obs Calculated

112.9 CH2 123.3 + "' +2$' + (' = 113.3 5

144.9 CH3 CH 123 + " + 2$ + ( = 146.8\ /

CH*

CH2

*

CH3

There are quite characteristic differences between the two olefinic carbons as a function of substitution:

e.g. for n $ 3

H2C=CH(CH2)nH CH3HC=CH(CH2)nH CH3CH2HC=CH(CH2)nH

115.1 139.6 125.7 131.7 132.8 129.9

)* = 24.5 )* = 6.0 )* = -2.9

6-CMR-7.1

1JCH = 500 %s100

1JCH = 570 %s100

18.4

sp3 (25% s)(predict 125 Hz))

H-CH3 125.0 Hz

H-CH2CH3 124.9

H-CH(CH3)2 119.4

H-C(CH3)3 114.2

sp2 (33% s)(predict 167 Hz)

H2C=CH2 156.2

H2C=C=CH2 168.2

159

CH3

HCH3

+ 168

sp (50% s)(predict 250 Hz)

H-C≡C-H 249

H-C≡C-Ph 248

H-C≡N 269

H-C≡C-F 275

H-C≡N +

-H 320H

H-CH2NH2 133.0

161

S

170.5

O

175.5

N H

171167

HH

136

228.2

HH180

H

153.8H

212

131127

168.6

H

H

H H

H

156.2

H-CH2OMeH-CH2FH-CH2Cl

H-CHCl2H-CCl3

140.0149.1150.0

178.0

209.0

H-CH3 125.0 Hz

H-CHF2

H-CF3

184.5

239.1

H-CH(OMe)2

H-C(OMe)3

161.8

186.0

H-CH2SiMe3 118 H-CH2MgBr 107.7

H-CH2Li 98

H

H H

H

156.2

H

H H

F

159.2 200.2

162.2H

HO

172.0

H

HNH

175.0

F

HO

267.0

HO

HO

222.0

O

HO

194.8

H-C(SiMe3)3 100.4

H-CH(SiMe3)2 107

6.7 One-Bond Carbon-Proton Coupling (1JCH)

The size of 1JCH is correlated closely with the hybridization of the C-H bonding orbital - the values areroughly proportional to the % s-character. This arises because the principal coupling mechanism is the Fermicontact term, which involves transmission of coupling information between the nuclei via the s-electrons (onlys-electrons have finite electron density at the nucleus).

The above formulas can be used to estimate hybridization for simple hydrocarbons, but the method worksless well for systems having electronegative substituents. For these the coupling constants go up consistentwith increased s-character in the C-H bond (see CHF3) but the molecular structures do not show the largedistortions from tetrahedral geometry that would be expected from simple application of these formulas.

Electronegative substituents cause increases in 1JCH, electropositive substituents a decrease.

Strained rings show unusually large C-H couplings, consistent with the idea that carbons in such ringshave high s-character in the C-H bonds and high p-character in the endocyclic C-C bonds.

6-CMR-7.2

H-CH3 125.0 Hz

H-CH2SiMe3 118

H-CH2MgBr 107.7

H-CH2Li 98

H

H H

H

156.2

H

H H

Li

93.0

JA-93-10871(dimer, THF, -90 °C)

Ph-CH2Li (benzene) 116132

151Ph-CH2K (PMDTA complex, THF)

Ph-CH3 126

1JC-H δ20.8

18.329.8

52.6

(THF)

1JCH = 144 Hz 147 Hz 174 Hz

PhH

PhSeH

PhH

PhSeLi

PhHPhSe

Li+(HMPA)4: -

Ph3SiH

PhSLi

131 Hz

Ph3SiHPhSLi+(HMPA)4

151 Hz

-:

Ph3SiH

PhSH

1JCH = 135 Hz

SiS

Li+Ph

Ph

Si

H

S

Li

Ph

Ph

H-

:

Si

H

S

H

Ph

Ph 135 114 154

1JCH = 135 Hz 114 Hz 154 Hz

Hybridization effects in 1JC-H in Carbanions

Organometallic compounds of electropositive metals generally show the effects of significantrehydridization to accomodate the negative charge on carbon. For localized lithium and magnesium reagentsthere is a tendency for the "lone pair" orbital to maximize s-character, resulting in enhanced p-character forthe C-H bonding orbitals. This can be seen in the sequence of methyl derivatives, where the 1JC-H becomesprogressively smaller as the substituent becomes more electropositive. Similarly for the vinyl series.

For lithium reagents where B or F delozalization is possible, the opposite effect can be seen, in that thecoupling becomes larger as the C-M bond becomes more polarized, or is broken entirely. This is assigned toincreased planarization of the carbanion center (towards sp2 hybridization) to maximize B overlap. Botheffects can be seen for benzyllithium - in benzene solution the benzyl carbon is strongly coordinated to lithium(in an aggregate) and J is smaller than in toluene, whereas in THF, and even more so for benzylpotassiumthe J becomes larger as the carbanion becomes less strongly coordinated by the metal cation. The chemicalshift behavior can also be interpreted in these terms (Waack, McKeever, Doran Chem. Commun. 1969, 117;Bauer J. Am. Chem. Soc. 1994, 116, 528)

The effect ion pair separation for lithium reagents which are delocalized is generally to increase the iJC-H asa result of planarization of the carbanion center (Reich, H. J.;Dykstra, R. R. J. Am. Chem. Soc. 1993, 115,7041)

6-CMR-7.3

H

H

122.4

126.4

JACS-77-6750 (-104 °C)

OO

H

H

157.4

167.5

Bock, ACS, 1973, 27, 2676

SS

H

H

154.1

144.9

Bailey TL 1988, 29, 5621

OO

H

H

+

OO

H

DO

O

D

HS

S

H

DS

S

D

H

ΔG* = 49 cal/moleΔG* = 0 cal/mole

Stereoelectronic Effects on 1JC-H

There are well-defined stereoelectronic effects on the C-H couplings of axial and equatorial protons incyclohexanes (Perlin effects). These are most pronounced for situations where strong electronic interactionsof n 6 F* type or F 6 B* type cause perturbations of the C-H bond length and bond strength either by electrondonation into the C-H F* orbital or electron withdrawal from the F orbital. In cyclohexane itself the axial C-Hcoupling is slightly smaller than the equatorial ()J = 4.0 Hz), attributable to a stronger donation by the axialH-C F bond, compared to the equatorial C-C bond. In 1,3-dioxane the difference is much larger ()J = 10.1Hz), reflecting the larger donation by the p lone pair on each oxygen.

It is interesting that dithiane shows an inverse effect, attributed to a relatively weak n 6 F*CH interaction,and a stronger FCS 6 F*CH interaction. There are other indications that n 6 F*CH interaction in dithianes isweak. For example, the conformational equilibrium of H vs D (measured by the Saunders' isotopeperturbation method) indicates no preference for 4,4-dimethyl-1,3-dithiane, but a significant preference forC-H to be axial for the 1,3 dioxane and diazane (Anet Chem. Comm. 1987, 595).

6-CMR-8.1

JH-H

JC-H

H

HO

CH3

HO

H

H H

H

CH3

H H

H

+41 +2.3 +19.0

+11.5

+7.6

+12.7+5.0+26.7

C CH3

H

HH-13

+8

C CH3

CH3

HH-4.5

4.9

H H

CH3 H

+9.1

3.4

H1JC-H = 122.4

2JC-H = -3.943JC-H = 2.12

4JC-H = -0.31

H

1JC-H = 126.4

2JC-H = -3.693JC-H = 8.12

4JC-H = -0.50

Cyclohexane-d11 at -104 °CSergeyevJ. Am. Chem. Soc.1977, 99, 6750

C

H

C H

3Jtrans = 7-15 Hz 3Jcis = 5-9 Hz

Ph

H

PhO

OEtO

10.2

8.3

Ph

H

CH3

PhO

8.5

6.4CO2HH7.4

7.7CO2H

H

13.2

6.9

CO2H

Br

H

8.7

5.7

CO2H

H

10.2

6.9Br

N

H

7.0N

H5.9

Ph

Ph

O2C CO2

H

10.8

7.3

O2C

CO2H6.7

8.3O2C

Br

CO2

H

9.5O2C

CO2

Br

H4.3

6.8 Two and Three Bond Carbon-Proton Couplings

Couplings between carbon and protons across two and three bonds are generally small, and can be bothpositive and negative. They show many of the trends found for H-H couplings, including the effects of B andF donors and acceptors for 2J, and the Karplus relationship for 3J.

A very useful effect is the reliable difference in cis and trans C-H couplings across double bonds, whichallows assignment of stereochemistry to trisubstituted olefins where H-H couplings are not available. Inapplying this technique, it is important to recognize that any given carbon may be coupled to a number ofother protons. Thus some means of recognizing the coupling to the proton of interest must be available,either from the size of J or multiplicity of the coupling pattern, or from NMR techniques such as 2Dheteronuclear correlation or decoupling experiments.

To determine stereochemistry this way it is desirable to have both isomers, because the cis and transcoupling ranges do overlap.

6-CMR-8.1

CO2HH

H H2JHH = -22.0

2JCH = -11.0 Hz

5JHH5JCH

9.19 7.57

5.75 4.65

cis trans

JACS-1977-321

6.9 Long Range C-H Couplings

Longer range couplings also show many of the trends found for H-H couplings, including the exceptionallylarge 5-bond couplings in 1,3-cyclohexadienes.

6-CMR-10.1

6.10 Assignment of Carbon-13 NMR Signals

The complete assignment of all of the 13C signals of a complex molecule can be a very difficult and time-consuming process, but one that is necessary for the detailed use of 13C spectra for stereochemicaldeterminations and conformational analysis, or isotopic labeling studies in biosynthesis or physical organicchemistry. The techniques that are used are the following:

1. Chemical Shifts. The principal method of roughly grouping 13C signals is by their chemical shift. Hybridization (sp3, sp2, sp) and electronegative groups (" effect of O, N, F, Cl, Br) cause large 13C chemicalshift effects which can be used to classify groups of resonances. Within groups there are smaller effectswhich are useful: resonance interactions within B systems cause predictable upfield and downfield chemicalshift effects. Heavy atoms (e.g., iodine, tellurium) cause upfield shifts, as does the accumulation of adjacentsterically crowded carbon atoms (branching effects). For detailed assignments involving stereochemicalconsiderations the (-effect is important.

Even applying chemical shift arguments in a sophisticated way does not provide a way of assigning closelyspaced resonances. In most cases a complete assignment requires a group of compounds with very similarstructures. Within a series of model compounds substituent effects and stereochemical effects can providevery powerful tools for assignments of even very closely spaced resonances. This is because the directionand magnitude of a change in chemical shift ()*) resulting from a small structural change is much easier topredict than the absolute magnitude of the shift (*).

2. Attached Proton Tests (APT). There are a variety of techniques for distinguishing carbons signals onthe basis of the number of attached protons (CH3, CH2, CH, C).

The simplest methods is to measure the 13C NMR spectrum without decoupling (coupled spectrum). Thishas the disadvantage that overlapping multiplets are observed for all but the very simplest molecules. Sincea given carbon may be coupled to a number of protons two or three bonds removed, in addition to the one-bond coupling of interest, these multiplets can be very complicated.

More efficient are various APT tests, in particular the DEPT pulse sequences, which can be run so thatonly C-H carbons are visible (DEPT-90), or that all carbons with an even number of hydrogens attached givepositive signals, and all with odd give negative signals (DEPT 135). Quaternary carbons give no signal. Such techniques depend on the size of 1JCH, and can give ambiguous results when these are unusually largeor small (such as for acetylenic carbons).

3. Proton-Carbon Correlation. For most molecules, the proton signals are easier to assign than thecarbon signals. H-H coupling information is usually easily obtained, and supplements chemical shiftarguments. Some techniques such as homonuclear decoupling and 2D-COSY experiments, which are notavailable for carbon because of its low natural abundance, can be easily used. Thus techniques for makingcorrelations between proton signals and carbon signals, using JC-H, are valuable for assigning 13C NMRspectra. These experiments include various 2D heteronuclear correlation experiments (HETCOR, HMBC,HMQC, see Section 8) and can use either 1-bond or longer range (2-bond, 3-bond) CH couplings for thecorrelation.

4. Isotopic Labeling. Replacement of an atom attached to carbon by a lighter or heavier isotope resultsin small chemical shift changes of the attached carbon, as well as of other nearby carbons. If the isotopiclabeling is done with high specificity, then assignment of several nearby carbons may be possible.

Replacement of H by D in some positions can be easily carried out, for example by base-catalyzed H/Dexchange of protons " to carbonyl groups. There are two effects: the C-D signal will be split into a 1:1:1triplet by coupling with the spin 1 deuterium nucleus (JCD . JCH/6, typical coupling constant is 20 Hz), and thecarbon signal will be isotopically shifted (the center peak of multiplet will be upfield from that of the C-H signal,typically by 0.5 ppm, see Section 7). If there are no protons attached to the C-D carbon, then the signal willalso be much weaker because of longer relaxation times (loss of C-H dipole-dipole relaxation), some line

6-CMR-10.2

broadening (due to relatively short deuterium T1), and loss of NOE intensity enhancement. Carbons two andeven three bonds removed from the C-D carbon may also show small chemical shifts and intensity losses(due to broadening by 2JCCD and 3JCCCD, typical couplings of 1-2 Hz), thus distinguishing them from moreremote carbons, which will be unaffected.

5. Shift Reagents. Lanthanide shift reagents (Eu or Pr $-diketone complexes, see Section 8) will causediagnostic chemical shift changes of carbons near polar functional groups complexed to the Lewis acidiclanthanide atom.

6. T1 Effects. There are predictable effects on T1 relaxation times which can occasionally be used tomake assignments of carbon signals. Carbon signals may be distinguishable either by their relative distancefrom nearby protons, by the variable effects of anisotropic motion on carbons on or off a principal axis ofrotation of the molecule, or by differences in the degrees of segmental motion. See Section 8, Dipole-Dipolerelaxation.

38-02