Chemistry Department, The University of Liverpool, PO Box 147, Liverpool, UK L69 3BX

Transcription

1 hemial shifts in NMR. Part hemial shifts in ketones and the magneti anisotropy and eletri field effet of the arbonyl group Raymond J. Abraham* and Nik J. Ainger Chemistry Department, The University of Liverpool, PO Box 147, Liverpool, UK L69 3BX Reeived (in Cambridge) 16th November 1998, Aepted 16th Deember 1998 The proton resonane spetra of a variety of yli ketones inluding 2-tert-butylylohexanone, 4-tertbutylylohexanone, fenhone, trans-1-dealone, androstan-3-one, androstan-17-one, androstane-3,17-dione and androstane-3,11,17-trione were obtained and ompletely assigned. These data together with previous literature data allowed the determination of the arbonyl substituent hemial shifts (SCS) in a variety of yli moleules. These SCS were analysed in terms of the arbonyl eletri field, magneti anisotropy and steri effet for long-range protons together with a model (CHARGE6) for the alulation of the two-bond and three-bond effets. The anisotropi effet of the arbonyl bond was found to be well reprodued with an asymmetri magneti anisotropy ating at the arbon atom with values of χ parl and χ perp of 17.1 and 3.2 (10 30 m 3 moleule 1 ). This together with the eletri field effet of the arbonyl group gave good agreement with the observed proton shifts without the need to invoke any steri effets. The short range effets of the arbonyl group (i.e. HCC O) were modelled by a os θ funtion whih was found to be dependant on the ring size of the yli ketone via the CC(O)C bond angle. This model gives the first omprehensive alulation of the SCS of the arbonyl group. For the data set of a. 200 proton hemial shifts spanning a. 2 ppm the rms error of the observed vs. alulated shifts was ppm. Introdution The influene of the arbonyl group on the hemial shifts of neighbouring protons has been the subjet of onsiderable debate and some ontroversy sine the beginning of organi NMR and the standard desripton of the C O anisotropy (Fig. 1) must be one of the most well known illustrations in NMR. 2 Despite this interest there is still no definitive investigation of the arbonyl substituent hemial shifts (SCS) in a suffiiently wide variety of ompounds to rigorously test the known interations determining the proton hemial shifts in simple ketones. The early investigations onentrated on the arbonyl anisotropy and Narasimhan and Rogers 3 onluded that the proton hemial shifts in formamide and DMF were entirely due to the C O anisotropy. However even the C O anisotropy was unertain as Jakman 4 suggested that there is a large diamagnetism in the diretion normal to the nodal plane of the π-orbitals whereas Pople s alulations 5 suggested a paramagnetism entred on the arbon atom, large in the y diretion and the largest diamagnetism on the O atom in the x diretion (i.e. along the C O bond). An authoritative review of these and other early investigations has been given by Pople and Bothner-By. 6 In his pioneering treatment of proton hemial shifts, Zurher 7 was limited to observing only the methyl groups in steroids but onluded that both the C O bond anisotropy and the eletri field effet were needed to explain the observed SCS. Zurher used the MConnell equation 8 to alulate the C O anisotropy and also used the arbonyl dipole to alulate the eletri field effet. Due to lak of data Zurher did not onsider near (<4 bonds) protons nor did he need to invoke any steri effets of the arbonyl group. ApSimon and o-workers, 9 again using only the methyl groups of steroids for their data, reformulated the MConnell equation in order to obtain the anisotropy effets on near nulei (<3 Å away from the substituent). They also found that both anisotropy and eletri field effets were neessary to predit the SCS of the arbonyl group. Subsequently Homer et al. 10 observed that the original MConnell equation was just as aurate in their investigations. Toyne 11 reviewed the literature alulations of the C O anisotropy in whih the position of the magneti dipole varied from the arbon atom to the oxygen atom. He onluded that taking the dipole to be approximately mid-way along the C O bond at 0.6 Å produed the best results. More reently Shneider et al. 12 obtained all the proton shifts in three keto steroids and analysed these SCS in terms of both anisotropy and eletri field effets. They obtained rather large values for the arbonyl anisotropy (see later) and also they were not able to alulate the hemial shifts of the protons viinal to the arbonyl group. Reently Williamson et al. 13 performed similar alulations for the α C H protons in proteins. They used the known rystal strutures of the proteins and inluded eletri field and anisotropi effets, the latter from both the C O bonds and also from the aromati residues present. They obtained good agreement with the observed data when both the eletri field and anisotropy terms were inluded. As these proton shifts were measured in aqueous solution the eletri field effet is onsiderably diminished ompared to non polar solvents. Again protons viinal to the C O bond were exluded from their treatment. We give here the omplete assignment of the proton spetra of 2-tert-butylylohexanone (1), 4-tert-butylylohexanone (2), fenhone (3), trans-1-dealone (4), androstan-3-one (5), androstan-17-one (6), androstane-3,17-dione (7) and androstane-3,11,17-trione (8). In addition the spetra of norbornanone (9) and amphor (10) are remeasured. These plus previous literature results provide suffiient data for an analysis of arbonyl SCS based on a previous model of proton hemial shifts. 1 In previous parts of this series this model, whih is based on simple harge alulations over one, two and three bonds and steri, eletri field and anisotropi ontributions over > three bonds, has been applied suessfully to a variety of saturated hydroarbons, 14,15 haloalkanes 16 and J. Chem. So., Perkin Trans. 2, 1999,

2 ethers. 1 We shall show that this model provides a quantitative treatment for arbonyl SCS and that these are due to eletri field and anisotropi effets of whih the eletri field effet is the major ontributor. Theory As the theory has been detailed previously 1,17 only a brief summary of the latest version (CHARGE6) is given here. The theory distinguishes between substituent effets over one, two and three bonds, whih are attributed to the eletroni effets of the substituents, and longer range effets due to the eletri fields, steri effets and anisotropy of the substituents. The CHARGE sheme alulates the effets of atoms on the partial atomi harge of the atom under onsideration, based upon lassial onepts of indutive and resonane ontributions. If we onsider an atom I in a four atom fragment I-J-K-L the partial atomi harge on I is due to three effets. There is an α effet from atom J given by the differene in the eletronegativity of atoms I and J, a β effet from atom K proportional to both the eletronegativity of atom K and the polarisability of atom I and a γ effet from atom L given by the produt of the atomi polarisabilities of atoms I and L. The important arbon γ effet (i.e. CCCH) is parametrised separately and is given by a simple osθ dependane where θ is the CCCH dihedral angle. There are also routines for the methyl γ effet and for the derease in the γ effet of the eletronegative oxygen and fluorine atoms for CX 2 and CX 3 groups. The total harge is given by summing these effets and the partial atomi harges (q) onverted to shift values using eqn. (1). δ = q 6.68 (1) The effets of more distant atoms on the proton hemial shifts are due to steri, anisotropi and eletri field ontributions. H H steri interations were found to be shielding and X H (X = C, F, Cl, Br, I) interations deshielding aording to a simple r 6 dependane [eqn. (2)], where a S is a oeffiient for the steri effet of the atom. δ steri = a S /r 6 (2) Furthermore any X H steri ontributions on a methylene or methyl proton resulted in a push-pull effet (shielding) on the other proton(s) on the attahed arbon. The effets of the eletri field of the C X bonds (X = H, F, Cl, Br, I, O) were alulated from eqn. (3) where A Z was determined as esu (63 ppm au) and E Z is the omponent of the eletri field along the C H bond. The eletri field for a univalent atom (e.g. fluorine) is alulated as due to the harge on the fluorine atom and an equal and opposite harge on the attahed arbon atom. The vetor sum gives the total eletri field at the proton onerned and the omponent of the eletri field along the C H bond onsidered is E Z in eqn. (3). This δ el = A Z E Z (3) proedure is both simpler and more aurate than the alternative alulation using bond dipoles. The magneti anisotropy of the C C bond was originally inluded using the MConnell equation [eqn. (4)] for a bond with ylindrial symmetry as illustrated in Fig. 1 for the arbonyl group. δ an = χ C C (3os 2 φ 1)/3R 3 (4) In eqn. (4) R is the distane from the perturbing group to the nuleus of interest in Å and is taken from the mid-point of the perturbing group for a symmetri bond suh as the C C bond, Fig. 1 Representation of the anisotropy in an axially symmetri moleule. Note, the signs refer to the hange in the δ values, not to the shielding. Fig. 2 The prinipal axes of the arbonyl bond. φ is the angle between the vetor R and the symmetry axis and χ C C the molar anisotropy of the C C bond. ( χ C C = χ C parl χ C perp) where χ C parl and χ C perp are the suseptibilities parallel and perpendiular to the symmetry axis respetively. These ontributions were then added to the shifts of eqn. (1) to give the alulated shift of eqn. (5). δ total = δ harge δ steri δ an δ el (5) Appliation to the arbonyl group The viinal (HCC O) effets are treated separately in CHARGE and these will need to be evaluated from the observed data. The arbonyl group also has in priniple steri, eletri field and anisotropi effets on protons more than three bonds distant, thus all these have to be inorporated into the model. The steri effets of both the arbonyl arbon and oxygen atoms are not known and therefore a value of the oeffiient a S in eqn. (2) for these atoms must be determined. We assume that the ketone arbon atom has a similar steri effet to a saturated arbon, thus the same value of a S is used. The value of a S for the arbonyl oxygen atom is unknown and needs to be obtained. This and the assoiated push-pull oeffiient are the only additional parameters required for the steri effet. The eletri field of the arbonyl group is alulated in an idential manner to that for any C X bond. The eletri field is alulated as due to the harge on the oxygen atom and an equal and opposite harge on the arbon atom. As the oxygen harge is already alulated in CHARGE and the oeffiient in eqn. (3) is known the eletri field effet is given immediately without any further parametrisation. The anisotropi effet of the arbonyl group also needs to be alulated. The C O group is not an axially symmetri group and has different magneti suseptibilities (χ 1,χ 2 and χ 3 ) along the X 1, X 2 and X 3 axes respetively (Fig. 2). There are two anisotropy terms required for a non-axially symmetri group and thus the full MConnell equation [eqn. (6)] must be used. δ an = [ χ 1 (3os 2 θ 1 1) χ 2 (3os 2 θ 2 1)]/3R 3 (6) In eqn. (6) θ 1 and θ 2 are the angles between the radius vetor R and χ 1 and χ 3 respetively and χ 1 (χ 1 χ 2 ) and χ 2 (χ 3 χ 2 ) are the two anisotropies for the C O bond whih may be termed the parallel and perpendiular anisotropy respetively. In order to apply this alulation to ketones the two anisotropies need to be determined and also it is neessary to determine the effet of the position of the magneti dipole along the C O bond. 442 J. Chem. So., Perkin Trans. 2, 1999,

3 Experimental Materials 2-tert-Butylylohexanone (1) was synthesised by the oxidation of 2-tert-butylylohexanol (Aldrih Chem. Co.) using hromi aid. 4-tert-Butylylohexanone (2), fenhone (3), trans-1- dealone (4), norbornanone (9) and amphor (10) were also obtained from Aldrih. 5α-Androstan-3-one (5), 5α-androstan- 17-one (6), 5α-androstane-3,17-dione (7) and 5α-androstane- 3,11,17-trione (8) were kindly donated by GlaxoWellome. The solvents were obtained ommerially, stored over moleular sieves and used without further purifiation. Spetrometers and spetral details 1 H and 13 C NMR spetra were obtained on a Bruker AMX400 spetrometer operating at MHz for proton and MHz for arbon. Spetra for 2, 4, 5 and 7 were reorded on a Varian 600 (EPSRC servie, Edinburgh University) and 7 and 8 on a Varian 750 MHz spetrometer (GlaxoWellome). HMQC, HMBC and NOE experiments were arried out on the Varian 750 MHz spetrometer. Spetra were reorded in 10 mg m 3 solutions ( 1 H) and a. 50 mg m 3 ( 13 C) with a probe temperature of a. 25 C in CDCl 3 and referened to TMS unless otherwise stated. Typial 1 H onditions were 128 transients, spetral width 3300 Hz, 32k data points, giving an aquisition time of 5 s and zero-filled to 128 k to give a digital resolution of 5 Hz. 2D Experiments were performed on the AMX400 and the Varian 750 MHz spetrometers using the standard Bruker COSY-DQF and HXCO-BI and the standard Varian HMQC and GHMQC-DA pulse sequenes. 18,19 The geometries of the ompounds investigated were obtained by geometry optimizations using the GAUSSIAN94 programme at the RHF/6-31G* level. 20 Full details of these optimizations and geometries are given in ref. 21. The GAUSSIAN94 alulations were performed on the University of Liverpool Central Computing faility, and the CHARGE omputations were performed on a PC. Compound assignments The assignments of ompounds 1 10 are given in Tables 2 to 5. 2-tert-Butylylohexanone (1). The 1 H spetra of 1 in CDCl 3 onsists of a number of omplex patterns whih were assigned from a HET-CORR experiment with the aid of a literature 13 C assignment. 22 This gave the assignment of H2 (δ 2.15) uniquely and the assignments of the protons of the various CH 2 groups. The assignments of the 3, 4 and 5 axial and equatorial protons were made on the basis of their fine struture. The 3e, 5e and 4e protons have omplex splitting patterns entered at δ 2.18, 2.06 and 1.90 respetively, the 4a, 5a and 3a protons have harateristially axial splitting patterns entered at δ, and 1.47 respetively. The 6e and 6a protons give a strongly oupled multiplet entred at δ 2.28 and inspetion of the splitting pattern suggests that H6e is to lower field. This provisional assignment ontrasts with that predited from the alulations (Table 3) in whih the two protons are reversed. 4-tert-Butylylohexanone (2). The H2a and H2e protons are easily assigned as they are the most low field and further examination of the splitting pattern (again an AB type) shows that H2e is at δ and the H2a at δ 2. The H3e proton is at δ but even at 600 MHz the H3a and H4a protons are oinident at δ 0. Fenhone (1,3,3-trimethylbiylo[2.2.1]heptan-2-one) (3). The assignment of this ompound was straightforward, the only diffiulty enountered was the assignment of the 7syn and 7anti protons. This was performed by examining the NOE from the 3exo methyl group, assuming that there would be an NOE to the 7syn proton but not to the 7anti whih formed the basis of the assignment. From this experiment we assign 7syn at δ 1.80 and 7anti at δ The H4 proton is a multiplet with integration 1 entered at δ 2.14, the 5x, 5n, 6x and 6n protons were all assigned by analysis of splitting patterns and examination of a HET-CORR spetrum using a literature 13 C assignment. 23 trans-1-dealone (4). The assignment of this ompound was performed by a variety of methods, the analysis of the AB pattern at δ orresponding to the 2a and 2e protons was arried out using the LAOCOON programme. 24 The results of these analyses are reported separately. 25 The other protons were assigned by onnetivity (HMBC), oupling (COSY- DFTP) and H C orrelation (HMQC) experiments. 5α-Androstan-3-one (5). The 600 MHz spetrum of this ompound onsists of 30 losely oupled protons over a range of 2.4 ppm. Analysis of the multiplets between δ 2.40 and 2.22 shows that unusually the axial 2β proton is downfield of the equatorial 2α proton, due to the ombined deshielding effets of the axial C19 methyl group and the viinal 3-keto group. Further analysis of COSY and HET-CORR experiments at 750 MHz onfirms the previous assignment given by Shneider 12 of the 400 MHz spetrum though in ref. 12 only the SCS were given. 5α-Androstan-17-one (6). The assignment of this ompound has also been reported previously 12 though again only the SCS were given. Again analysis of COSY and HET-CORR experiments at 750 MHz onfirms the assignment. 5α-Androstane-3,17-dione (7). The lowfield part of the 1 H spetrum reveals two well separated AB patterns due to the C2 and C16 protons and a HET-CORR plot together with a previous 13 C assignment 23 showed that the 16β proton is the most downfield. A strong orrelation with this proton in the COSY plot identified the 16α and C15 protons. Analysis of the splitting patterns assigned 15α at δ and 15β at δ The COSY orrelations of the C15 protons assigned the H14 at δ and this proess was repeated for all the ring protons. These assignments were onfirmed from a alulated spetrum using the Bruker WIN-DAISY programme 18 of all the protons in this ompound exept the H6 and H7 protons whih even at 600 MHz are a very strongly oupled multiplet. The results of this analysis are reported elsewhere. 25 5α-Androstane-3,11,17-trione (8). Although this is the most substituted of the 5α-androstanes studied, the spetrum of this ompound showed onsiderable overlap at 400 MHz and thus the spetrum was obtained at 750 MHz. This together with the 13 C spetrum, COSY, HMQC and HMBC experiments were suffiient to obtain a omplete assignment of this ompound. Again a detailed analysis inluding the oupling onstants is given in ref. 25. The spetra of 9 and 10 were also re-examined in detail beause of the importane of these ompounds in the parametrisation (see later). Norbornanone (9). The proton spetrum of 9 was given previously 26 and the assignment was onfirmed by a COSY plot. Camphor (10). The assignment of the proton spetrum of 10 has been the subjet of some ontroversy Both COSY and HET-CORR experiments were performed in order to hek the assignment. Sanders and Hunter 27 assigned all the protons in this moleule inluding the three methyl groups on the basis of a series of elegant NOE experiments and this assignment was subsequently onfirmed by Kaiser et al. 28 Our experiments also J. Chem. So., Perkin Trans. 2, 1999,

4 Table 1 SCS for the 3-keto, 11-keto and 17-keto group in 5α-androstane 3-keto a 11-keto a 17-keto a This work Ref. 12 This work b Ref. 12 This work Ref. 12 1α 1β 2α 2β 3α 3β 4α 4β 5 (CH) 6α 6β 7α 7β 8 (CH) 9 (CH) 11α 11β 12α 12β 14 (CH) 15α 15β 16α 16β 17α 17β 18-Me 19-Me a δ(ketone) δ(androstane). b δ(8) δ(7). SCS < 0.01 ppm. Fig. 3 Carbonyl SCS in trans-1-dealone and norbornanone. Fig. 4 Nomenlature used for 5α-androstan-17-one. onfirmed this assignment though the hemial shifts measured here differ slightly from those reorded previously. Results The above data ombined with the proton hemial shifts of the parent ompounds given previously 15 allow the arbonyl SCS to be obtained in these ompounds. The arbonyl SCS for 4 vs. trans-dealin and 9 vs. norbornane are given in Fig. 3. Also the SCS for the arbonyl group at the 3, 11 and 17 positions in the steroid nuleus obtained here from the data for ompounds 6, 7 and 8 together with the proton hemial shifts of androstane are given and ompared with the results obtained by Shneider et al. 12 in Table 1. In ref. 12 only the SCS were tabulated not the atual proton hemial shifts. Also the SCS for the 11-keto group has been obtained in this investigation as δ(8) δ(7) whereas Shneider et al. 12 obtained this SCS diretly from the analysis of 11-keto androstane. The exellent agreement of the two sets of results in Table 1 is impressive and the additivity of the SCS values in the steroid nuleus is very learly shown by the agreement of the two sets of values for the SCS of the 11-keto group. The arbonyl SCS in these well defined systems are of some interest. In general the γ effet of the arbonyl oxygen atom (i.e. HCC O) is strongly deshielding with however an orientational dependane. For example, in trans-dealone the SCS of the arbonyl group on H2ax (1.07) and H9 () is signifiantly greater than on H2eq (0.69) and this pattern is reprodued in the ylohexanes and steroids. In ontrast in norbornanone the SCS of the arbonyl on H3endo (0.68) is similar to that on H3exo (0.59) and again this is observed in amphor. The long range (>3 bonds) effets of the arbonyl group are also large and extend over both the biyloheptene and dealin system. The effets are usually deshielding with only the 5ax and 6ax protons in trans-dealone showing an upfield shift. This pattern is also observed in the steroid nuleus (Table 1) where very few of the protons show an upfield SCS and these shifts are usually very small with the proton far removed from the keto group. The only marked exeption to this is the SCS of the 11-keto group at the 1α proton ( 0.15 ppm) and this is aompanied by a large positive SCS (0.74 ppm) at the 1β proton. The ombined effet of these shifts is so large that these two methylene protons our at the two extremes of the proton spetrum in 8 (apart from the methyl groups). We shall show that these shifts may be ompletely explained by our present theories. The data olleted in Tables 2 5 provide a rigorous test of the appliation of both the CHARGE model and also present theories of arbonyl SCS to these ompounds. The ompounds listed in the tables are all of fixed onformation with the possible exeption of the five membered rings of ylopentanone and ring D of the steroid nuleus, whih may exhibit some onformational flexibility. The GAUSSIAN94 (6-31G*) alulations gave the ylopentanone geometry as the half-hair (Cs) onformation in agreement with both moleular mehanis (PCMODEL) alulations 31 and the experimental gas phase geometries. 32 Similar alulations for the saturated ring D of androstan-3-one gave the same geometry as obtained for androstane, 15 i.e. as a C13-envelope with C14, C15, C16 and 444 J. Chem. So., Perkin Trans. 2, 1999,

5 Table 2 Observed vs. alulated proton hemial shifts (δ) of ayli and yli ketones Compound Cal. Compound Cal. Aetaldehyde Aetone Cylopentanone Pinaolone Cylohexanone Me CHO Me Hα Hβ Me t Bu H2,6 H3,5 H trans-1-dealone 2a 2e 3a 3e 4a 4e 5a 5e 6a 6e 7a 7e 8a 8e a Ref. 29. b This work. Table 3 Observed vs. alulated hemial shifts in substituted ylohexanones 2-Methylylohexanone 3-Methylylohexanone 4-Methylylohexanone 2-tert-Butylylohexanone 4-tert-Butylylohexanone Cal. Cal. Cal. Cal. Cal. 2a 2e 3a 3e 4a 4e 5a 5e 6a 6e t Bu a Ref. 30. b This work. Table 4 systems 1 3x 3n 4 5x 5n 6x 6n 7s 7a 8(Me) 9(Me) 10(Me) 3x(Me) 3n(Me) Calulated vs. observed hemial shifts in biyloheptane Camphor Cal Norbornanone Cal Fenhone (Me) Cal. 1.00(Me) a Data from ref. 25, assignments from refs. 26 and 27. b Ref. 25. This work. C17 more or less in a plane with only a 9.5 twist. In the 17-keto ompounds (6, 7 and 8) the GAUSSIAN (and PCMODEL) alulations gave the onformation of ring D as a C14 envelope with C13, C15, C16 and C17 almost oplanar and this is in agreement with the observed oupling onstants for ring D. 21 In the CHARGE model the γ effets of the substituents are onsidered to be due to eletroni effets and therefore they are modelled on a simple empirial basis. For the ketones studied here we initially made the assumption that the eletroni γ effets of the arbonyl arbon (HCCC O) are the same as for a saturated arbon atom whih is already inorporated into the CHARGE sheme. Subsequently a small orretion (0.1 ppm) was added. However the γ effets of the arbonyl oxygen (HCC O) need to be determined. As mentioned earlier inspetion of the data of Fig. 3 and Tables 1 5 shows that there is learly an orientation dependane of the arbonyl γ SCS. In the similar analysis of saturated arbon (HCCC) and oxygen (HCCO) γ effets a simple angular funtion (A Bos θ) was found to be appropriate with values of the oeffiients A and B determined by the observed data. Thus this approah was initially used here. However more detailed inspetion of the observed data showed that the arbonyl γ SCS were also dependant on the bond angle (α) of the arbonyl group (CC(O)C). In partiular the five-membered ring ketones with arbonyl bond angles a have quite different SCS to the six-membered ketones with bond angles a This additional funtionality was therefore inorporated into the arbonyl oxygen γ effet again as a simple os α dependane. The oeffiients in this equation were then determined from the observed SCS by an iterative least mean squares alulation to give finally eqn. (7) for the arbonyl gamma effet (GSEF). J. Chem. So., Perkin Trans. 2, 1999,

6 Table 5 Observed a vs. alulated hemial shifts in 5α-androstanones 3-one (5) 11-one 17-one (6) 3,17-dione (7) 3,11,17-trione (8) Cal. Cal. Cal. Cal. Cal. 1α 1β 2α 2β 3α 3β 4α 4β 5 6α 6β 7α 7β α 11β 12α 12β 14 15α 15β 16α 16β 17α 17β 18(Me) 19(Me) a This work. b δ values from SCS (Table 1) and δ(5α-androstane), ref. 15. GSEF = 0.09 ( osα)(2.0 os θ) (7) This equation gave generally good agreement for all the viinal protons in the data set (a total of 50 protons). These results will be disussed later. Long-range effets The interations onsidered to be responsible for the long range effets of the arbonyl group have been doumented earlier as steri, eletri field and magneti anisotropy effets. We are now in a position to test these theories against the observed data presented in the tables. It is onvenient to onsider first the eletri field effet as there are no additional parameters required to alulate the eletri field effets of the arbonyl group from eqn. (3). There is the impliit assumption that the harges used in eqn. (3) provide a reasonable measure of the eletri field of the arbonyl group. The partial atomi harges alulated in the CHARGE routine have been derived from the observed moleular dipole moments and the extent of the agreement provides one hek of the eletri field alulation. The alulated and observed (in parenthesis) dipole moments (in debye) of formaldehyde, aetaldehyde, aetone and ylohexanone are 2.28 (2.34), 2.68 (2.68), 3.03 (2.86) and 3.03 (3.08) and the exellent agreement provides strong support for the use of these harges in the alulations. As the oeffiient in eqn. (3) is known together with the moleular geometries the eletri field effet of the arbonyl group at any proton more than three bonds removed from the arbonyl oxygen atom is given immediately. These values will be disussed later. In ontrast to the above, the steri and anisotropi terms are not known and both the steri oeffiient a s [eqn. (2)] for the oxygen atom and the magneti anisotropies χ 1 and χ 2 [eqn. (6)] need to be evaluated. In addition there is a push-pull oeffiient for the steri effet and also the position of the magneti anisotropy along the arbonyl bond needs to be determined. It is beause of this multifuntional parametrisation that it is essential to have a large and diverse data set. The data set of the non-viinal protons used here omprises 112 proton shifts and the iterations were ahieved using a non-linear least mean squares programme (CHAP8). 33 The iterations were initially arried out on the observed SCS in order to eliminate any errors in the alulated shifts of the parent hydroarbons, but subsequently the observed hemial shifts were used. The results are of some interest. All the iterations inluding the steri term plus the anisotropy terms gave no better results than the orresponding iterations without the steri term. Thus the steri term for the arbonyl oxygen atom was removed. Also the values of the parallel anisotropy ( χ 1 ) obtained from the iterations were always muh larger than those for the perpendiular anisotropy χ 2. These alulations were all performed with the arbonyl anisotropies plaed at the midpoint of the C O bond. It was found that the best iteration still gave signifiant errors for some protons in the biyloheptanones (Table 4). In partiular the observed 6exo and 6endo SCS were muh smaller than alulated. However plaing the anisotropy at the arbonyl arbon atom gave muh better agreement for these protons without any signifiant effet for the remaining protons in the data set. The final values of the anisotropies obtained were χ and χ (10 30 m 3 moleule 1 ) and these together with the results obtained an now be onsidered. The observed vs. alulated proton shifts for the ketones onsidered are given in Tables 2 5 and it is of some interest to onsider these results. The general agreement of the observed vs. alulated shifts is very good and the great majority of the observed shifts are reprodued to better than 0.1 ppm. This is as good as ould be expeted as the observed vs. alulated proton shifts for the orresponding hydroarbons are only to a. 0.1 ppm. The agreement is partiularly striking for the hair onformations of dealone (Table 2) and the methylylohexanones (Table 3) with no error larger than 0.2 ppm. Also the general agreement for the steroid ketones is enouraging though in this quite sterially ompressed system there are 446 J. Chem. So., Perkin Trans. 2, 1999,

7 larger errors in the alulated shifts for some of the protons in the base hydroarbon androstane. In partiular the 7β and 15β protons are the only resolved protons in androstane with errors >0.2 ppm probably due to large steri interations and this transfers to the steroid ketones. The good agreement for the C1 protons in the 3,11,17-trione (Table 5) is partiularly noteworthy as the 1β proton in the 11-ketosteroids is very lose to the 11-keto oxygen and the SCS for this proton provides a ritial test of the model. Indeed Shneider et al. 12 noted that the 1β proton deviated appreiably (by 0.6 ppm) from their alulated value, based on a dipole model of the eletri field and ApSimon s anisotropy equation. The alulated shifts in the biyloheptanone systems are also in generally good agreement with the observed shifts (Table 4) though there are some signifiant errors. It may be signifiant that in the biyloheptane system it was neessary to onsider possible orbital interations between the bridging C7 arbon and the ring arbons in order to reprodue the observed shifts in these moleules using the CHARGE model. 17 However the largest errors in Table 4 are for the 6exo and 6endo protons in amphor and fenhone in whih both the alulated proton shifts and the SCS are muh less than the observed values (by a ppm). This deviation does not appear to be a funtion of the biyli ring system as in norbornanone both the alulated shifts and the SCS at the C6 protons are in good agreement with the observed values. Why the introdution of methyl groups should affet the SCS of the arbonyl group is not lear. The proton shifts of amphor were obtained in solvents of varying polarity (CCl 4, CDCl 3, aetone and methanol) in order to determine if any intramoleular hydrogen bonding between the arbonyl oxygen and the methyl protons was ourring but the shifts were as expeted with no evidene of any suh interation. The only ayli ompounds investigated are the simple ompounds in Table 2 as all other ayli ketones exist in two or more onformations. The observed shifts for aetone and aetaldehyde are both slightly greater than alulated and this may be due to solvation effets. On the reation field model for any given solvent the solvation shifts are proportional to both the dipole moment and to the reiproal of the volume of the solute. 34 Thus in these small polar moleules solvent effets will be most pronouned. The values of the arbonyl anisotropy determined here are also of interest. In all the iterations performed the value of the parallel anisotropy χ 1 remained reasonably onstant at a. 20 (10 30 m 3 moleule 1 ). In the final iteration the value obtained was However the value of the perpendiular anisotropy χ 2 varied onsiderably with both positive and negative values obtained during the iterations. The last iteration gave a value of 3.2. The variability is a onsequene of the small effet this parameter has on the proton hemial shifts. The only definitive method of determining this parameter would be to obtain SCS from protons situated both at the sides and immediately above the arbonyl group. Although examples of the first type are present in the olleted data (e.g. the C8 protons in 1-dealone ) we were unable to obtain suitable ompounds in whih protons were situated immediately above the arbonyl group. The value of the arbonyl anisotropy obtained here (f. Fig. 2) is χ 1 χ and χ 3 χ 2 3.2, hene χ 1 χ 3 equals Comparison with the results of previous investigations is not failitated by the different nomenlatures used. Zurher 7 defined χ 1 = χ 1 χ 3 and χ 2 = χ 2 χ 3. ApSimon 9 and also Shneider 12 and Williamson 13 write the anisotropy equation [f. eqn. (6)] as (1 3os 2 θ) whih merely reverses the sign of χ. Also the definition of the x, y, and z axes differs in these investigations. Converting to the nomenlature of Fig. 2 and eqn. (6) gives values of χ 1 χ 2, χ 3 χ 2 and χ 1 χ 3 of 17.1, 3.2, 13.9 (this work), 13.5, 12.2, 25.7 (ref. 7), 21, 6, 27 (ref. 9), 24, 12, 36 (ref. 12) and 4, 9, 13 (ref. 13). There is generally reasonable agreement for the value of the parallel anisotropy Table 6 Calulated vs. observed SCS for trans-1-dealone (4) with the eletri field and anisotropy ontributions 2a 2e 3a 3e 4a 4e 5a 5e 6a 6e 7a 7e 8a 8e 9H 10H (χ 1 χ 2 or χ 1 χ 3 ) apart from Williamson s value but the value of χ 3 χ 2 is not well defined. This reinfores the aveat above onerning the unertainty in the value of χ 2. It is probable that Shneider 12 used the orretion to the MConnell eqn. (6) given by ApSimon though this is not expliitly stated in ref. 12 and this may affet the values of the anisotropies they obtained. It is of some interest to onsider the atual magnitudes of the various ontributions to the arbonyl SCS and Table 6 gives the observed vs. alulated SCS for trans-1-dealone with the alulated eletri field and anisotropy ontributions. The table learly shows that both effets are important in determining arbonyl SCS. The table also shows that other ontributions are present in determining the SCS. For example, the sum of the eletri field plus anisotropy ontributions for the 8a and 8e protons are and 0.01 ppm whereas the alulated SCS are 0.40 and 0.30 ppm. The additional ontribution in this ase stems from the H H steri interation. The 8a and 8e protons in trans-dealin experiene a large high-field shift due to the proximity of the 1a and 1e protons and these protons are upfield from axial ylohexane (δ 0.93 vs for the axial protons and δ 1.54 vs for the equatorial protons) as a result. This steri interation is removed when these protons are replaed by the arbonyl group giving an additional low-field shift. This effet is also observed in the SCS of H10 in whih there is a 1,3-diaxial H H interation with H1ax in transdealin whih is absent in 1-dealone. Apart from these speial ases the anisotropi and eletri field ontributions determine the arbonyl SCS though the relative size of these ontributions varies onsiderably with the orientation of the proton from the arbonyl group. Aknowledgements We thank the EPSRC and GlaxoWellome Ltd. for a CASE researh studentship (N. J. A.) and Drs Rihard Upton and John Hollerton for the samples of the keto-steroids and for the 750 MHz spetrum of 4, 7 and 8 and for their ontinuing support during this work. We also thank Dr I. Sadler and the high-field NMR servie at Edinburgh for the 600 MHz spetra of 2, 4, 5 and 7. We are pleased to aknowledge the assistane of Dr P. D. Mallinson and the University of Liverpool entral omputing faility for the operation of GAUSSIAN94. Referenes Cal Eletri field Anisotropy Part 12, R. J. Abraham, L. Griffiths and M. A. Warne, J. Chem. So., Perkin Trans. 2, 1998, R. J. Abraham, J. Fisher and P. Loftus, Introdution to NMR Spetrosopy, J. Wiley, 1988, p P. T. Narasimhan and M. T. Rogers, J. Phys. Chem., 1959, 63, J. Chem. So., Perkin Trans. 2, 1999,

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