Showing papers on "Steric effects published in 1994"

Layered Materials by Molecular Design: Structural Enforcement by Hydrogen Bonding in Guanidinium Alkane- and Arenesulfonates

Abstract: Single crystal X-ray structures of a series of guanidinium alkane- and arensulfonates C(NH 2 ) 3 + RSO 3 - (R=(CH 2 ) x CH 3 (x=0-3), (1S)-(+)-10-camphor, benzene, 1-naphthalene, and 2-naphthalene) reveal self-assembly of the ions into unique two-dimensional hydrogen-bonded sheets directed by hydrogen bonds betwen the six guanidinium protons and the six lone electron pairts of the sulfonate oxygen atoms. The sheets assemble in the third dimension as either single layers or bilayers with interpenetrating R groups, depending upon the steric requirements of the R groups

Molecular Lipophilicity Potential, a tool in 3D QSAR: Method and applications

Abstract: A new method is presented to calculate the Molecular Lipophilicity Potential (MLP). The method is validated by showing that the MLP thus generated on the solvent-accessible surface can be used to back-calculate log P. Because the MLP is shown to be sensitive to conformational effects, the MLP/log P relation is best sought by taking all conformers into account. The MLP method presented here can be used as a third field in CoMFA studies, as illustrated with two series of alpha 1-adrenoceptor ligands. In the first series, the steric, electrostatic and lipophilic fields are highly intercorrelated, and taken separately yield comparable models. In the second series of ligands, the best model is obtained with the lipophilic field alone, allowing insights into ligand-receptor interactions.

Highly Efficient and Accelerated Suzuki Aryl Couplings Mediated by Phosphine-Free Palladium Sources

Abstract: Suzuki aryl cross-couplings employing aryl bromides and aryl iodides proceed under mild conditions (65 o C) with high efficiency (substrate-to-catalyst ratios in excess of 500) in the presence of phosphine-free palladium catalysts derived from palladium acetate, Pd 2 (dba) 3 .C 6 H 6 (dba=dibenzylideneacetone), and [(η 3 -C 3 H 5 )PdCl] 2 . Phosphine inhibition is shown to play a key role in limiting catalytic efficiency; qualitative comparison studies show that the phosphine-free systems are 1-2 orders of magnitude more active than phosphine-supported catalytic systems. Pd[P(Ph) 3 ] 4 proved to be the least active of the catalytic species screened. The phosphine-free methodology appears to be generally applicable; cross-couplings of aryl iodides yielding biaryls 6 and 7 proceed without noticeable steric or electronic effects. Cross-couplings employing aryl bromides are insensitive to electronic effects in the synthesis of 6 but are slowed by steric hindrance in the synthesis of 7. Acceleration of cross-coupling is observed in the presence of polar cosolvents and at high pH

Novel, Very Strong, Uncharged Auxiliary Bases; Design and Synthesis of Monomeric and Polymer‐Bound Triaminoiminophosphorane Bases of Broadly Varied Steric Demand

Abstract: The synthesis and properties of a number of very strong iminophosphorane bases up to an extremely high level of steric hindrance are described. They cover a range of ca. 4 pK units in basicity and a range of more than 11 orders of magnitude in their rates of methylation with methyl iodide. Most of the systems are readily prepared in up to molar quantities, conveniently recovered from their salts and are of high chemical and thermal stability. Crystal structures were determined in order to parametrize a force field, which is utilized in molecular modeling studies offering a rationalization of the observed differences in steric hindrance and basicity. Depending on the degree of steric protection of the basic center, these novel bases are proposed as unprecedented, versatile auxiliary bases in E2 eliminations and in reactions involving deprotonation in the presence of more or less strong electrophiles.

Bilirubin conformational analysis and circular dichroism

Abstract: Typical linear and porphyrin-like structure representations of bilirubin give an incorrect impression of its actual shape and expected solution properties. Conformational alnalysis of bilirubin, assisted by molecular dynamics computations, indicates that (i) nonbonded intramolecular steric interactions are minimized in a ridge-tile shape conformation lying at a global energy minimum on the conformational energy map and (ii) considerable additional stabilization is achieved though a network of intramolecular hydrogen bonds. The linear and porphyrin-like conformations are computed to lie some 37-48 kcal/mol above the isoenergetic global minimum energy conformations, which correspond to superimposable (identical) or to nonsuperimposable (enantiomeric) mirror image intramolecularly hydrogen-bonded ridge-tile conformers

Consequences of Oxidation in Nonplanar Porphyrins: Molecular Structure and Diamagnetism of the .pi. Cation Radical of Copper(II) Octaethyltetraphenylporphyrin

Abstract: Crystal structures are reported for the sterically crowded porphyrin Copper(II) 2,3,7,8,12,13,17,18-octaethyl-5,10,15,20-tetraphenylporphyrin (Cu(OETPP), 1) and its [pi] cation radical Cu(OETPP)[sup [sm bullet]+]ClO[sub 4][sup [minus]] (2). 1 was chosen to assess the consequences of oxidation in a nonplanar porphyrin on the expectation that its multiple peripheral substituents not only induce an S4 saddle conformation on the macrocycle but should also prevent the dimerizations in the solid that have complicated several previous crystallographic studies of porphyrin [pi] cation radicals. Interest in the consequences of oxidation arises from the presence of nonplanar bacteriochlorophylls in photosynthetic reaction centers in which the chromophores lie in van der Waals contact so that even small structural changes induced by electron transfer would alter the electronic coupling between the [pi] cation and anion radicals generated by the primary photochemical charge separation. Oxidation of 1 does indeed result in further conformational changes in 2: an additional ruffling is imposed on the original saddle shape of 1 in which the pyrrole rings twist, the meso carbons move alternately up and down out of the porphyrin plane by approximately 0.2 angstroms, and the phenyl groups rotate further into that plane by more than 10[degree]. 61 refs., 11 figs., 4 tabs.

Amide-amide and amide-water hydrogen bonds : implications for protein folding and stability

Abstract: As a protein folds, many of its main-chain amide groups exchange hydrogen bonds with water for hydrogen bonds with other main-chain amides. The energetic contribution of this exchange to the folding and stability of proteins is unclear.1 Theoretical2, calorimetric3, and spectroscopic4,5 studies indicate that amide–amide hydrogen bonds form readily in nonpolar media. In contrast, amide–amide hydrogen bonds form only at extremely high amide concentrations in water.6 Extensive efforts7 to evaluate the contribution of amide–amide hydrogen bonds to the aqueous stability of a particular receptor–ligand complex ultimately failed to exclude contributions to binding from other forces.8 To assess the importance of amide–amide hydrogen bonds in protein folding and stability, we have determined the relative strength of amide–amide and amide–water hydrogen bonds. Our analyses were performed on the simple peptide Ac-Gly–[β,δ-13C]Pro-OMe (1) and the related amide [13C=O]Ac-Pro-OMe (2).9 In a previous study, the kinetic barrier to prolyl peptide bond isomerization of 1 was shown to depend on the ability of the solvent to donate a hydrogen bond to the amidic carbonyl group.10 Here, the effects of amide solvents and water on this same kinetic barrier were determined using inversion transfer 13C NMR spectroscopy.11 Solvent effects on the amide I vibrational mode of 2 were determined using IR spectroscopy.12 The amide solvents studied mimic amide groups found in proteins.13 The relationship between the free energy of activation for the isomerization of 1 and the frequency of the amide I absorption band of 2 is shown in Figure 1. The amide I vibrational mode absorbs at lower frequencies with increasing strength of a hydrogen bond to the amide oxygen.14 Also, the rate of prolyl peptide bond isomerization is related inversely to the strength of hydrogen bonds formed to the amide oxygen.11 The axes in Figure 1 report independent measures of the ability of a solvent to donate a hydrogen bond to an amide oxygen.15 Figure 1 Plots of ΔG‡ for isomerization of 1 vs υ of amide I vibrational mode of 2 in different solvents. The solvents (neat concentration, M; pKa in Me2SO, if known24) were as follows: ◇, dioxane (11.7); △, N,N-dimethylformamide ... The data in Figure 1 show that water donates a strong hydrogen bond to an amidic carbonyl group. The analogous ability of secondary amide solvents, which resemble the main chain of proteins, to donate a hydrogen bond is dramatically less. The concentration of each solvent studied here was >10 M, which is likely to exceed the effective concentration of peptide bonds to one another, at least during the early stages of protein folding. These results suggest that amide–amide hydrogen bond formation alone is unlikely to drive protein folding.16 The data in Figure 1 also show that formamide, which mimics the primary amide in the side chains of asparagine and glutamine residues, is a significantly better hydrogen bond donor than is any of the secondary amides studied, and is almost as good as water.17 This result suggests that side-chain–main-chain hydrogen bonds can contribute more to protein stability than can main-chain–main-chain hydrogen bonds. This idea is consistent with asparagine, glutamine, and glycine being preferred residues at the C-terminus of α-helices.18 There, an amide side chain can donate a hydrogen bond to a main-chain carbonyl group, and a glycine residue can maximize the exposure of a main-chain carbonyl group to solvent water.19 What is the origin of the dramatic difference observed between the hydrogen bond donating abilities of secondary amides and formamide? An important contribution may arise from the effective concentration of donors, since an additional potential donor is always proximal to every hydrogen bond donated by formamide. Alternatively, the observed difference may result largely from steric constraints that restrict the number or geometry of hydrogen bonds donated by secondary amides, as has been proposed for large alcohols.4c,20 Regardless of its origin, the observed differences in hydrogen bond donating abilities are likely to be manifested during protein folding and in folded proteins. Approximately ¾ of the main-chain amides in globular proteins form hydrogen bonds with other main-chain amides.21 Although the formation of such intramolecular amide–amide hydrogen bonds in water can be exothermic,22 the results presented here and elsewhere4 indicate that amides form stronger intermolecular hydrogen bonds with water than with other amides. We conclude that main-chain–main-chain hydrogen bonds can form only in a cooperative process, which is likely to be facilitated by the hydrophobic collapse of the unfolded protein and the consequent shedding of water molecules from main-chain amides.1a We also suggest that the desolvation of individual main-chain amides diminishes the stability of folded proteins.1b,23

Copper(I)/Dioxygen Reactivity of Mononuclear Complexes with Pyridyl and Quinolyl Tripodal Tetradentate Ligands: Reversible Formation of Cu:O2 = 1:1 and 2:1 Adducts

Abstract: Copper(I) complexer possessing a series of related tripodal tetradentate ligands with pyridyl- and/or quinolylcontaining groups have been investigated in reactions with dioxygen (O 2 ). The ligand variations allow for the terting of effects of ligand donor ability and steric factors. Copper-dioxygen complex stabilitier, preference for formation of 1:1 Cu-O 2 and/or 2:1 Cu 2 -O 2 adducts, Cu n -O 2 (n=1, 2), spectroscopic propesties, and reactivity characteristics have been invertigated

The conformation of the sialyl Lewis X ligand changes upon binding to E-selectin.

Abstract: High-field NMR spectroscopy has been used to study the complex formed by the tetrasaccharide sialyl Lewis X and its receptor, E-selectin. Transferred NOEs demonstrate a specific interaction between the protein and ligand and enable measurement of the dissociation constant for the complex to be between approximately 1.1 and 2.0 mM. Differences between Overhauser spectra for free and bound sialyl Lewis X highlight a conformational change upon binding. This can be pinpointed to a change in the torsion angle of the glycosidic link between the sialyl and galactosyl residues and used to select a likely "bound" conformation from four low-energy species. Docking the bound form of sialyl Lewis X onto a model of the lectin domain of E-selectin suggests that the conformational change upon binding results primarily from steric interactions.

Hydrogen bond strength and β‐sheet propensities: The role of a side chain blocking effect

Abstract: Amino acid side chains can enhance peptide group hydrogen bond strength in protein structures by obstructing the competing hydrogen bond to solvent in the unfolded state. Available data indicate that the steric blocking effect contributes an average of 0.5 kJ per residue to protein hydrogen bond strength and accounts for the intrinsic beta-sheet propensities of the amino acids. In available data for helical models, the contribution to alpha-helix propensities is obscured especially by large context-dependent effects. These issues are all related by a common side chain-dependent steric clash which disfavors peptide to water H-bond formation, peptide to catalyst complexation in hydrogen exchange reactions (Bai et al., Proteins 17:75-86, 1993), and peptide to peptide H-bonding in the helical main chain conformation (Creamer and Rose, Proc. Natl. Acad. Sci. U.S.A. 89:5937-5941, 1992) but not in beta-strands.

Palladium-catalysed asymmetric allylic substitution: a ligand design incorporating steric and electronic effects

Abstract: Enantiomerically pure ligands containing a 4,5-dihydrooxazole moiety tethered to an auxiliary sulfur or phosphorus donor have been prepared. These ligands have been exploited for palladium-catalysed asymmetric allylic substitution, providing enantioselectivities of 40–96% ee. The origin of the enantioselectivity in the catalytic reaction is discussed in terms of the steric and electronic influences provided by the ligand.

Enantioselective palladium catalysed allylic substitution. Electronic and steric effects of the ligand.

Abstract: Ligands containing an enantiomerically pure oxazoline and a sulfur-containing tether have been examined for their ability to provide asymmetric induction in palladium catalysed allylic substitution reaction. The enantioselectivity obtained was found to be highly dependent upon the stereochemistry at sulfur (for sulfoxides), and also somewhat dependent upon the nature of the aryl group attached to the sulfur.

Chemical pathways of peptide degradation. VI. Effect of the primary sequence on the pathways of degradation of aspartyl residues in model hexapeptides

Abstract: The influence of the primary sequence on the degradation of Asp4 residues (e.g., formation of the cyclic imide and Asp-X and/or X-Asp amide bond hydrolysis) was investigated using Val-Tyr-Y-Asp-X-Ala hexapeptides. These reactions were proposed to involve cyclization, which would duly be sensitive to steric hindrance. The effects on the rates of individual degradation routes and product distribution under both acidic and alkaline conditions were assessed upon substitutions made on the C-terminal side (X) and on the N-terminal side (Y) of the Asp residue. As expected, the rate of intramolecular formation of cyclic imide and, thus, the product yield were most affected by the size of the amino acid on the C-terminal side of the Asp residue. However, such structural changes had little or no impact on the rate of Asp-X and Y-Asp amide bond hydrolysis. In the former case, the substituted site was one atom removed from the reaction site, accounting for the diminished steric effect observed. As for the latter, the site of substitution was not a participant in the reaction itself, and hence, the rate was unperturbed by this modification. Placing Ser and Val C terminally to the Asp residue prompted racemization and peptide bond hydrolysis to occur under alkaline conditions. N-Terminal substitution of Pro with Gly had no effect on the rate of isomerization via cyclic imide formation but greatly enhanced the rate of Y-Asp amide bond hydrolysis.

Small molecule binding to an artificially created cavity at the active site of cytochrome c peroxidase.

Abstract: In the oxidized "ES" state of cytochrome c peroxidase, Trp-191 is reversibly oxidized to a stable cation free radical by the hypervalent heme. To explore the potential for engineering a binding site for heterocyclic compounds at this site, the mutant W191G was constructed. Two independent crystal structures of W191G at 2.1- and 2.3-A resolution show that W191G contains a well-defined, approximately 180-A3 cavity at the Trp-191 site. The cavity is occupied by five ordered water molecules which participate in an extensive hydrogen-bonding network with each other, with polar main-chain atoms, and with the carboxylate of Asp-235. After a number of heterocyclic compounds were screened, evidence was obtained that substituted imidazoles bind to the cavity of W191G. Titration of W191G with imidazole resulted in a perturbation of the Soret absorption band that was not observed for W191H, W191F, or the native enzyme. The dissociation constants for binding of benzimidazole, imidazole, 2-ethylimidazole, 1-methylimidazole, 2-methylimidazole, and 1,2-dimethylimidazole to W191G were respectively 2.58, 0.70, 0.36, 0.057, 0.047, and 0.027 mM at pH 6.0. The highest binding affinity was exhibited by 1,2-dimethylimidazole, indicating that steric interactions and the efficiency of filling the cavity are important determinants for specificity. The Kd for imidazole binding increased from 0.7 mM at pH 6 to 3.0 mM at pH 8 and could be fit to a single proton ionization curve with a pKa of 7.4, demonstrating the preferential binding by the imidazolium ion (pKa = 7.3). The binding of a number of substituted imidazoles to the cavity of W191G was verified by X-ray crystallographic analysis. The most clearly defined density was observed for W191G crystals soaked in 1 mM 1,2-dimethylimidazole and was consistent with an oriented occupation in which the unsubstituted nitrogen forms a hydrogen bond or ion pair interaction with Asp-235. Thus, enhanced binding of positively charged molecules may be the result of interactions with this carboxylate. An analogous interaction may stabilize the developing positive charge on the Trp-191 radical of the wild-type enzyme. While the oxidation of imidazoles by the ferryl intermediate of W191G was neither expected nor observed, this study has defined the structural determinants for small molecule binding to an artificially created cavity near a heme center which is capable of generating oxidized species at a potential of over 1 V, and these results will guide future attempts for novel substrate oxidation by CCP.

Controlling stereochemistry in C-C and C-H bond formation with electronically asymmetric organometallics and chiral poisons

Abstract: Air stable (cyclopentadienyl)Mo(NO)(halide)(q3-allyl) complexes add to aldehydes to yield homoallylic alcohols in high enantioselectivity and diastereoselectivity. A new strategy, chiral poisoning, is applied to asymmetric hydrogenation and the kinetic resolution of allylic alcohols using transition metal catalysts prepared from racemic bis-phosphine ligands. The activation afforded an organic moiety by complexation led to the extensive development of transition metal reagents for organic synthesis. The increased reactivity is influenced by differences in the steric and electronic nature of the metal and its ligands. Ultimately the environment at the metal can induce high stereoselectivity in reactions involving the coordinated ligands. Our aim has been the improvement of our understanding of the origins of selectivity in these reactions and the application of these principles to the rational design of reagents and catalysts. Our approach modifies the conventional emphasis on steric effects in catalyst design and focuses attention on electronically controlled selectivity. Our initial work emphasized the control which could be obtained with nucleophilic additions to chiral (CpMo(allyl)(NO)(CO))* cations, wherein the difference in electronic influences of the carbonyl and

Lithium Dialkylamide Mixed Aggregation: MNDO Computational Study of Salt and Solvent Dependencies

Abstract: Mixed aggregation of lithium dialkylamides with various LiX salts is studied by semiempirical (MNDO) computational methods. The relative stabilities of mixed aggregates of lithium diisopropylamide and lithium 2,2,6,6- tetramethylpiperidide with LiCl as well as theenolates derived from acetone, cyclohexanone, and 2,4-dimethylpentanone are described. The unsolvated forms are compared with the analogous structures solvated by tetrahydrofuran and hexamethylphosphoramide. The structural types studied include mixed cyclic dimers (R2NLi-LiX), trimers ((R2- NLi)z(LiX)2), and tetramers ((RzNLi)2(LiX)2); 3-rung ladders ((RzNLi)z(LiX)) and 4-rung ladders ((RzNLi)z- (Lix)~); two isomeric open dimer topologies corresponding to cyclic dimers fragmented at N-Li and X-Li bonds; triple ions (RzNLiX-//+Li). A complex interplay of steric effects appears to be the dominant influence on the mixed aggregate structures and relative stabilities.

Hydrogen-bond basicity of esters, lactones and carbonates

Abstract: The thermodynamic hydrogen bond basicity scale pKHB(logarithm of the formation constant of 4-fluorophenol–base complexes in CCl4) has been determined for esters, lactones and carbonates, and correlated to a spectroscopic basicity scale. In the esters R1CO2R2 the hydrogen bond basicity is decreased by bulky alkyl R1 substituents (steric effect) but increased by branched and lengthened alkyl R2 substituents (electronic effects). Quantitative structure–basicity relationships have been established in the XCO2Et (X varying from CF3 to NMe2) and XC6H4CO2Et (X varying from 4-NO2 to 4-NMe2) series. Vinylology strongly increases hydrogen bond basicity—Me2NCHCHCO2Et is the most basic ester presently known. Cyclisation increases the hydrogen bond basicity of esters and carbonates.

Electronic effects in asymmetric catalysis: Enantioselective carbon-carbon bond forming processes

Abstract: Transition metal complexes of 1,Zdiol phosphinites and phosphites derived from readily available sugars catalyze a variety of asymmetric reactions of prochiral olefins including the asymmetric Makovnikov addition of HCN to vinyl arenes. The enantioselectivity of this reaction can be optimized by steric and electronic tuning of a readily available carbohydrate-derived ligand system. Both R and S enantiomers of a prototypical 2- arylpropionitrile, a precursor to widely used 2-arylpropionic acids, can thus be synthesized over 90 % enantiomeric excess at or below room temperature. An unusual electronic effect on the selectivity of this reaction may have wider implications for other related reactions.

Dioxygen and Carbon Monoxide Binding to Apolar Cyclophane Hemes: Durene-Capped Hemes

Abstract: Detailed solution kinetic and equilibria data (mainly in toluene) are presented for the reversible binding of CO and O2 to the five-coordinate hemes Fe(por)B, where B is 1,5-dicyclohexylimidazole or 1,2-dimethylimidazole (chosen to mimic the R- and T-states, respectively) and por = the dianion of some durene-capped porphyrins with variable length linking methylene straps on either side of the durene moiety (4/4, 5/5, or 7/7 methylencs). Use of spectrophotometric equilibrium titrations from 30 to -50 °C, stopped-flow data, and laser flash photolysis under either CO or CO /02 mixtures, has allowed for determination of on and off rates, equilibrium constants, and, in the case of the 4/4-system, thermodynamic constants for the binding. Increasing steric hindrance provided by the durene cap, in the order 7/7 < 5/5 < 4/4, is generally less than expected from studies with other heme derivatives; in combination with the complete absence of polarity effects, as within nonpolar distal sites, the durene hemes exhibit poor differentiation between CO and O2• However, the distorted 4/4-derivative discriminates between CO and O2 in a novel way through a "proximal effect" associated with deformation of the porphyrin skeleton from planarity, the effect being largely reflected by an increased CO dissociation rate. Reversible dioxygen carrying hemoproteins show considerable differentiation in the coordination of small ligands such as CO and O2 to the iron center. In efforts to elucidate the extent to which this differentiation is governed by steric versus electronic or polar factors associated with the distal environment of the heme (surrounding the vacant sixth site), numerous sterically­ encumbered iron(II) porphyrin model systems, which attempt to mimic the protein active sites, have been synthesized and studied. I - 7 Consistency within studied systems strongly suggests that while steric effects can alter affinity for both O2 and CO, electronic factors largely enhance O2 affinity without appreciably affecting CO affinity.7

Reduction of steric interactions in thiophene–pyridino[c]thiophene copolymers

Abstract: An electroactive polymer with an energy gap of 1.4 eV has been obtained from the monomer 2,5-di(2-thienyl)pyridino[c]thiophene.

Oxyfunctionalization of Nonnatural Targets by Dioxiranes. Selective Oxidation of Centropolyindans

Abstract: The oxyfunctionalization of four centropolyindans, i.e., triptindan (2), 1,1'-(o-phenylene)-2,2'-spirobiindan (3), 10-methyltribenzoquinacene (4), and fenestrindan (5) at the benzylic and/or benzhydrylic C-H bonds of their rigid polycyclic framework has been achieved using dimethyldioxirane 1a and methyl(trifluoromethyl)dioxirane 1b. The latter reagent was found to be considerably more effective than 1a, allowing both partial and complete oxyfunctionalization of the substrates examined. The rigidity of the polycyclic framework and steric factors in 2-5 seem to moderate the reactivity and selectivity of the dioxiranes with respect to O-insertion into benzhydrylic vs benzylic C-H bonds; for instance in the oxyfunctionalization of the angular centrotriindan 3, the secondary benzylic alcohol 12 and the corresponding ketone 10 are obtained, along with the isomeric tertiary alcohol 11. The potentiality of 1b in effecting multiple oxygen insertion into C-H bonds under quite mild conditions was demonstrated by the remarkable high yield 4-fold hydroxylation of fenestrindan (5) at the bridgehead positions. The results are interpreted in terms of an essentially concerted O-insertion by the dioxirane into the C-H bonds encompassed in the rigid framework of the substrates. Adoption of an FMO model, which envisages dioxirane attack along the O-O bond axis toward the carbon atom of the given C-H bonds, provides a rationale for the reactivities and selectivities recorded.

Deuterium and 18O isotope effects on 13C chemical shifts of sterically hindered and/or intramolecularly hydrogen‐bonded o‐hydroxy acyl aromatics

Abstract: A series of sterically hindered o-hydroxy aromatic ketones were synthesized, including benzene, naphthalene, phenanthrene and pyrene derivatives. Deuterium isotope effects on the 13C chemical shifts of 2-hydroxy-1-acenaphthone and other sterically hindered, intramolcularly hydrogen-bonded aromatic ketones (OH exchanged) are shown to be unusual. The two-bond isotope effects are very large. Likewise are the istope effects on CO, C1, C3 and C4 carbon resonances and some show unusual signs. These unusual effects are explained by a higher degree of twist in the deuterio than the protio compound. Steric isotope effects are also observed on OH chemical shifts of sterically hindered o-hydroxy acetyl aromatic compounds deuteriated at the methyl group. These isotope effects show non-additivity. For one-bond isotope effects, 1Δ13C(18O), hydrogen bonding leads to a decrease, whereas twisting of the carbonyl group leads to an increase. Two hydrogen bonds to the same acceptor has a reduced cumulative effect. Data for sterically hindered, hydrogen-bonded compounds are found to fall outside the correlation between δ(17O) and 1Δ13C(18O).