We have seen that staggered conformers of small hydrocarbons (e.g. ethane & butane) are more stable than eclipsed conformers and generally predominate at equilibrium. This structural preference is usually attributed to steric effects, and has been termed torsional strain (or Pitzer strain). In the case of ethane, rotation towards an eclipsed structure brings the electrons in C–H bonds on the different C atoms closer to each other, thereby increasing repulsion. The distance between closest hydrogen atoms in ethane is roughly 2.5 Å in the staggered form, compared with 2.3 Å in the eclipsed rotamer. This latter distance is comparable to known instances of steric hindrance, such as the hydrogens in axial-methylcyclohexane and ortho hydrogens in biphenyl. However, since the bond vectors in ethane are diverging by nearly 40º, this comparison may not be compelling.
Since the eclipsed conformer of ethane has three eclipsed C–H bonds, it is tempting to attribute 1.0 kcal/mole of strain to each, resulting in a total of 3 kcal/mole torsion strain. Indeed, it has been noted that the rotational energy barriers in methyl amine and methanol are lower by 1 kcal/mole for each eclipsed C–H bond that is missing, as shown in group A of the following diagram. Although the non-bonding electron pair(s) in these compounds are shown in spatially directed sp 3 orbitals, the exact location is a subject of debate and they do not appear to offer any significant steric hindrance. It might be argued that the C–X bond length is shortened and the C–X–H bond angle narrowed in the alcohol and amine, but molecular structure calculations indicate the eclipsed H—H distance remains the same.
Recent studies of rotational barriers in substituted ethanes suggest that a significant contribution comes from sigma bond-antibond interactions which stabilize an anti configuration of W and Z groups in W –C–C– Z constitutions, relative to their gauche orientation. This stereoelectronic factor, which is similar to hyperconjugation, becomes larger as the electronegativity difference between W and Z increases. The conformational preferences of 1,2-difluoroethane and 1-fluoropropane provide instructive examples, as shown on the right.
Although 1,2-difluoroethane should suffer dipole repulsion as the fluorine atoms approach each other, the gauche form is more stable than the anti conformer (ΔHº = 0.6 kcal/mol). This surprising fact may be explained by the two hyperconjugative bond interactions in the gauche form, shown by the resonance formulas in the gray-shaded box. These act to stabilize the gauche rotamer, and do not exist in the anti conformer. The overall barrier to rotation in this compound is about 6 kcal/mol, significantly lower than the dichloro analog discussed above.
A comparison of 1,2-difluoroethane and 1,2-dichloroethane is informative. The bond dipoles of C–F and C–Cl are similar, with the latter being slightly larger because of its longer bond. The hyperconjugative interactions that stabilize the gauche rotamer are stronger for fluorine than for chlorine, due to the former’s greater electronegativity relative to hydrogen. Taken together, these differences shift the conformational equilibria of 1,2-dihaloethanes from preferentially anti in the chloro, bromo and iodo compounds to gauche for the difluoride.
The case of 1-fluoropropane demonstrates another factor. The C2–C3 rotational barrier is about 1 kcal/mol less than that of butane, and the gauche conformer is slightly favored (ΔHº = 0.09 kcal/mol). A similar behavior is observed for 1-chloropropane. Hyperconjugative stabilization is possible for all staggered conformations, and is probably not a determining factor. When the strong C–F bond dipole rotates to approach the CH3–CH2 bond it induces an opposite dipole in that bond. As drawn on the right above, this may actually result in an attractive interaction between the methyl and fluorine substituents (as well as methyl and chlorine in 1-chloropropane).
The concepts described above have been used to explain and predict many other cases of conformational isomerism. Three such examples are shown below, all measured in the gas phase. The rotational barriers of the two 2,3-dichlorobutane diastereomers are significantly different, the meso isomer being ΔHº = 12.5 kcal/mol, and the racemic compound being ΔHº = 9.5 kcal/mol.
Rotamer Barriers in Unsaturated Compounds
The rotation of a methyl group (or any alkyl group) relative to a double bond is an important conformational event. Propene provides a simple example, as shown below. In the course of the methyl rotation a C–H bond eclipses either an sp 2 C–H bond or the C=CH2 bond, but not simultaneously. The energy of this rotation follows a simple sine-curve similar to the rotational barrier of ethane, with a smaller amplitude (ca. 2 kcal/mol). The conformer in which the C=CH2 bond is eclipsed is the lower energy rotamer, possibly reflecting a stabilizing interaction between σ-C–H bonds of methyl and the π*-antibonding orbital. This conformer will be termed eclipsed, and the higher energy alternative bisected.
Adding a methyl group to propene, as in 1-butene, doubles the number of eclipsed and bisected conformers. Interestingly, the overall rotational barrier is reduced, and the energy difference between the two eclipsed rotamers is over twenty times greater than the difference between the two bisected forms. This is illustrated in the following diagram. The eclipsing shown by magenta colored arrows in conformer B2 is referred to as allylic 1,2-strain (A 1,2-strain). If the vinyl hydrogen is replaced by a larger methyl group, as in 2-methyl-1-butene, this strain adds about 1.3 kcal/mol to the rotational barrier.
A larger substituent, such as tert-butyl in 3,3-dimethyl-1-butene, does not change significantly the stability order of eclipsed relative to bisected rotamers.
Double bond stereoisomers, such as (E) and (Z)-2-pentene have very different rotational energy barriers. The E-isomer, shown below, has a rotational profile very similar to that of 1-butene (above). Since the C-1 methyl is directed away from the ethyl group, this is not surprising.
For the Z-isomer, the C-1 methyl is cis to the ethyl group, leading to severe steric crowding in the E1 and B1 conformers, shown again by colored arrows. This destabilizing hindrance is called allylic 1,3-strain (A 1,3-strain). Unexpectedly, A 1,3-strain renders eclipsed conformer E2 slightly higher in energy than bisected conformer B2. The perpendicular conformation, P, is lower in energy than either E2 or B2.
To examine an energy plot of these rotamers click the following button:
Aldehydes and Ketones
The conformations and rotational energy profile of acetaldehyde, shown below, are very similar to propene. The activation energy for rotation is half that of propene, reflecting the absence of a hydrogen on the oxygen atom. This is the same kind of change noted earlier for ethane compared with methanol.
By comparison, the conformational energy profile of propanal differs significantly from that of 1-butene. As shown below, conformer E1 is more stable than E2 by roughly 0.8 kcal/mol, reflecting the relatively small size of oxygen. Even the larger substituent in 3-methylbutanal prefers this conformation. Furthermore, the activation energy for interconversion of the chiral eclipsed E2 conformers is very small, and it is not possible to relate experimental behavior to a preferred conformer. Ketones, of course, will exhibit A-1,2-strain in conformer B2.
Although the conformational differences shown here are not large, addition reactions to aldehydes and ketones are sensitive to the configuration of substituents on the α-carbon atom. Because of the importance of such asymmetric induction in the stereoselective formation of new stereogenic centers, it has been extensively studied. A full discussion of this topic is available in the stereoelectronic effects section of this text.
Esters and Amides
Esters and amides generally have higher rotational barriers and greater conformational preference than do aldehydes and ketones, with the s-Z form (sometimes termed s-trans) being more stable, as illustrated in the following diagram. (This notation, which refers to the alkoxy sigma-bond to the carbonyl carbon, corresponds to that used for diene conformations.) For example, the CH3O–CHO barrier in methyl formate is 12 to 13 kcal/mol (s-Z is more stable than s-E by 4.75 kcal/mol), and the enthalpic preference for s-Z increases to ca. 8 kcal/mol in methyl acetate (R 1 = R 2 = CH3).
These planar conformations are favored by a stabilizing n-π conjugation, as shown by the resonance formulas on the right. This requires the delocalizing n-electron pair on the ether oxygen to occupy a p-orbital-like orientation ortho to the plane of the carbonyl group. The remaining n-electron pair must then occupy a sp 2 -orbital, designated by the cyan colored oval. In the s-Z conformer this electron pair overlaps with the anti-bonding C–O σ- bond of the carbonyl group, as described elsewhere. Dipole repulsion also contributes to a destabilization of the cis form.
The contribution of n-π conjugation to the structure of amides is even greater than observed in esters, as indicated by their lower C=O stretching frequency. Thus, the barrier to rotation about the NH2–CHO bond in formamide is over 18 kcal/mol, and the CH3NH–CHO bond in N-methylformamide is more than a kcal/mol greater. Such barriers permit the observation of conformational isomers of amides by room temperature nmr. For simple amides like N-methylacetamide and the formamides noted above, the trans conformer is more stable than cis by more than 1.5 to 2.5 kcal/mol.
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Conformations of cyclohexane and its simple substituted derivatives have been described elsewhere in this text. The chair conformation is the favored configuration, and bulky substituents prefer to occupy an equatorial location. The left hand structures and table in the following diagram summarize the free energy differences between equatorial and axial orientations of some simple groups. These energies are commonly reported as A values. An axial methyl group is hindered by two gauche butane interactions, each accounting for ca. 0.9 kcal/mol. Since an axial ethyl group may rotate so that it appears no larger than a methyl to the remaining axial hydrogens on the same side of the ring, its A value is the same as methyl. Larger alkyl groups have increased A values, commensurate with increased crowding with the axial hydrogens. The trimethylsilyl group has a value half that of a tert-butyl group, reflecting the longer bond length of C–Si. Click the button for a table of common A values.
The heterocyclic compounds on the right side of the diagram illustrate the decreased axial hinderance that results from the absence of nearby axial hydrogens. From the smaller but significant energy differences shown, it may be concluded that the steric hindrance of non-bonding electron pairs on oxygen cannot be ignored. Other factors in these cases are the shorter bond length and tighter C-O-C angle, which may act to increase hindrance, as shown by the lower right example.
Inserting a double bond into a cyclohexane ring (exo or endo) introduces distortion that influences structural and chemical behavior. In the case of an exocyclic double bond, an axial hydrogen is removed from one side of the ring, and the increased bond angle at the sp 2 -carbon expands some of the remaining axial:axial distances. The conformational preference for an equatorial methyl substituent in 3-methylcyclohexanone is thereby reduced, as shown on the left of the following diagram. However, the change in bond angle perturbs the strain free cyclohexane configuration to such a degree that double bond addition reactions are exceptionally favored. Thus, the heat of hydrogenation of methylenecyclohexane is roughly 1 kcal/mol greater than that of methylenecyclopentane or methylenecycloheptane. Furthermore, the rate and equilibria constants for addition reactions of cyclohexanone are greater than those for comparable reactions of similar ketones.
The endocyclic double bond in cyclohexene produces an even greater change in structure, as illustrated on the right side of the above diagram. The planar configuration of the double bond favors a pair of half-chair conformations, having a 5.3 kcal/mol equilibrium barrier. A model of a twist chair is displayed on the right. Twisting of the allylic carbons skews the orientation of their axial and equatorial bonds into pseudo axial or equatorial directions. These locations may be identified in the model by clicking the last button.
Allylic strain exists when an equatorial allylic substituent is hindered by a substituent on the double bond. A good example of how this strain may influence the course of a reaction is found in enamine formation from α-substituted cyclohexanones. The following equations are typical. Most significantly, the enamine double bond is generally formed away from the α-substitution, especially with pyrrolidine. The A 1,3-strain shown in the bracketed formulas is undoubtedly responsible for this regioselectivity. Second, when a reference point exists, the α-substituent is found to be axial in the final product, reflecting A 1,2-strain.
Allylic strain We have seen that staggered conformers of small hydrocarbons (e.g. ethane & butane) are more stable than eclipsed conformers and generally predominate at equilibrium. This
1,3-Allylic Strain as a Strategic Diversification Element For Constructing Libraries of Substituted 2-Arylpiperidines
Dr. Thomas C. Coombs
Chemical Methodologies and Library Development Center, University of Kansas, Delbert M. Shankel Structural Biology Center, 2121 Simons Drive, West Campus, Lawrence, KS 66047 (USA)
Dr. Gerald H. Lushington
Molecular Graphics Laboratory, University of Kansas, 1251 Wescoe Hall Drive, Malott Hall, Room 6044, Lawrence, KS 66047 (USA)
Dr. Justin Douglas
NMR Laboratory, University of Kansas, 1251 Wescoe Hall Drive, Malott Hall, Room 6044, Lawrence, KS 66047 (USA)
Prof. Dr. Jeffrey Aubé
Chemical Methodologies and Library Development Center, University of Kansas, Delbert M. Shankel Structural Biology Center, 2121 Simons Drive, West Campus, Lawrence, KS 66047 (USA)
Minimization of 1,3-allylic strain is a recurring element in the design of a stereochemically- and spatially-diverse collection of 2-arylpiperidines. Here, stereochemically-diverse scaffolding is first constructed using A 1,3 strain to guide the regioselective addition of nucleophiles, which serve as handles for further substitution. N-substitution with alkyl and acyl substituents again leverages A 1,3 strain to direct each stereoisomer to two different conformer populations, doubling the number of library members.
Screening approaches to probe and drug discovery require access to high-quality small molecule libraries. One contemporary challenge in providing such access is the construction of libraries that maximize the coverage of chemical (functional group), stereochemical, and spatial diversity in a given chemotype.  Although the problem of functional group diversity has been addressed since the earliest days of combinatorial chemistry and parallel synthesis, the incorporation of stereochemical diversity and, more broadly, shape diversity has required the development of new strategies. These include the use of spatially diverse scaffolds or the pre-construction of stereochemically diverse building blocks that are then combined to afford final products (“build–couple–pair”  is an example of this).
In this paper, we describe a conformational switching approach toward shape-diverse piperidine libraries in which the presence or absence of 1,3-allylic strain  is leveraged to enhance both (1) scaffold diversity by regiodivergent opening of epoxide intermediates and (2) the conformational space of the final library through the simple expedient of changing the nature of nitrogen substitution.  The concept is illustrated Figure 1 for a series of 2-aryl substituted piperidines. For a given epoxide isomer, the conformation of the piperidine ring will depend on whether the N1 atom is sp 3 hybridized (Ar preferring an equatorial position due to minimization of 1,3-diaxial interactions) or sp 2 (Ar axial, due to A 1,3 strain in the equatorial isomer  ). Nucleophilic addition to the epoxide would then take place according to the Fürst–Plattner principle  (trans–diaxial opening), leading to two constitutional isomers from this epoxide intermediate (2,4- vs. 2,5-cis Ar/Nu relationships). Stereochemical diversity would then follow by applying the same principles to the alternative epoxide diastereomer, affording the analogous 2,4- and 2,5-trans isomers. Once prepared – and likely following the downstream introduction of functional group diversity – the library could then be N-substituted by a different set of alkyl or acyl substituents, leading to a doubling of the library members through conformational diversity.
Use of A 1,3 strain to control constitutional (2,4- vs. 2,5-Ar/Nu relationship), stereochemical (cis vs. trans), and conformational diversity in piperidine libraries. Functional group diversity arises from variations in Ar, Nu, and R.
We chose to demonstrate this approach by preparing a library based on the triazole-containing piperidines shown in Figure 2 (selected because the arylpiperidine chemotype appears in a number of bioactive compounds and is therefore a desirable library scaffold for broad screening  ). To a first approximation, the expected conformations in one such library are shown (four isomers bearing two different N-groups), demonstrating the range of conformational and configurational space covered by these compounds.
Conformational diversity of targeted library containing sp 3 and sp 2 hybridized N-substituted versions of scaffolds A and B. In all, eight idealized conformers (four amines and four amides, all chair piperidines) are shown in the two overlays. Details, including the calculations of individual structures, are provided in Supporting Information.
To demonstrate the value of 1,3-allylic strain in scaffold preparation, we first carried out the stereochemically- and constitutionally-differentiated scaffold syntheses shown in Scheme 1 . Four 2-aryl-1,2,3,6-tetrahydropyridines were constructed from substituted benzaldehydes  in two steps via bisallylation/N-acylation followed by RCM. The N-acylated derivatives underwent highly stereoselective epoxidation reactions, presumably because the top faces as drawn were blocked by the aromatic groups in the most stable conformations.  Using m-CPBA or methyl(trifluoromethyl)dioxirane,  epoxidation from the less-hindered bottom alkene face afforded anti epoxides 3 (after DBU-mediated Fmoc removal) and 5.  Alternatively, NBS/H2O produced an uncharacterized bromohydrin intermediate,  resulting from trans-diaxial addition of H2O to the bromonium ion formed on the less-hindered bottom alkene face. Treatment with base delivered the corresponding synepoxides 4 and 6. 
Preparation of scaffold precursors via (a) tetrahydropiperidine synthesis and (b) stereoselective epoxidation reactions and allylic strain control of regiochemistry of epoxide ring opening (general conditions for azidation: NaN3, NH4Cl, MeOH/H2O, 60 °C).
Both NH and N-acylated epoxy piperidines were prepared as each was expected to react through the divergent conformations shown in Scheme 1 (b) to provide regioisomeric nucleophilic addition products according to the well-established Fürst–Plattner principle of trans–diaxial epoxide ring opening. [6a] In this way, allylic strain controlled both the stereochemical and regiochemical outcome of scaffold synthesis, delivering all four isomers of the trans-4,5-disubstituted 2-arylpiperidines desired for the targeted library. In only one stereochemical series was no selectivity obtained: epoxide 6 gave an essentially 1:1 mixture due to competing electronic and stereoelectronic preferences for this epoxide (see Supporting Information for details). However, even in this case, we were able to isolate >700 mg quantities of the desired NH azido alcohols in high purity (as was the case for all 16 of the desired scaffolds) for further diversification.
The scaffolds were decorated by removal of the Boc group (if present) followed by either reductive alkylation or N-acylation, and finally, a Cu-induced triazole formation step ( Scheme 2 ).  For this initial, speculative screening library, we chose a relatively small number of substituents that represent a range of aliphatic and aromatic diversity at the newly-introduced positions. The total number of compounds targeted in these steps, where R 1 and R 2 were one of the three substituents shown, was 16 × 9 × 2 = 288 compounds. Following parallel synthesis, the library was prepared for screening by mass-directed HPLC purification, yielding ultimately 268 compounds in >90% purity (UV) and >10 mg quantities. All compounds were characterized by high-resolution mass spectrometry.
A subset of 32 compounds (16 amines and the 16 corresponding amides), comprising four substitution patterns for each of the four stereochemical and constitutional isomers, was subjected to conformational analysis by 1 H NMR coupling constant analysis. The data revealed that each functionalized amino-piperidine isomer adopted the same conformation in solution, regardless of the substituents appended to the core. The same held true for the corresponding amides.
The conformational profiles of the 8 stereochemical families of the triazol-containing piperidines (4 amines and 4 amides) are shown in Figure 3 .  Figure 3a shows overlays of each amino-piperidine (blue) paired with the corresponding amido-piperidine (green) counterpart, highlighting the conformational differences achieved through the introduction of 1,3-allylic strain. Three of the four families of amino-piperidines adopted chair forms placing the 2-aryl substituents equatorial. The 2,4-trans family of amino-piperidines exhibited a slight distortion from ideal chair conformation, while still placing the 2-aryl substituents in a pseudoequatorial. The corresponding 2,5-cis and 2,4-trans families of amido-piperidines adopted the opposite chair forms, placing the 2-aromatic substituents axial. However, rather than adopting chair forms placing all three non-hydrogen substituents (Ph, OH, triazole) in axial positions, the 2,5-trans amido-piperidines exhibited twist-like conformations, and the 2,4-cis amido-piperidines adopted boat conformations. Thus, each of the eight compounds in the family presents the piperidine substituents in a unique three-dimensional array. Taken together, these compounds (and by extension the entire library that they represent) comprise a shape-diverse collection with predictable three-dimensional shapes for use in biological screening and structure-activity relationship (SAR) development ( Figure 3b ).
(a) Overlays contrasting amino-piperidine conformation (blue) with the corresponding amido-piperidine conformation (green) for each isomeric pair (NMR). (b) Overlay showing the chemical space occupied by the entire library. For each case: Ar = Ph, R 1 = 2-thiphene, R 2 = CH2OBz. For individual conformational analyses, see the Supporting Information.
Through these efforts, we have demonstrated a useful protocol for maximizing the stereochemical diversity in a piperidine library using a limited number of scaffolds and building blocks. This approach features the use of 1,3-allylic strain for controlling both the ring opening of epoxide precursors and, thus, constitutional isomerism, as well as the conformations of the final library members. In so doing, a library of 268 drug-like compounds having predictable conformations has been prepared. The compounds prepared in this work are being scrutinized by high-throughput screening whereas the concepts utilized in the present case are currently being applied to the construction of other heterocyclic libraries.
This work was supported by the National Institute of General Medical Sciences (P50 69663).
Supporting information for this article is available on the WWW under http://www.angewandte.org or from the author.
Dr. Thomas C. Coombs, Chemical Methodologies and Library Development Center, University of Kansas, Delbert M. Shankel Structural Biology Center, 2121 Simons Drive, West Campus, Lawrence, KS 66047 (USA)
Dr. Gerald H. Lushington, Molecular Graphics Laboratory, University of Kansas, 1251 Wescoe Hall Drive, Malott Hall, Room 6044, Lawrence, KS 66047 (USA)
Dr. Justin Douglas, NMR Laboratory, University of Kansas, 1251 Wescoe Hall Drive, Malott Hall, Room 6044, Lawrence, KS 66047 (USA)
Prof. Dr. Jeffrey Aubé, Chemical Methodologies and Library Development Center, University of Kansas, Delbert M. Shankel Structural Biology Center, 2121 Simons Drive, West Campus, Lawrence, KS 66047 (USA)
1,3-Allylic Strain as a Strategic Diversification Element For Constructing Libraries of Substituted 2-Arylpiperidines Dr. Thomas C. Coombs Chemical Methodologies and Library Development