5.5 Vicinal Proton-Proton Coupling 3 J HH

Transcription

1 5.5 Vicinal Proton-Proton Coupling 3 J Copyright ans J. Reich 21 All Rights Reserved University of Wisconsin The single most useful - coupling relationship is that between vicinal protons. The size of 3 J - is predictable and provides detailed information about the spacial orientation between the two protons. Almost all 3 J values are positive (a rare exception is the -2 z 3 J - in cis-1,2-difluoroethylene), but their magnitude varies widely (from close to z up to 22 z) depending on structural and conformational details. In acyclic systems with small conformational preferences, vicinal couplings are generally in the range - z, with electronegative substituents causing smaller J values. C 3 C 2 3 J E Li.9-1. SiEt I Br C Cl NEt Et F Et 2.7 C 3 CCl 2 3 J = 5.9 z C 3 C(Me) 2 3 J = 5.52 z For a methyl group, the observed coupling is the average of the three couplings, since these will be fully averaged by methyl rotation: g a g Y 3 J obs = J g + J g + J a 3 J trans J cis Cl CN C 2..5 C Cl 3.2. JA Ac E a a JCP 191, 3, The Karplus relationship gives us approximate values for 3 J as a function of dihedral angle between the protons. It should be remembered, however, that this relationship strictly applies only in unstrained hydrocarbon systems, and that electronegative substituents and ring constraints may cause substantial perturbations (in both positive and negative directions) to the values predicted by this equation. Nevertheless, the Karplus curve is the mainstay of conformational analysis for all ring systems, and has generally proved reliable if care is taken. The constants J o and K are used to correct for substituent effects in more sophisticated uses of the Karplus equation, different J o values are also used for the to 9 and the 9 to 1 sections of the curve. The Bothner-By equation provides an empirical "Karplus" curve that does not require different J values for the -9 vs 9-1 sections: 3 J / z Karplus Equation Bothner-By equation Θ = 3 J = 7-11 z Karplus Equation 3 J = J o cos 2 Θ - K J o = 1 (9-1 ), J o = 1 (-9 ), K = Bothner-By equation Θ = Θ = 9 Θ = 1 3 J = 2-5 z 3 J = -2 z 3 J = -15 z Θ Θ 3 J = 7 -cos Θ + 5 cos 2Θ 5-MR

2 A convenient graphical form of the Karplus equation is given in Figure below. ere two curves, separated by, represent the predicted coupling constants for a proton 1 coupled to an adjacent methylene group ( cis and trans ), as a function of the dihedral angle. 1 Θ 1-c / c 1 c axial t t c eclipsed with 1 c t 1 1 equat. 1 Bothner-By equation 3 J = 7 -cos Θ + 5 cos 2Θ J / z 1 1 J / z Θ 1-t / Figure Karplus Curve for Vicinal coupling in Cycloalkanes. 5-MR-5.2

3 5.5.3 Determination of Stereochemistry in Cyclic Compounds Using 3 J Cyclohexanes. It is often straightforward to establish stereochemical relationships among substituents, provided that the spectrum can be analyzed. In chair cyclohexanes, the relationship among vicinal protons is restricted to the narrow regions for Θ 1-c = - on Figure (i.e. to the left of the 1 -eq crossing point at, and to the right of the 1 -ax point). These regions correspond to flattening of the cyclohexane, which is energetically easy. The opposite distortion (Θ 1-c = -5 ) cannot occur to any significant extent. J aa is usually much larger (9- z) than J ee or J ea (each usually 3- z). Below is reproduced the 1 Mz NMR signal of the 1 proton of iodocyclohexane at - C (from F. R. Jensen, C.. Bushweller, Beck JACS , 3, 3223). Under these conditions the ring inversion is slow on the NMR time scale, and separate signals are seen for the two conformational isomers. The couplings are not always this well resolved, but the axial proton will almost invariably be much broader than the equatorial one. At room temperature, the ring inversion will be fast on the NMR time scale, so an average spectrum will be observed. It will look much like that of the axial proton, since the equatorial isomer is the major one. I I z Iodocyclohexane at equilibrium, - C ( Mz) The coupling constants in cyclohexane itself were determined by analysis of the AA'BB' pattern of 1,1,2,2,3,3,,-octadeuteriocyclohexane at -13 C (Garbisch, J. Am. Chem. Soc. 19, 9, 53). The top spectrum (deuterium decoupled) is the experimental one, the bottom one is a simulation with the parameters listed. Exp. Calcd. D D D D D D D A' D B B' A A' B J AB = (J gem ) J AA' = 13. (J aa ) J BB' = 2.9 (J ee ) J AB' = 3.5 (J ae ) δ A = 1. δ B = z A B' The spectra of iodocyclohexane and cyclohexane itself also illustrate another feature common to many axial and equatorial cyclohexane protons: the chemical shift of the axial proton is usually upfield of the equatorial one, in the case of cyclohexane by.5. The near identity of the magnitudes of the gem ( 2 J AB = -13.5) and axial-axial ( 3 J AA' = 13.) couplings seen in cyclohexane is a common feature of substituted chair cyclohexanes and half-chair cyclohexenes. In molecules with electronegative substituents (e.g. pyranose sugars) the vic couplings are smaller than these, with typical values between and 11 z. 5-MR-5.3

4 In an idealized cyclohexane, J ee and J ae would be identical, since each corresponds to a dihedral angle of. owever, cyclohexanes are typically slightly flattened, presumably due to axial-axial repulsions. This moves the dihdral angle for J ee to slightly higher than, hence smaller coupling, and that of J ae to slightly below, resulting in larger coupling (see the shaded areas in Figure 5.5.2). The dihedral angle in cyclohexane itself is 57, and this leads to the slightly smaller value for J ee (J BB' = 2.9) compared to J ae (J AB' = 3.5). Similar effects are also commonly seen in substituted cyclohexanes which are conformationally homogeneous, especially if there are axial substituents of any size. If the flattening is substantial, J ee can become too small to detect (as is the case for some bicyclo[3.3.1]nonanes with Θ 1-t = 9 ), and J ae can become substantially larger than the normal values of 3- z. Thus you cannot always rely on getting an exact count of vicinal neighbors to a proton from its multiplicity. Θ 1-c / Idealized cyclohexane a e e axial t 1 c c a ring flattening J / z 1 t 1 equat. 1 J / z Flattened cyclohexane a a e e 3 (J larger) 9 (J smaller) 2 Flattened cyclohexane Θ 1-t / Figure Karplus Curve (using the Bothner-By equation: 3 J = 7 -cos Θ + 5 cos 2Θ) for vicinal coupling in cycloalkanes. The shaded area represents the conformational space of chair cyclohexanes, showing ring flattening. 5-MR-5.

5 Analyze the NMR spectrum of the mixture of 3,5-diphenylbromocyclohexanes below (assign signals): Mz 1 NMR spectrum CDCl 3, Mike Bowe Br Br z Examine the 22 Mz spectrum of proto-quercitol reproduced below, and analyze the couplings and chemical shifts (McCasland, G. E.; Naumann, M..; Durham, L. J., J. rg. Chem. 19, 33, 22) proto-quercitol Mz J 1,2 = 9. J 2,3 = 9. J 3, = 3. J,5 = 3.1 J 5,e = 3.1 J 5,a = 2.9 J a,e = 13. J 1,e = 5. J 1,a = Mz z e a 22 Mz MR-5.5

6 The pyranose forms of pentose and hexose sugars provide many examples where vicinal proton coupling constants allow complete assignment of stereochemistry. Analyze the NMR spectrum of glucose pentaacetate reproduced below, assuming that you don't know the stereochemistry Ac Ac 5 3 Ac 2 Ac Ac 1 Glucose pentaacetate 1 z Boat Conformations. In boat and twist-boat cyclohexanes there are multiple conformations, each of which have available several C-C-C-C dihedral angles. In an idealized twist-boat there are four kinds of hydrogens, with eight dihedral angle relationships (ca 3, 3, 5, 5, 7, 9,15, 17 degrees). In addition, there are six different twist boats possible for a multiply-substituted cyclohexane so stereochemical assignments are very difficult. Fortunately, twist-boat cyclohexanes are quite rare, being commonly seen only in bicyclic structures, or in -membered rings with multiple heteroatoms or those containing multiple sp 2 carbons. Twist-boat cyclohexane 5-MR-5.

7 Cyclopentanes. Energy differences between various envelope and twist conformations in five- membered rings are generally small. Conformational analysis is made very complex by the fact that there are as many as ten different envelope and ten different twist conformations, and each conformation has multiple dihedral angle relationships. Several of the 2 possible conformations may be populated in an individual structure. Thus the vicinal coupling in 5-membered rings are highly variable because of this conformational flexibility. For cyclopentanes in envelope conformations J cis > J trans in the flat part part of the envelope, whereas in twist conformations the tendency is for J trans > J cis. In general, no firm assignments of stereochemistry can be made using the size of couplings alone unless a specific substitution pattern or heterocyclic system has been carefully investigated, or if substitution patterns allow prediction of the conformation. J cis > J trans Θ 1-t t 1 1 axial c 1 c c t 1 Envelope c eclipsed with 1 c t 1 t J 1 equat. J J trans > J cis Twist boat Θ 1-c In most cyclopentanes, the C-C-C-C dihedral angles are significantly smaller than the found in cyclohexanes. Cis protons will tend to have -C-C- dihedral angles close to, and trans near. The cis couplings (-1 z) are usually larger than trans (2-9 z). owever the Karplus curves for cyclopentane have a region where the cis and trans lines cross (Figure above, at ca 2 dihedral angle), so there are cases where cis and trans couplings are identical (see below, where the allylic proton is a quartet of doublets, arising from accidental equivalence of three vicinal couplings), as well as a region where J trans > J cis. Et The three vicinal couplings to the allylic hydrogen (cis and trans in the 5-membered ring, and the coupling to the vinyl ) are accidentally equivalent MR-5.7

8 There are also cases where the ring is puckered enough so that J trans > J cis. Thus stereochemical relations among vicinal protons in 5-membered rings cannot be reliably determined by simply measuring coupling constants, except in cases where the substitution pattern of the specific ring system has been carefully investigated. For example, in the benzodihydrofurans below, changing the steric size of the substituent R causes a reversal in the size of J cis and J trans. In rigid cyclopentanes, J cis > J trans Y Y Y J = -9 z J = 7-9 z J = 2-3 z R R = Me Et 3 J cis J trans. 7.1 ipr.. Cyclobutanes. Cyclobutanes are even flatter than cyclopentanes, so that cis couplings are almost always larger (-9 z) than trans (2-). owever, if structural features which promote strong puckering of the ring such as a trans ring fusion, large or electronegative substituents are present, then trans couplings can become larger than cis, as shown for 1,3-dibromocyclobutane and cyclobutanol below. 3 J cis 3 J trans 1..9 Br 7.1. Br cis trans Cyclopropanes. Dihedral angles in cyclopropanes are rigidly fixed by the geometry of the ring system. We therefore find that J cis (7-1 z) is always larger than J trans (2- z). The same relationship holds for the 3-membered ring heterocycles, although the range of observed couplings is wider. C 2 Et C 2 Et Y Y = C 2 N S S= 3 J cis J trans J cis =.7 z 3 J trans = 5. z 5-MR-5.

9 Summary: n the double Karplus curve below are indicated the dihedral angles and hence the cis and trans 3-bond couplings that can be observed for various rings. Chair cyclohexanes are conformationally well defined, with a relatively small range of 3 J couplings possible (J eq-eq and J eq-ax typically 3- z, and J ax-ax typically -13 z). With 5 and membered rings a wider range of couplings are seen depending on the extent and type of puckering present. Cis couplings will typically be larger than trans couplings. Unfortunately for both cyclopentanes and (less commonly) cyclobutanes, J trans can occasionally be larger than J cis for pseudoaxial protons, if the conformation places the dihedral angle to the left of the crossing point at ca 2. For such systems both J trans and J cis will be relatively large (-1 z). Cyclopropanes are rigid, and J cis (eclipsed, Θ = ) is always greater than J trans (Θ = ). With this in mind, the appearance of only well defined large (ca 1 z) and small (ca 3 z) in a C coupled vicinally to one or more C 2 groups is quite characteristic of cyclohexanes. Cyclopentanes and cyclobutanes, on the other hand, tend to more frequently have intermediate size couplings (5- z). C Θ 1-t c c t 1 axial 1 c t 1 c t 1 1 eclipsed with c t J 1 equat. J Θ 1-c Chair cyclohexane Cyclopentane Cyclobutane Cyclopropane MR-5.9

10 5-MR-5.1 Acyclic Stereochemistry using 3 J Two products formed in an aldol condensation: + A syn (erythro) B + B anti (threo) In non-polar media, a hydrogen bond between and the carbonyl group is expected. Since in the syn isomer both hydrogen bonded conformations have a gauche relationship between A and B, we expect a smaller 3 J for the syn isomer than for the anti, where one of the -bonded conformations has an anti relationship between A and B (Stiles-ouse rule: Stiles J. Am. Chem. Soc. 19,, 3337; ouse J. Am. Chem. Soc. 1973, 95, 331; eathcock, JC, 19, 5, ; Mukaiyama JACS, 197 9, 753). A C 3 B B B B B C 3 C A 3 A J AB = 3- z J AB = 3- z J AB = 1- z J AB = 3- z syn (J AB =.5) no -bond anti (J AB =.5) J syn A J anti C 3 δ syn A δ anti A C This method will only work if the intramolecular hydrogen bonded conformations are the principal ones for both diastereomers. Thus it sometimes fails in situations where the α and/or β-substituent is large, as in the α-t-bu aldols below. ere gauche interactions destabilize the hydrogen bonded six-membered ring of the syn isomer, leading to a large coupling because of a high population of the conformations with t-bu and anti periplanar (eng, Simpson, Smith J. rg. Chem. 191,, 2932). Similarly, in more complicated systems additional conformational constraints can overwhelm the hydrogen bond effect. For example a 3-alkyl substituent in a cyclohexanone aldol has J syn > J anti (Kitamura, Nakano, Miki, kada, Noyori J. Am. Chem. Soc. 21, 3, 939). tbu B A J syn = 1. z large groups anti tbu A J anti = 3.5 z B J syn =. z For use of 13 C shifts to assign stereochemistry see: eathcock, J. rg. Chem., 1979, 29. J anti = 9.3 z 5-MR-5.1

11 5-MR-5.11 Allylic 3 J Couplings of vinyl hydrogens to vicinal protons across single bonds follow Karplus relationships similar to those of other vicinal couplings. The size of J is maximal at dihedral angles of 1 and, and minimal when the C- bonds are perpendicular (Θ = 9 ), although the coupling does not go to J =. z 3 J = 11.2 z 3 J =. cos 2 Θ + 2. sin 2 Θ ( < Θ < 9 ) 3 J = 2. z J / z 1 3 J = 11. cos 2 Θ + 2. sin 2 Θ (Θ > 9 ) 5 Θ For cyclic olefins, the 3 J coupling decreases as the ring size gets smaller. In cyclohexenes the couplings of an adjacent C 2 group to the vinyl hydrogens are typically -5 z for the equatorial, and 1-3 z for the axial, as shown in the figure above. In cyclohexene itself the average of these is observed. 3 J = 5.7 z C Θ / In acyclic systems without strong conformational restrictions, rotational averaging produces couplings of 5- z, very similar to those observed in aliphatic chains. 3 J = 3.1 z 3 J = 2.1 z 3 J = 1. z Dienes: The central 3 J coupling in acyclic dienes is typically 1 z, very similar to the 3 J cis across double bonds, provided that steric effects do not prevent the diene from achieving a near planar conformation. The coupling is again reduced in cyclic dienes, both because the dihedral angle is now instead of 1, and because of inherent reduction in the coupling because of angle distortions. S 3 J = 1. z Me 3 J = 11.3 z Me 3 J = J =.9 3 J = 1.9 z 3 J = 5. z Aldehydes: In unconjugated aldehydes the 3 J coupling is typically small (1-3 z). The coupling becomes considerably larger in conjugated aldehydes, where the dihedral angle will be either or 1 to maximize overlap of the π systems. 3 J = 1. z 3 J = 1.2 z 3 J = z 3 J = 7.7 z 5-MR

12 5-MR-5. lefinic 3 J The cis and trans couplings across a double bond are very reliable indicators of stereochemistry. With virtually no exeptions, 3 J trans > 3 J cis. owever, the ranges do overlap for very strong electron donating and withdrawing groups. J c J t E Y J t = - 2 z Y J c = 3-19 z Li SiMe C Me F.7.7. The coupling varies with bond order. Thus the cis coupling in benzene and other aromatic six and larger membered rings is typically below 1 z (one empirical equation is: 3 J =.5 (π bond order) + 1.): J =. J = 11. J = 7. J =. The tropone shows larger bond-alternation than the tropylium ion or the azulene JA Cycloalkenes smaller than cyclohexene show substantially reduced 3 J values (Chem. Rev. 1977, 77, 599). Thus cyclehexenes and cyclopentenes can be easily distinguished if this coupling can be identified. 3 J = 1. (11. -.) 3 J = 11. ( ) 3 J = 1.1 ( ) 3 J = 5. (5.1-7.) 3 J = 2.9 ( ) 3 J = 1.3 ( - 2.1) eterocycles also generally have smaller 3 J values than hydrocarbon systems. N N z.3 2 z 5-MR