教学课件高等有机化学lecture 31

1、Lecture 31: pp Stacking and Cation-p InteractionsE. KwanChem 106Key Questions1. How stabilizing are p-p interactions? Which geometry is optimal?pp Stacking and Cation-p InteractionsEugene E. KwanNovember 21, 2011.Scope of Lecturedifferent p-stacking configurations2. What influence do substituents ha

2、ve on p-p stacking and cation-p interactions?applications in proteins and synthesissubstituent effects + + + + + +charge transfer vs. electrostaticscation-p interactionspp stacking and cation-p interactionsd+ dattractived+ drepulsiveelectrostatic modelbetter than crystal structures of packed benzene

3、sNMR spectroscopy and double mutant cycles+ + + + + + + + +3. What are some synthetic manifestations of these interactions?CO2CsCsO2COHelpful References1. Aromatic Interactions. Hunter, C.A. et al. J. Chem. Soc. Perkin Trans. 2. 2001, 651-699.MeNI2. Chemical Double-Mutant Cycles: Dissecting Non-Cova

4、lent Interactions. Cockroft, S.L.; Hunter, C.A. Chem. Soc. Rev. 2007, 36, 172-188.NO ROH2ORO3. Substituent Effects in the Benzene Dimer are Due to Direct Interactions. Wheeler, S.E.; Houk, K.N. J. Am. Chem. Soc. 2008, 130, 10854-10855.4. The Cation-p Interaction. Ma, J.C.; Dougherty, D.A. Chem. Rev.

5、 1997, 97, 1303-1324.+ MeIk/k= 80catuncatCsO2CCO2CsI thank Professor Stephen Wheeler (Texas A&M) for helpful discussions in the preparation of this lecture.Lecture 30: pp Stacking and Cation-p InteractionsE. KwanChem 106Noncovalent Interactions in CrystallographyQ: Are hydrogen bonds, p-p stacking i

6、nteractions, and other noncovalent interactions real?While unconstrained hydrogen bonds prefer linear arrangements (marked as gray), cyclic ones are constrained:Problem: Precise geometries in the solution phase are hard to obtain. Computed geometries in the gas phase may not be real.Strategy: Use da

7、ta-mining techniques to examine interactions in the solid state by analyzing crystal structure data.Caveats: Crystal structures may not accurately represent what goes on in solution. Also, just because two things are close together doesnt mean theres actually an interaction. In the words of Dunitz:

8、all the atoms in a crystal have to go somewhere!Hydrogen BondsOn average, the donor-hydrogen-acceptor angle is 150. There seems to be something special about forming intramolecular hydrogen bonds of ring size 6 (J Med Chem 2010 53 2601):Legend: magenta (5-membered rings), green (6), red (7), gray (u

9、nconstrained). You can ignore the black lines. The5-membered intramolecular contacts may be largely electrostatic in nature, given their unfavorable orbital alignment.Regardless, there is a linear correlation between bond length and the donor-hydrogen-acceptor angle is observed; stronger bonds are m

10、ore directional.In general, a variety of medium-strength donor-acceptor pairs show contacts within the sum of van der Waals radii (J Med Chem 2010 53 5061). y=0 represents the sum of vdW radii:Lecture 30: pp Stacking and Cation-p InteractionsE. KwanChem 106These close contacts are thought to be indi

11、cative of hydrogen bonding:The dashed lines represent different definitions of vdW cutoff radii. So it seems there are many structures inside the radii, regardless of which criteria one chooses.But the directionality of C-H.O contacts is much less than that of O-H.O contacts:What about aromatic inte

12、ractions? How close do aromatic rings get in crystal structures? Here are data from many aromatic- aromatic contacts in the PDB (J Biol Chem 1998 273 15458):What about weaker bonds? It seems that C-H.O interactions are real, but are much less directional. Here are some neutron diffraction data (Stei

13、ner Chem Commun 1997 727)(centroid-centroid distance)Lecture 30: pp Stacking and Cation-p InteractionsE. KwanChem 106C-H/p contacts are also prevalent, particularly for hydrogens bound to heteroatoms or sp2 carbons (red = lots of contact) J Med Chem 2010 53 5061Q: Whats the point of all this?A: One

14、answer is that these interactions can be exploited when designing drugs, which are generally inhibitors of proteins.This is called structure-based drug design.Here is an example of arene/perfluoroarene stacking in an inhibitor of carbonic anhydrase II (PDB code: 1G54):In most cases, however, many in

15、teractions will combine cooperatively to give overall binding. Heres an example of a thrombin inhibitor (Diederich ACIE 2003 42 2507):The graph shows theres clearly a preference to put hydrogens above the plane of the C-H, but its not a very strong one. The distances seem to be inversely correlated

16、with interaction strength; weaker bonds have shallower potentials:Lecture 30: pp Stacking and Cation-p InteractionsE. KwanChem 106p Stackingp-p interactions are very important in catalysis, protein-ligand interactions, and molecular recognition. As weve done for other bonding interactions, well firs

17、t examine it in the antiseptic realm of high level ab initio calculations and contrived experimental systems, and then look at it in real life.However, one could also imagine a parallel displaced version:The benzene dimer is the prototypical system. Experimentally, it is bound by 2-3 kcal/mol in the

18、 gas phase, with an estimated4.96 A separation between the centers of mass. Note that unlike many hydrogen bonds, these are weak interactions which are outside the sum of the relevant van der Waals radii. Although there is still considerable controversy in what forces are responsible, it is common t

19、o invoke quadrupole-quadrupole or London dispersion forces. London forces are thought to involve instantaneously correlated multipole-induced multipole charge fluctuations.3.9 What is the geometry of binding? A priori, there are a number of possible geometries:The one people think of the most is the

20、 sandwich configuration:Finally, a T-shaped configuration, which can be rotated into anedge to face configuration is possible.3.9 5.0 Which do you think is lowest in energy? (Its not really intuitive.)Lecture 30: pp Stacking and Cation-p InteractionsE. KwanChem 106p StackingA resolution to this prob

21、lem did not come until relatively recently, when Sherill published very high level MP2-R12/A computations using a very large counterpoise-corrected aug-cc-PVTZ basis sets. Some sophisticated techniques allowed complete basis set CCSD(T) estimates which should be within a few kcal/molof the ab initio

22、 limit. So these calculations are very accurate (JACS 2002 124 10887) and give these results:SCS-CCSDsandwichparallel displaced T-shaped-2.0 kcal/mol-2.8 kcal/mol-2.7 kcal/mol(1) All of these configurations are substantially bound. Rotations, like spinning the sandwich or the the T-shaped into an ed

23、ge- to-face interaction are not energetically costly. However, the sandwich is a saddle point (transition state), rather than an energy minimum.(3) In contrast, hydrogen bonding interactions of all strengths are modelled correctly, even by uncorrelated methods. This suggests that these are fundament

24、ally different interactions, and that one should not think of this as a hyperconjugative interaction between two p-systems.(4) Hyperconjugative interactions are strongly distance dependent and the monomers are well outside van der Waals contact:(2) CCSD(T) estimates were required because substantial

25、 errors are introduced with other techniques: HF and B3LYP predict that benzene dimer is unbound, while MP2 overpredicts the dispersion interaction. M05-2X seems to underbind the dimer somewhat, but M06-2X does better. Here are some recent numbers (Sherill J Chem Phys A 2009 113 10146),all at the co

26、mplete basis set (CBS) limit:CCSD(T)M05-2XM06-2Xsandwichparallel displaced-1.7-2.7-0.5-1.6-1.0-2.5T-shaped-2.7-2.2-2.4From Intermolecular Forces and Clusters by David Wales:Lecture 30: pp Stacking and Cation-p InteractionsE. KwanChem 106This distinguishes between parallel and edge/face orientations:

27、This is the same data, plotted against the separation of the closest carbon-carbon atom contacts. Note that the vdW radius of carbon is approximately 1.7 , which means that most of these contacts are not touching.parallel displaced: small gface to face: small qedge to face: large gEvidently, there i

28、s a gentle preference for the parallel-type, but a continuum of geometries is actually observed:The distribution is clearly bimodal, and the authors interpret this as a cutoff where thermal energy (kT) exceeds the binding energy of the p-p complexes.What are the preferred orientations of the rings?

29、Using themetric below, similar histograms were made:gRcenqRcloThe arrows represent vectors normal to the aromatic planes.Lecture 30: pp Stacking and Cation-p InteractionsE. KwanChem 106Substituent EffectsSupport for this interpretation comes from the odd result that adding substituents, regardless o

30、f whether they are electron withdrawing or donating increases the binding energy. Adding substituents also changes the relative energies of the various configurations (Sherill, J Phys Chem A 2003 107 8377 and JACS 2004 126 7690).T-shaped (2) (-2.2 kcal/mol)benzene-fluorobenzene complexessandwich (-2

31、.3 kcal/mol)benzene and X-benzene interaction energies(kcal/mol, estimated CCSD(T)/aug-cc-pVTZ)sandwich-1.8-2.2-2.2-2.3-3.1T-shaped-2.6-2.6-2.6-2.8-3.3T-shaped(2)-2.6-2.7-3.0-2.4-2.2substituent X=H X=OH X=Me X=F X=CN(1) Substitution of any sort enhances the interaction.(2) Substitution decreases the

32、 difference between the sandwich and T-shaped forms. (There are two T-shaped forms, depending on which C-H(3) The sandwich forms represent p stacking interactions, while the T-shaped forms represent C-H/p interactions.(4) More subtle changes in the relative orientation (sandwich vs. parallel displac

33、ed) were not considered here.T-shaped (-3.3 kcal/mol)(5) Symmetry-adapted perturbation theory suggests that a mixture of dispersion and steric effects is important here, and that electrostatics are not the controlling force.Lecture 30: pp Stacking and Cation-p InteractionsE. KwanChem 106Substituent

34、EffectsAn important clue as to what is going on comes from a clear correlation between the strength of the interaction energies with Hammett s(meta) values. Recall that Hammett values measure the position of the acid-conjugate base equilibrium in substituted benzoic acids. s(meta) values are thought

35、 to measure the strength of s-inductive withdrawl, while s(para) values are though to reflect p-donation.Wheeler and Houk (JACS 2008 130 10854) computed the interaction energies for a variety of sandwich benzene- substituted benzene dimers at M05-2X/6-31+G(d), which is less accurate than CCSD(T) met

36、hods, but is good enough to largely reproduce the energy values (at substantially decreased cost). See Houk et al. JACS 2010 132 3304 for more details.absolute energies: benzene - substituted benzene (sandwich)Note that the blue line is always below the x-axis, which means that as before, all the su

37、bstitutents increase the interaction. But with hexafluorobenzene - substituted benzene dimers the opposite trend is observed: more electron withdrawing substitutents make the interaction worse:relative energies: C6H6 - X-C6H6 vs. C6F6 - X-C6H61.61.41.21.00.80.60.40.20.0-0.2-0.4-0.6-0.8-1.0-1.2-1.4-1

38、.6-1.8C H - X-C H6 66 6C F - X-C H6 66 61.41.21.00.80.60.40.20.0-0.2-0.4-0.6-0.8-1.0-1.2-1.4-1.6-1.8-2.0-0.4-0.20.00.20.40.60.8smeta(1) The first graph is interaction energies relative to separated monomers. The second is interaction energies relative to the unsubstituted cases: (C6H6)2 (blue line,

39、absolute: -0.5 kcal/mol) and C6F6-C6H6 (red line, absolute: -4.9 kcal/mol).X=Hy = -1.69 s - 0.82X=CH OH2m(2) This means that all the complexes with hexafluorbenzene are inherently stronger, but EWGs make the interaction worse. Conversely, the complexes with benzene are inherently weaker, but EWGs ma

40、ke the interaction better.Whats going on? Whats behind these interactions?0.2smeta-0.4-0.20.00.40.60.8interaction energy (kcal/mol)relative interaction energy (kcal/mol)Lecture 30: pp Stacking and Cation-p InteractionsE. KwanChem 106Electrostatic ModelsHere is an explanation, which is partially base

41、d on the electrostatic Hunter-Sanders model (Hunter JCS PT2 2001 651) and partially on the direct interaction Wheeler-Houk model:(1) Benzene has no net dipole moment, but a substantial quadrupole moment (-29 x 10-40 C m2). Hexafluorobenzene has a large quadrupole moment, but it is reversed in sign.

42、These quadrupole moments arise from the differential electronegativities of C vs. H and C vs. F:(4) The T-shaped or edge-to-face configurations have the correct orientation for attractive quadrupole-quadropole interactions. Alternatively, one can think of dipole-quadrupole inteactions with the local

43、 C-H dipoles on the edge ring: + + +essentially isoenergetic + + + + + + + + + + + + However, the atoms are farther apart.(Actually, some ofthem are closer, but dispersion interactions have a r-6 dependence, so more distant atoms are penalized more than closer atoms.) Thus, parallel displaced and sa

44、ndwich are similar in energy.(5) Any substituent will increase the interaction energy because of increased dispersion forces. An interesting case is X=CH2OH, which has s=0.0, but still increases the interaction strength (by 0.4 kcal/mol for benzene and by 0.7 kcal/mol for hexafluorobenzene).benzeneh

45、exafluorobenzeneThe local C-H dipole means that there is positive charge on the periphery of the ring, and correspondingly negative charge on the faces of the ring. This is reversed for C-F.(2) London dispersion attracts the two monomers, with a strengththat increases with decreasing monomer separat

46、ion.(3) That the sandwich orientation is not as good as the parallel displaced orientation suggests that the increased dispersion interactions (attractive) do not make up for the increased quadrupole-quadrupole interactions (repulsive):(6) Inductively electron withdrawing substituents also introduce

47、 a dipole-quadrupole interaction, which is stabilizing in the case of benzene - substituted benzene sandwich dimers. For hexafluorobenzene complexes, this is repulsive: + + + + + repulsive quadrupole- quadrupole interaction + + + + + + +worse thand+ dattractived+ drepulsive + + +better than+ + + + +

48、 + +sandwichparallel displaced + + + + + +Lecture 30: pp Stacking and Cation-p InteractionsE. KwanChem 106Electrostatic ModelsThis local interaction model is justified by the surprisingly good correlation between the interaction energies of benzene- substituted benzene complexes and analogous comple

49、xes in which the carbon and hydrogen atoms of the substituted benzene are replaced by a hydrogen:Evidence from NMR SpectroscopyWhat are some experimental indications of p-p stacking? One of the early attempts to look at these interactions was reported by Cozzi and Siegel (JACS 1992 114 5729):XXXXcor

50、relate strongly withHXinteraction energies ofMe MeMe Despite this apparently dramatic change, the correlation coefficient is very high for both the benzene and hexafluorobenzene cases:The barrer to rotation in these 1,8-diaryl naphthalenes was interpreted as being due to the loss of p-stacking in th

51、e transition state. Barriers were higher with electron withdrawing substituents X: (kcal/mol: OMe, 14; H, 15; NO2, 17).1.6complexes with C H6 6y = 0.68x + 0.01 (r = 0.94)1.2complexes with C FHowever, in light of the above discussion, this merely seems to be measuring the difference between the sandw

52、ich and edge-to-face orientations, rather than the strength of thep-stacking itself.A more sophisticated approach reported by Diederich (Chem Commun 2008, 4031) uses the molecular torsion balance approach introduced by Wilcox (JACS 1994 116 4497):6 60.80.40.0-0.4-0.8OOMeMeO-1.2O-1.6R1R1y = 1.00x - 0

53、.04 (r = 0.92)N NN N-2.0R2R2-2.0-1.6-1.2-0.8-0.40.00.40.81.21.6The ratios of the folded and unfolded states can be measured by NMR. A key problem in this approach is the influnece of solvation-it is a competition between internal solvation byinteraction energy (C H or C F ) - X-C H (kcal/mol)6 66 66

54、 6interaction energy (C H or C F ) - X-H (kcal/mol)6 66 6Lecture 30: pp Stacking and Cation-p InteractionsE. KwanChem 106Evidence from NMR Spectroscopyp-stacking (desired) and external solvation by C6D6 or CDCl3 (undesired). The key is to use R1=CF3, which increases the preference for the folded state. This can be understood through the direct interaction model. In contrast, electron donating substitutents at R2 increase the preference for the folded state through an electrostatic attraction between the substituent dipoleWith R1 = H, the influ