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CHIRAL RECOGNITION OF ETHERS BY NMR SPECTROSCOPY example,electrostatic charges versus steric effects in duce two diastereomeric derivatives,each in enantiopure oxiranes. form.For example with (+)-CDAeq.1: Oxygen Functionalities and Soft Lewis Acid (+)S+(-)S+2(+)-CDA- [(+)-S-(+)-CDA]+[(-)-S-(+)-CDA](1) 2 ard bases and,by n the al metals like gh.Ir. se pair. appears twice :HOMO-LUMO of different Asvalues of the dia io-induceds is called dia ric resoluti ion Since the charg erally low, pinding ene has tokeep in mind that the Avparameter increases (or d NMR signals ex t for the CDA d atives,each o its relative sigal inte △v,are no longer ab olute values but plus(+)or minus e is no obli eomer is first and which is second in this differential ETHERS CHIRAL RECOGNITION BY NMR expres △△8=8[(+-S-(+CDA-8-S-(+-CDA(in ppm (2a vever.an achira ated by their Av=vl(+)-S-(+)-CDA]v[(-)-S-(+)-CDA](in Hz) (2b) are isochronous and give rise to identical NMR si which eferen s are int oduced.It is a commo fea ture o with or v addition of Chiral derivatiz ation.A racemate of a chiral sub- Chirality DOI 10.1002/chinexample, electrostatic charges versus steric effects in oxiranes. Oxygen Functionalities and Soft Lewis Acids Much less literature reports exist for this combination of oxygen bases and soft Lewis acids as adduct partners; all oxygen functionalities are hard bases and, by principle, poor donors when soft Lewis acids are involved. Soft acids are, for example, many heavy transition metals like Rh, Ir, Pd, Pt, Ag, Au, Cd, Hg and, particularly, their low-charge cations. It has been described that two important terms exist in the binding of a Lewis acid–base pair: (i) electrostatic attraction and (ii) electron donation via orbital interaction; mostly HOMO-LUMO interaction.48,53 It is important to note that the latter term is effective only when both partners, acid and base, are soft. Therefore, oxygen functionalities bind to soft bases merely via eletrostatic attraction; the HOMO-LUMO gap is too large for a significant contribution from orbital interaction. Since the charge at the soft base site is generally low, the binding energy is low as well. An instructive experimental result confirms this interpretation: sulfoxides (e.g., Me2S¼¼O) bind to hard acids predominantly by the hard oxygen atoms but to soft acids preferably by the soft sulfur atom,48,58 and this in accordance with the HSAB principle. Nevertheless, oxygen functionalities are able to form complexes quite effectively, particularly carbonyl groups; ethers, alcohols, and water can generally not go beyond some solvent-like complexation. As an example, ether complexes of platinum and palladium are essentially unknown and believed to exist merely in situ. 48 This differential behavior was observed with dirhodium tetracarboxylate complexes59,60 acting as soft Lewis bases as well (see later). ETHERS—CHIRAL RECOGNITION BY NMR SPECTROSCOPY General Principles A fundamental theorem in stereochemistry says that chirality can be recognized only in the presence of a chiral reference. NMR spectroscopy, however, is an achiral method so that only constitutionally heterotopic or diastereotopic nuclei can be discriminated by their different chemical shifts (anisochrony). Enantiotopic nuclei, however, are isochronous and give rise to identical NMR signals. In other words, NMR spectroscopy cannot differentiate enantiotopic nulei or hemispheres. Nevertheless, NMR is most popular in chiral recognition because a variety of techniques has been invented over several decades in which chiral references are introduced. It is a common feature of all these techniques that enantiotopic nuclei are converted into diastereotopic and, thereby, anisochronous nuclei by reaction with or by addition of an enantiopure auxiliary.61 Basically, two different ways exist to reach this target.24 Chiral derivatization. A racemate of a chiral substrate (1)-S/(–)-S is allowed to react with an enantiopure derivatizing auxilliary, either (1)-CDA or (–)-CDA, to produce two diastereomeric derivatives, each in enantiopure form. For example with (1)-CDA eq. 1: ðþÞ-S þ ðÞ-S þ 2ðþÞ-CDA ! ½ðþÞ-S ðþÞ-CDA þ ½ðÞ-S ðþÞ-CDA ð1Þ In the ideal case, these diastereomers exist in the same ratio as the enantiomers before. Principally, every signal in the CDA-derivative is shifted to higher or lower frequencies as compared with those in the isolated components S and CSA, respectively. This is called complexation-induced shift Dd (in ppm). Moreover, every signal appears twice because of different Dd-values of the diastereomeric S–CSA derivatives, although it occurs quite frequently that such differences are undetectably small (incidental isochrony). This difference in the complexation-induced shifts is called diastereomeric resolution or dispersion, and the parameter is DDd (in ppm) or Dm (in Hz). The DDd parameter is independent of the spectrometer frequency. In cases where resolutions/dispersions are low, it may be more convenient to use Dm (in Hz) but one has to keep in mind that the Dm parameter increases (or decreases) proportionally with the external field strength. These parameters must be recalculated if values recorded at different field B0 are to be compared. If the mole fractions of the enantiomers in a nonracemic mixture are significantly different, e.g., 2:1, two sets of dispersed NMR signals exist for the CDA-derivatives, each of which can be assigned to the respective diastereomer by its relative signal intensity. Then, the parameters, DDd or Dm, are no longer absolute values but plus- (1) or minussigns (2) can be attributed to each dispersion according to eq. 2; note that there is no obligatory rule which diastereomer is first and which is second in this differential expressions. DDd ¼ d½ðþÞ-S ðþÞ-CDA d½ðÞ-SðþÞ-CDA ðin ppmÞ ð2aÞ Dm ¼ m½ðþÞ-S ðþÞ-CDA m½ðÞ-SðþÞ-CDA ðin HzÞ ð2bÞ Then, NMR signal integration of the dispersed signals reflects the enantiomeric ratio (1)-S and (2)-S from which enantiomeric excess data (e.e.) and the optical purity can be derived. However, it is indispensable in such experiments to make sure that there was no kinetic resolution in this reaction and both enantiomers react with exactly the same yield, optimally 100%. Of course, any purification by recrystallization or chromatography should be avoided strictly. On the other hand, chiral derivatization is the method of choice when the absolute configuration (AC) of a pure enantiomer, e.g., a natural product isolated, is to be determined.62 Then, the reaction with an enantiopure CDA of known AC affords one diastereomer only. If single crystals CHIRAL RECOGNITION OF ETHERS BY NMR SPECTROSCOPY 55 Chirality DOI 10.1002/chir