The Anomeric Effect - It's Complicated - The Journal of Organic

Subscriber access provided by Kent State University Libraries

The Anomeric Effect - It's Complicated Kenneth B Wiberg, William F Bailey, Kyle M Lambert, and Zachary D. Stempel J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00707 • Publication Date (Web): 05 Apr 2018 Downloaded from http://pubs.acs.org on April 6, 2018

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 54 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry

The Anomeric Effect – It’s Complicated Kenneth B. Wiberg,*,†1 William F. Bailey,*,‡ Kyle M. Lambert‡ and Zachary D. Stempel‡ †Department of Chemistry, Yale University, 275 Prospect Street, New Haven, CT 06520-8107, United States ‡ Department of Chemistry, University of Connecticut, 55 North Eagleville Rd, Storrs, CT, 06269-3060, United States

[email protected]; [email protected]

ABSTRACT: The origin of the anomeric effect has been reexamined in a coordinated experimental and computational investigation. The results of these studies implicate a number of different, but correlated, interactions that in the aggregate are responsible for the anomeric effect. No single factor is uniquely responsible for the axial preference of a substituent that is the hallmark of the anomeric effect. A CH•••G non-bonded attraction between a polar axial substituent (G) and the syn-axial hydrogen(s) in the heterocycle has been demonstrated experimentally. The hyperconjugation model involving electron transfer from a ring heteroatom to an excited state of an axial C–G bond was shown to be, at most, a minor contributor because of the very small changes in charge density at the ring heteroatom(s): the main charge transfer is 1 ACS Paragon Plus Environment

The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

from hydrogen to G in the H–C–G unit. This appears to result from lengthening the C–G bond to minimize repulsion with the ring atom lone pair(s), and the advantage of having a more positive hydrogen that leads to a stabilizing Coulombic interaction with the ring heteroatom(s). In short, the anomeric effect arises mainly from two separate CH•••G non-bonded Coulombic attractions.

INTRODUCTION Most six-membered heterocycles prefer to adopt chair conformations with equatorially situated alkyl groups. To be sure, there are qualitative differences between such heterocycles and cyclohexane: carbon-heteroatom bond lengths are shorter than carbon-carbon bonds and carbonheteroatom-carbon bond angles are generally smaller than are the corresponding C-C-C bond angles.2 Consequently, alkyl groups generally have a greater preference for the equatorial conformation in heterocycles than in cyclohexane: for example, the conformational energy (– ∆G° or A-value) of a 2-methyl group in 1,3-dioxane is 3.98 kcal/mol3 but only 1.76 kcal/mol in methylcyclohexane.4 Conformational studies of glycosides in the field of carbohydrate chemistry (some of which predate similar studies of carbocycles)5 demonstrated that, although qualitative similarities exist between heterocyclic compounds and their carbocyclic analogs, the presence of a heteroatom in the ring can lead to dramatic differences in conformational behavior. One of the most significant discoveries of the early carbohydrate work was the observation that the ring oxygen in a glycoside influences the conformational preference of a polar substituent at the anomeric carbon. Pyranose derivatives having such substituents were found to adopt a conformation that preferentially places the aglycone in the α-position. Not surprisingly, this contrasteric preference for the axial orientation at the anomeric position in pyranose derivatives was termed the “anomeric effect” in 1958 by Lemieux and Chu.6 The phenomenon is also termed the “Edward2 ACS Paragon Plus Environment

Page 2 of 54

Page 3 of 54 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Lemieux effect” in recognition of similar, contemporary studies by Edward.7,8 It was subsequently found that this so-called effect was not limited to carbohydrates but was a general occurrence observable when a hetero-substituent is located adjacent to a heteroatom in a sixmembered ring. Suffice it to note that the etiology of these observations has been the subject of numerous studies and the resulting voluminous literature has been extensively reviewed.9 In short, the search for a cause (or causes) for this “effect” has captivated chemists for more than 50 years.10 A number of hypotheses have been advanced to account for the anomeric effect.9 The four most frequently considered explanations are summarized pictorially in Figure 1 for the case of a tetrahydropyran. Edward in 1955 suggested that the preference for certain polar substituents (X) at C(1) to adopt the axial position was due to repulsive dipolar interactions in the equatorial conformation that are relieved in the axial conformation of the molecule.7 Indeed, the magnitude of the anomeric effect has been found to be solvent dependent; the more polar isomer, having an equatorial X substituent, seems to be stabilized relative to its less polar anomer in solvents of high dielectric constant.9 Lemieux and Chu subsequently noted that such electrostatic dipolar interactions may be viewed as Coulombic interactions.6,11 When the bond moments responsible for the dipole-dipole repulsions of Edward are treated as point charges located at the center of each atom, the operation of an attractive Coulombic interaction between an axial X substituent at C(1) and the C(5) position of the ring can be envisioned which enhances the preference for the substituent to adopt the axial position. More recently, this view was extended by the suggestion that an attractive, non-classical CH•••X hydrogen bond exists between the axial X group at C(1) and the syn-axial hydrogen attached to C(5) and this has been reviewed by Takahashi, Kohno and Nishio.12 A currently popular explanation for the effect, first suggested by Altona almost 60

3 ACS Paragon Plus Environment


years ago,13 is a hyperconjugative interaction involving electron delocalization of a 2p-type lone pair on oxygen (often, as here, more conveniently rendered as an sp3 hybridized lone pair) into the adjacent antibonding σ*-orbital of the C(1)–X unit; this stabilizing interaction is most effective when the X group is axial because the sp3 lone pair on oxygen and the axial C–X bond are antiperiplanar.14 Such an interaction should lead to a lengthening of the axial C(1)–X bond and a shortening of the C(1)–O bond as is often observed in molecules that display an anomeric effect.9 It has been argued by many that this stereoelectronic, hyperconjugative interaction is the principal factor that results in the anomeric effect9,10 but this view is not universally accepted.15,16


Page 4 of 54

Page 5 of 54 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 1. Hypotheses advanced to account for the anomeric effect.

We were prompted by our longstanding interest in the anomeric effect17 to reexamine all four of the hypotheses summarized in Figure 1 in a coordinated experimental and computational investigation of the anomeric effect.



RESULTS AND DISCUSSION Experimental Studies of the Role of Intramolecular Coulombic Attraction. There is abundant experimental evidence that electrostatic effects, arising from dipole-dipole interactions that are affected by solvents, play a role in the anomeric effect.9 Much less is known about the potential significance of Coulombic interactions in systems displaying an anomeric effect. We recently presented evidence for an attractive, non-bonded Coulombic interaction of the type CH•••G in a simple cyclohexane derivative that serves to stabilize an axial CN group.18 As illustrated in Figure 2, replacement of cis-3,5-dimethyl holding groups in anancomeric models with electron-withdrawing CF3 groups dramatically increases the proportion of the axial cyano isomer present at equilibrium in cyclohexane solvent. The CF3 groups render both the C(3,5) carbons as well as the attached syn-axial hydrogens more positive vis-à-vis the 3,5-dimethyl cyclohexane. This observation implicated an attractive, non-classical CH•••CN hydrogen bond of the type illustrated in Figure 1 between the axial CN and the rather positive syn-axial hydrogens as a major contributor to the axial stability in the system bearing CF3 groups. Moreover, it is known from experimental studies that the hydrogen of C–H bonds in alkanes has a small positive charge19 and a more modest CH•••CN hydrogen bond may also be involved in the di-CH3 system.18

Figure 2. Effect of electron-withdrawing holding groups on the conformational energy of a CN group. 6 ACS Paragon Plus Environment

Page 6 of 54

Page 7 of 54 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


In an effort to explore the extent to which Coulombic interactions of this kind contribute to an anomeric effect in heterocyclic systems, we have investigated the axial-equatorial energy difference in 1,3-dioxanes bearing 2-OCH3 or 2-CN substituents. Conformational equilibria of this sort are investigated most conveniently by equilibration of configurationally isomeric models for the conformational isomers and, as Eliel has demonstrated,20 a cis-4,6-dimethyl-1,3dioxane is a good surrogate for the unbiased system. We reasoned that the axial preference of a polar group such as methoxy or cyano at C(2) of the 1,3-dioxane should be enhanced when cis-4,6-di-CH3 holding groups are replaced with strongly electron-withdrawing CF3 groups as was the case for the cyanocyclohexanes depicted in Figure 2. The electron-withdrawing CF3 groups at C(4) and C(6) would render the both the carbons as well as the attached syn-axial hydrogens more positive than is the case in a 1,3dioxane bearing di-CH3 groups at these positions. Moreover, it might reasonably be anticipated that the CF3 holding groups would withdraw electron density as well from the ring oxygens and lessen a hyperconjugative interaction with the adjacent antibonding σ*-orbital of the polar group at C(2). Both r-2-methoxy-trans-4, trans-6-dimethyl-1,3-dioxane (1) and r-2-methoxy-cis-4, cis-6dimethyl-1,3-dioxane (2) were prepared as described by Eliel and Nader.21 It proved considerably more difficult to prepare the corresponding 4,-6-bis-CF3 substrates (3 and 4): the syntheses are illustrated in Scheme 1.

Scheme 1. Preparation of 2-Methoxy-4,6-bis(trifluoromethyl)-1,3-dioxanes (3 and 4)



Transacetalization of the fluorinated diol mixture with benzaldehyde dimethyl acetal affords the 2-phenyl-1,3-dioxane analogue. Fortunately, r-2-phenyl-cis-4,cis-6-bis(trifluoromethyl)-1,3dioxane, a solid, is isolated as the major product of the condensation. It is worth noting that hydrolysis of the phenyl dioxane to afford meso-1,1,1,5,5,5-hexafluoro-2,4-pentanediol is very slow as the intermediate is apparently severely destabilized by the trifluoromethyl groups. The final step in preparing 3 and 4 was also difficult to accomplish as attempts to perform the condensation with typically employed acid catalysts such as p-TsOH, camphorsulfonic acid, or pyridinium p-toluenesulfonate resulted either in decomposition of the diol or failed altogether to initiate the condensation. Employing BF3•Et2O as a Lewis acid provided 3 and 4 in modest yield, as an approximately 5/1 mixture, but only if the reaction was conducted at room temperature; higher temperatures promoted dehydration of the diol. Careful column chromatography on neutral alumina as described in the Experimental Section allowed for isolation of analytically pure 3 and 4 in the low yields indicated in Scheme 1. The 2-methoxy-4,6-dimethyl-1,3-dioxane isomers (1 and 2) were equilibrated at room temperature (~ 23 °C) in sealed ampules under nitrogen as solutions in dry CH3CN, THF, Et2O,


Page 8 of 54

Page 9 of 54 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


cyclohexane, and n-pentane over dry Amberlyst-15 resin or BF3•Et2O. The 2-methoxy-4,6-bistrifluoromethyl-1,3-dioxane isomers (3 and 4) are rather more recalcitrant and required anhydrous AlCl3 as the catalyst for equilibration in dry THF, Et2O, and cyclohexane; other acids lead to substrate decomposition. Equilibrium was approached independently from samples of each isomer and, after the solutions were neutralized, the area ratio of the isomeric mixtures were determined by capillary GC analysis providing baseline separation. It was judged that equilibrium had been reached when the same area ratios were obtained from initially pure samples of each isomer. Area ratios for each equilibration, which reflect the equilibrium constant for the process, were taken as the average of 10 independent determinations from each side, and the free energy difference for the equilibrium was calculated in the normal way: ∆G° = −RTln K. The results of these studies are summarized in Table 1.

Table 1. Equilibria in 2-Methoxy-1,3-dioxanes 1 ⇌ 2 and 3 ⇌ 4. OCH3 R R

entry 1 2 3 4 5 6 7 8 a

CH3 (1, 2)b

CF3 (3, 4)c

O O

H K = eq / ax R

H

R

catalyst solvent

O O

OCH3

solvent

K

∆G°, kcal/mol a

CH3CN THF Et2O c-C6H12 n-C5H12 THF Et2O c-C6H12

1.075 ± 0.001 0.643 ± 0.002 0.508 ± 0.001 0.421 ± 0.004 0.399 ± 0.001 0.193± 0.001 0.148 ± 0.002 0.069 ± 0.001

–0.042 ± 0.001 +0.259 ± 0.002 +0.399 ± 0.003 +0.509 ± 0.002 +0.541 ± 0.001 +0.986 ± 0.002 +1.123 ± 0.006 +1.575 ± 0.004

Determined at 23 °C; errors in K and ∆G° are propagated standard deviations. b Equilibrated

over Amberlyst-15 or BF3•Et2O. c Equilibrated over anhydrous AlCl3. 9 ACS Paragon Plus Environment


The free energy difference between 1 and 2 in Et2O (Table 1, entry 3) of 0.40 kcal/mol favoring the axial isomer is identical to the 0.41 kcal/mol value determined by Nader and Eliel in 1970.3 There is, however, a substantial solvent effect in the axial-equatorial energy difference between 1 and 2 as would be expected given the rather large difference in the reported dipole moments of 1 (µ = 1.97 D) and 2 (µ = 2.93 D).21 In acetonitrile solvent, the equatorially substituted isomer, 2, is slightly favored by 0.04 kcal/mol (Table 1, entry 1) while in the least polar solvents, the axial isomer, 1, is found to be more stable by ~0.5 kcal/mol (Table 1, entries 4 and 5). An estimate of the free energy difference between 1 and 2 in the gas phase may be obtained by plotting the experimental ∆G° values in CH3CN, THF, pentane and cyclohexane versus the dielectric constant of these solvents using the Onsager function, (ε-1)/(2ε+1).22,23 The plot, shown in Figure 3, suggests that ∆G° in the gas phase is ~0.9 kcal/mol favoring the axial isomer.


Page 10 of 54

Page 11 of 54 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 3. Plot of ∆G° versus (ε-1)/(2ε+1) for 1 ⇌ 2.

Replacement of the CH3 holding groups in 1 and 2 with CF3 groups to give 3 and 4 results in a dramatic increase in the proportion of the axial methoxy isomer (4) present at equilibrium in all solvents studied (Table 1, entries 6 - 8). The effect of solvent polarity on the energy difference between isomers 3 and 4 is roughly twice that found for the di-CH3 isomers 1 and 2: the ∆∆G° for the more polar isomers bearing CF3 groups in THF and cyclohexane is ~0.59 kcal/mol (Table 1, entries 6 and 8) while that for the 4,6-diCH3 isomers in these solvents is only ~0.25 kcal/mol 11 ACS Paragon Plus Environment


(Table 1, entries 2 and 4). Comparison of the ∆G° value in cyclohexane solvent of the 2-OCH3 group (Table 1, entry 4) evaluated in the 4,6-dimethyl system (0.51 kcal/mol) with that found (Table 1, entry 8) in the 4,6-bis-trifluoromethyl system (1.57 kcal/mol) demonstrates that replacement of CH3 groups with CF3 groups effects a 1 kcal/mol change in the proportion of axial 2-OCH3 present at equilibrium. Remarkably, this large modification of the conformational energy of the methoxy group is almost twice as large as the ∆G° value of the group in 2methoxy-4,6-dimethyl-1,3-dioxane. Clearly, intramolecular Coulombic interactions involving attractive, CH•••OCH3 hydrogen bonds between the axial 2-methoxy group and the syn-axial hydrogens are at play here. In this connection, it might be noted that Juaristi and coworkers invoked non-classical hydrogen bonding of this sort to account for the pronounced axial preference of the 2-diphenylphosphoryl group in 1,3-dithiane24 and both Stolow25 and Kleinpeter26 have presented evidence for the operation of attractive Coulombic interactions in cyclohexane derivatives bearing remote, strongly electron-withdrawing substituents. For a direct comparison with the cyanocyclohexanes discussed above (Figure2), 2-cyano-1,3dioxanes with 4,6-dimethyl holding groups (5 and 6) as well as those with 4,6bis(trifluoromethyl) groups (7 and 8) were investigated. The preparation of these substrates is illustrated in Scheme 2.

Scheme 2. Preparation of 2-Cyano-4,6-dimethyl-1,3-dioxanes (5 and 6) and 2-Cyano-4,6bis(trifluoromethyl)-1,3-dioxanes (7 and 8).


Page 12 of 54

Page 13 of 54 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


O N O

R

OH OH OEt OEt

R

O

R N

p-TsOH, –H2O 12 h, reflux, hexanes

O

H2N

5 mol % ACT 4.5 mol % Pyr-HBr 2.6 equiv. Oxone

R

CN

O O

EtOH, 5 h

R

O

R 6 R = CH3; 82% 8 R = CF3; 96%

CN

t-BuOK O

Et2O, 6-12 h

pyridine, DCM rt, 12 h

R = CH3; 74% R = CF3; 77%

R

R = CH3; 88% R = CF3; 46%

O R

O

O

R = CH3 or CF3

R

N 2H 4

O

R 5 R = CH3; 24% 7 R = CF3; 47%

The equilibration of 5 ⇌ 6 with Amberlyst-15 or p-TsOH fails to proceed; the result, apparently, of the instability of the cationic intermediate required for the process. Compounds 5 and 6 were successfully equilibrated over anhydrous AlCl3 in Et2O and cyclohexane solvent in the manner described above; the process takes 1–2 weeks to reach equilibrium. Compounds 7 and 8 are even more reluctant to equilibrate over acid catalysts: a sample of 8 did not form any appreciable amount of 7 (less than 2%) upon standing in anhydrous Et2O with a 10-fold molar excess of AlCl3 for a period of two months. Equilibration of compounds 7 and 8 was finally accomplished under basic conditions (catalytic t-BuOK) in anhydrous Et2O solvent requiring ~ 2 d to reach equilibrium. Compounds 7 and 8 were equilibrated only in Et2O; neither compound is sufficiently soluble in cyclohexane to allow for accurate determination of an equilibrium constant and the dioxanes decompose before reaching equilibrium in CH3CN. The equilibration results are summarized in Figure 4.



Figure 4. Equilibria in 2-cyano-1,3-dioxanes 5 ⇌ 6 and 7 ⇌ 8. Cursory inspection of the equilibration data in Figure 4 reveals that a 2-CN substituent has a greater preference for the axial position than does a 2-OCH3 group in a common solvent (Table 1) in both the di-CH3 and CF3 series. The 2.1 kcal/mol difference between isomers 7 and 8 in Et2O favoring axially substituted 7 is rather extraordinary. Unfortunately, as noted above, it was not possible to evaluate the ∆G° for 7 ⇌ 8 in cyclohexane where the energy difference would undoubtedly be even larger. Nevertheless, the conformational equilibria summarized in Figure 4 and Table 1 implicate Coulombic interactions as at least one major factor in the operation of an anomeric effect. In order to obtain further information about the role of internal Coulombic interactions, we have carried out some computational studies of substituted and 1,3-dioxanes at the MP2/6311+G* level that we found to be useful in a study of phenyl substituted cyclohexanes.27 14 ACS Paragon Plus Environment

Page 14 of 54

Page 15 of 54 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Computational Studies. Initially, 1,3-dioxanes with 2-F, 2-CN and 2-OCH3 substituents were examined using MP2/6-311+G*. The fluorine case provides an easier examination since it involves a single atom, the CN and OCH3 molecules correspond to the experimental studies described above. The calculated axial-equatorial energy differences for these molecules, corrected for the difference in zero-point energy (ZPE) between the two isomers and the change in ∆H° on going from 0 K to 298 K, are given in Table 2. The 2-methoxy-1,3-dioxanes, 1 ⇌ 2 and 3 ⇌ 4, present an additional computational complication due to the differing rotameric arrangements of the methoxy group in the axial and equatorial isomers. In the axially substituted isomers (1 and 3), the methyl group adopts two energetically equivalent mirror image rotameric arrangements in which the methyl group is gauche to the equatorial hydrogen at C(2) and this contributes an entropy of mixing of ∆S = R ln 2 = 1.38 eu for the axial 2-methoxy isomers; the rotamer in which the CH3 group points into the ring is excluded on steric grounds. In the equatorially substituted isomers (2 and 4), the methoxy group may in principle adopt three rotameric arrangements: two mirror image arrangements in which the CH3 is gauche to the axial hydrogen at C(2) and one in which the CH3 group is anti with respect to that hydrogen and gauche to both ring oxygens. However, the anti-arrangement of the equatorial 2-methoxy group, which places the rather positive methyl hydrogens quite near the ring oxygens, is significantly more stable than the gauche forms in both isomer 2 (by 1.7 kcal/mol) and isomer 4 (by 2.1 kcal/mol). This manifestation of what has been termed the “exoanomeric effect”9 is almost certainly due to Coulombic attraction between the methyl hydrogens and the ring oxygens. The computed structure of 2, shown in Figure 5, dramatically reinforces this argument.



Figure 5. Computed MP2/6-311+G* structure of r-2-methoxy-cis-4, cis-6-dimethyl-1,3-dioxane (2) demonstrating close hydrogen – oxygen contacts; r (CH•••O) = 2.481 Å.

The ∆H° and ∆G° values for the 2-F and 2-CN compounds are fairly close, with the latter being a little smaller. This indicates that the entropy change is quite small and the values are consistent with a ∆S°~ –2 eu. For the 2-OCH3 compounds there is a significant entropy of mixing, noted above, that favors the axial isomers by 0.41 kcal/mol at 25 °C. The ∆∆H° and ∆∆G° values in Table 2 represent the effect of changing the holding groups from 4,6-di-CH3 to 4,6-bis-CF3. The computed MP2/6-311+G* structures of 1 and 3, along with relevant geometrical parameters, are shown in Figure 6; structures of all the compounds investigated may be found in the Supporting Information.


Page 16 of 54

Page 17 of 54 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 6. Computed MP2/6-311+G*structures of r-2-methoxy-trans-4, trans-6-dimethyl-1,3dioxane (1) and r-2-methoxy-trans-4, trans-6-bis(trifluoromethyl)-1,3-dioxane (3).

Table 2. Axial ⇌ Equatorial Energy Differences in 2-Substituted-1,3-dioxanes Calculated Using the MP2/6-311+G* Level in kcal/mol.

a

entry

G

R

∆H°

∆G°

1

F

CH3

3.76

3.73

2

F

CF3

4.83

4.75

3

CN

CH3

2.22

2.11

4

CN

CF3

2.95

2.83

5

OMe CH3

0.82

0.94

6

OMe CF3

1.83

1.87

∆∆H°

∆∆G°

1.07

1.02

0.73

0.72

1.01

0.93a

Includes the RTln2 (0.41 kcal/mol) symmetry correction; see text.



Page 18 of 54

The calculated ∆G° of 0.93 kcal/mol for the equilibrium of 1 ⇌ 2 is nicely comparable with the gas phase value of ~ 0.9 kcal/mol estimated from the experimental solution data (Figure 3). The ∆∆H° and ∆∆G° values for the 2-fluoro-1,3-dioxanes and the 2-cyano-1,3-dioxanes (Table 2) are similar to those calculated previously for the analogously substituted cyclohexyl fluorides and cyanide18 as might be expected for an attractive Coulombic interaction between a negatively charged substituent and the positively charged syn-axial hydrogens at the carbons bearing the holding groups. This leads to the question: how large are these charges? Here, it is convenient to convert the charge density about a nucleus to an effective atomic charge. We believe the Hirshfeld charges that are obtained directly from the charge density are the most useful for this purpose (see: Appendix, Atomic Charges, in the Supporting Information).28 We have calculated these charges, and they are summarized in Table 3. Here, Ha is the hydrogen at C(2) bearing the substituent, Hb is the charge of a syn-axial hydrogen at C(4,6), X is the charge at the atom of the substituent (G) attached to C(2), and O is the charge at the dioxane oxygens. A complete summary of these charges may be found in the Supporting Information.

Table 3. Calculated Hirshfeld Charges, q (e).

entry isomer

R

G

Ha

Hb

X

N

O

1

A

CH3

F

+0.0622

+0.0426

–0.1493

–0.1759

2

B

CH3

F

+0.0368

+0.0453

–0.1136

–0.1760


Page 19 of 54 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


3

A

CF3

F

+0.0771

+0.0549

–0.1286

–0.1659

4

B

CF3

F

+0.0476

+0.0514

–0.0898

–0.1697

5

A

CH3

CN

+0.0741

+0.0352

+0.0695

–0.2048

–0.1680

6

B

CH3

CN

+0.0468

+0.0341

+0.0844

–0.1945

–0.1681

7

A

CF3

CN

+0.0871

+0.0517

+0.0730

–0.1809

–0.1574

8

B

CF3

CN

+0.0563

+0.0521

+0.0906

–0.1709

–0.1583

9

A

CH3 OMe +0.0475

+0.0326

–0.1814

–0.1804

10

B

CH3 OMe +0.0228

+0.0301

–0.1744

–0.1763

11

A

CF3

+0.0490

–0.1739

–0.1720

12

B

CF3

+0.0481

–0.1628

–0.1681

OMe +0.0611 Me

+0.0318

The quantity of immediate interest is the charge, Hb, at the syn-axial hydrogens attached to the C(4,6) carbons bearing the CH3 or CF3 holding groups. It is seen that changing from CH3 holding groups to CF3 groups leads to a significant increase in positive charge that will lead to increased Coulombic interaction with a negatively charged axial substituent at C(2). It might be noted that even with the CH3 holding groups, Hb has a positive charge and will provide some Coulombic stabilization of an axial substituent. This is probably the origin of the increase in proportion of axial forms for cyclohexanes having polar substituents whereas it is commonly found that most non-polar substituents strongly prefer to be equatorial. An unexpected result of this analysis of effective atomic charge is the discovery that the charge at the C(2) hydrogen (Ha in Table 3) in compounds with an axial C(2) substituent (A in Table 3) is appreciably more positive than in the corresponding, but less stable, equatorial isomers (B in Table 3). We believe this feature is a fundamental but unrecognized factor that



contributes significantly to the anomeric effect. We defer discussion of this important topic to the sequel. Electrostatic Effects. As noted in the Introduction, the importance of repulsion involving the ring and substituent dipoles was first suggested by Edward as an explanation of the anomeric effect and this sort of interaction was more recently reinforced by Perrin, Armstrong and Fabian16 in their study of 2-substituted-N,N-dimethyl-tetrahydropyrimidines. The idea is a simple one. Taking the 1,3-dioxanes as an example, the ring dipole lies along the equatorial direction so that the dipole associated with the bond to an equatorial polar substituent will lead to a repulsive interaction, whereas, if the substituent were in the axial position, the repulsion would be smaller. As a result, the compound with an axial substituent should have the lower energy. Attempts have been made to make this qualitative argument a more quantitative one but they are not definitive.13 However, the consensus is that this interaction accounts for only a part of the anomeric effect.9 The measurements have always been carried out in solution, and as seen in the experimental results presented above, solvent effects can be quite large in these systems and this makes it very difficult to evaluate comparisons of results reported by different groups. The effect of solvent is an important electrostatic effect. A spherical ion in the gas phase has a large electrostatic effect that is given by: ∆G = q2/2r, where q is the charge on the ion and r is its radius. If this ion is placed in a medium with a dielectric constant of ε, the energy is only 1/ε as great. Clearly, solvation of ions is important. The same is true with molecules having a dipole moment. An early approximate treatment by Onsager found that the energy of a dipolar molecule is reduced in solution by a factor of (ε1)/(2ε+1).22 This concept has been extended and incorporated into modern ab initio codes so geometry optimizations can be carried out using this polarizable continuum model (PCM).29 It is


Page 20 of 54

Page 21 of 54 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


an approximation of course, but it proves to be useful. More accurate solvent effects can be obtained using molecular dynamics methods,30 but they are computationally much more difficult. The dipole moment of 1,3-dioxane is 2.293 D and it lies along the equatorial direction.31 As a result, polar equatorial substituents that are aligned along this axis will lead to a large dipole moment. The dipole moment of equatorial fluorocyclohexane is 2.428 D, for cyanocyclohexane it is 4.415 D and for methoxycyclohexane it is 1.362 D. The calculated dipole moments for the 2substituted 1,3-dioxanes of interest and estimates of the moments for the equatorially substituted compounds from a simple sum of the dipole moment of 1,3-dioxane and dipole moments of the appropriate substituted cyclohexane are given in Table 4.

Table 4. Calculated and Estimated Dipole Moments, µ, in D.

entry

isomer

G

calculated µ

1

A

F

2.872

2

B

F

4.812

3

A

CN

3.774

4

B

CN

6.152

5

A

OMe

1.979

6

B

OMe

3.168

estimated µ

4.668

6.654

3.601

It can be seen that the estimate for the equatorial forms are fairly good and the dipole moments for the axial forms must be considerably smaller since there is a large angle between 21 ACS Paragon Plus Environment


the dioxane and C–G dipoles. Clearly, electrostatic destabilization for the equatorial forms will be considerably greater than that for the axial forms. How large might this effect be? It may be estimated using PCM. The range of the Onsager function is from 0 for the gas phase to 0.5 for a very large dielectric constant. The value for cyclohexane is 0.202 and that for acetonitrile is 0.480 and so these solvents span the range of possible solvent effects. To take but two examples: the axial ⇌ equatorial free energy difference for 2-fluoro-1,3-dioxane decreases to 3.19 kcal/mol in c-C6H12 and 2.05 kcal/mol in CH3CN and that of 2-cyano-1,3-dioxane decreases to 1.69 kcal/mol and 0.80 kcal/mol in these solvents. It is clear that the electrostatic energy of these polar molecules is large and it favors the conformation in which the polar substituent is in the axial position. Solvents, which reduce the electrostatic energy, have a profound effect on the conformational free energy difference between such isomers and this term is a significant component of any experimentally determined anomeric effect that is determined in solution. In short, any solvent will decrease the actual magnitude of the effect. Hyperconjugation or Coulombic Interactions? Current conventional wisdom posits that hyperconjugation, the interaction of a heteroatom’s lone pair p-orbital with an axial substituent’s antibonding orbital, is the major cause of the anomeric effect. This hypothesis leads to the expectation that there should be a significant shift in charge from the ring heteroatom to an axial substituent. In light of the unexpected charge shifts discussed below, all compounds were reexamined at MP2aug-cc-pVTZ using the MP2/6-311+G* geometries and vibrational frequencies. In two cases, optimization and frequency calculations were carried out using MP2/aug-cc-pVTZ but the energy changes were the same as for the single point calculations. The use of the larger basis set led to only small changes in calculated energies and charges.


Page 22 of 54

Page 23 of 54 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


In the studies described above we focused on substituted dioxanes that would exhibit large anomeric effects. Some time ago Perrin16 suggested that a comparison with 2-methoxy-N,Ndimethylhexahydropyrimidines could be useful in this context because nitrogen is less electronegative than oxygen, its lone pair has a higher energy than that in dioxane, and this should lead to greater hyperconjugative interaction with the C(2) substituent. This system is a bit more complicated than the 1,3-dioxanes discussed above. The N-CH3 groups in 2-methoxy-N,Ndimethylhexahydropyrimidines may adopt aa, ae, or ee conformations. We found that the methoxy group in lower energy isomer, having an axial 2-OCH3, adopts a rotameric arrangement in which the methyl group is gauche to the equatorial hydrogen at C(2) and has ae-N-CH3 groups; the equatorial 2-OCH3 isomer has ee-N-CH3 groups and the OCH3 moiety adopts a rotameric arrangement in which the methyl group is anti with respect to the axial hydrogen at C(2). This later arrangement is similar to that of equatorial 2-methoxy-1,3-dioxane and, here again, is likely a consequence of attractive Coulombic attraction between the methyl hydrogens of the OCH3 and the ring nitrogens. In an effort to obtain further information, we also examined the corresponding 2-methoxy1,3-dithianes. We focus at the outset on the rotameric conformations of the 2-methoxy group: they are gauche with respect to the C(2)-hydrogen in both the axially and equatorially substituted 1-3-dithiane as found with the corresponding cyclohexanes. Indeed, for equatorial 2-methoxy1,3-dithiane, the anti-conformation of the OCH3 group was found to be a transition state. The difference with respect to the favored anti-conformation of equatorial 2-methoxy-1,3-dioxane discussed above is probably due to the much smaller charge at sulfur vis-à-vis oxygen. The calculated axial ⇌ equatorial energy differences for substituted cyclohexane, 1,3-dioxane, 1,3-



dithiane and N,N-dimethylhexahydropyrimidine are given in Table 5; a more detailed table may be found in the Supporting Information.

Table 5. Axial ⇌ Equatorial Energy Differences Calculated at the MP2/aug-cc-pVTZ Level in kcal/mol. entry

ring

2-substituent

∆H°

∆G°

1

cyclohexane

F

0.09

0.05

2

CN

0.53

0.53

3

OMe

0.22

–0.04

F

3.17

3.14

5

CN

2.00

1.89

6

OMe

0.75

0.78

F

4.52

4.54

8

CN

3.09

2.82

9

OMe

3.71

3.57

F

5.31

5.40

11

CN

3.40

3.59

12

OMe

–0.07

0.26

4

7

10

1,3-dioxane

1,3-dithiane

hexahydropyrimidine

Hirshfeld charges and relevant bond lengths for the substituted cyclohexanes, 1,3-dioxanes, 1,3-dithianes and hexahydropyrimidines were also calculated at the MP2/aug-cc-pVTZ level. The results are summarized in an unavoidably long Table 6. The quantities of foremost interest are the changes in these quantities (axial – equatorial) on going from an axial to an equatorial


Page 24 of 54

Page 25 of 54 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


conformation and these are highlighted in red. Among these charges and lengths, the larger variations are further highlighted in blue. An examination of the data in Table 6 demonstrates that an axial substituent (G) in the dioxane, the dithiane and the N,N-dimethylhexahydropyrimidines systems gains significant electron density with respect to one in the equatorial position. No such change is found with the cyclohexanes and, consequently, the increase in charge at the axial group must be due to the presence of a heteroatom in the ring. However, this increase in charge density at an axial G is not derived from the ring heteroatoms; the variation in the charge density of the ring heteroatoms is fairly small. Rather, there is a much larger reduction in charge density at the hydrogen attached to the C–G carbon. The bond lengths change accordingly: the axial C–G bond is lengthened, the adjacent equatorial C–H bond is shortened, and the carbon to ring heteroatom bond is also shortened in the isomer having an axial substituent.


The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47

Page 26 of 54

Table 6. MP2/aug-cc-pVTZ Calculated Hirshfeld Charges, q (e), and Relevant Bond Lenghts, r (Å). entry

system

substituent (G)

r (C–G )

r (C–H)

r (ring) a r (ring)b q (G)

q (C)

q (H)

q (ring atom)

1

cyclohexane ax-F

1.4128

1.0961

1.5176

–0.1548

0.0830

0.0339

–0.0576

2

eq-F

1.4082

1.0981

1.5149

–0.1622

0.0801

0.0317

–0.0590

3

changec

0.0046

–0.0020

0.0027

0.0074

0.0029

0.0022

0.0014

4

ax-CN

1.4693

1.0976

1.5395

–0.1532

0.0082

0.0519

–0.0431

5

eq-CN

1.4645

1.0982

1.5453

–0.1598

0.0072

0.0489

–0.0431

6

changec

0.0048

–0.0006 –0.0058

0.0066

0.0010

0.0030

0.0000

7

ax-MeO gauche

1.4282

1.1042

1.5229

1.5294

–0.0733

0.0526

0.0215

–0.0557

8

eq-MeO gauche

1.4255

1.1065

1.5200

1.5264

–0.0855

0.0507

0.0201

–0.0570

9

changec

0.0027

–0.0023

0.0029

0.0030

0.0122

0.0019

0.0014

0.0013

ax-F

1.4000

1.0880

1.3750

–0.1587

0.2023

0.0518

–0.1610

11

eq-F

1.3498

1.1035

1.3857

–0.1262

0.1972

0.0275

–0.1649

12

changec

0.0502

–0.0155 –0.0107

–0.0325

0.0051

0.0243

0.0039

13

ax-CN

1.4977

–0.1366

0.1421

0.0649

–0.1535

10

1.3-dioxane

1.0911

1.3980


Page 27 of 54 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47


14

eq-CN

1.4727

15

changec

0.0250

16

ax-MeO gauche

1.4040

1.0953

1.4036

17

eq-MeO anti

1.3671

1.1022

18

changec

0.0369

ax-F

1.3992

1.0935

20

eq-F

1.3792

1.0955

21

changec

0.0200

22

ax-CN

1.4620

1.0947

23

eq-CN

1.4578

1.0973

24

changec

0.0042

25

ax-MeO gauche

1.4068

1.1002

1.8071

26

eq-MeO gauche

1.3957

1.1017

1.8126

27

changec

0.0111

ax-F

1.4689

1.0928

eq-F

1.3858

1.1189

19

28 29

1,3-dithane

hexahydropyrimidine

1.1063

1.4048

–0.1151

0.1368

0.0395

–0.1522

–0.0152 –0.0068

–0.0215

0.0053

0.0254

–0.0013

–0.0695

0.1739

0.0376

–0.1656

1.4077

–0.0584

0.1720

0.0272

–0.1626

–0.0069 –0.0041

–0.0111

0.0019

0.0104

–0.0030

1.7982

–0.1467

0.0596

0.0500

–0.0241

1.8124

–0.1253

0.0655

0.0367

–0.0299

–0.0020 –0.0142

–0.0214

–0.0059

0.0133

0.0058

1.8195

–0.1468

0.0083

0.0677

–0.0050

1.8219

–0.1349

0.0098

0.0534

–0.0032

–0.0026 –0.0024

–0.0119

-0.0015

0.0143

–0.0018

1.8268

–0.0654

0.0388

0.0384

–0.0347

1.8318

–0.0500

0.0396

0.0267

–0.0360

–0.0015 –0.0055 –0.0050

–0.0154

–0.0008

0.0117

0.0013

1.4141

–0.1972

0.1398

0.0371

–0.0968

1.4382

–0.1296

0.1434

0.0082

–0.1051

1.3850


The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47

30

changec

0.0831

31

ax-CN

1.5111

1.0965

32

eq-CN

1.4766

1.1234

33

changec

0.0345

34

ax-MeO gauche

1.4206

1.1031

1.4474

35

eq-MeO anti

1.4032

1.1176

1.4556

36

changec

0.0174

a

–0.0261 –0.0241

Page 28 of 54

–0.0676

–0.0036

0.0289

–0.0083

1.4508

–0.1601

0.0779

0.0499

–0.0933

1.4606

–0.1215

0.0766

0.0217

–0.0954

–0.0269 –0.0098

–0.0386

0.0013

0.0282

–0.0021

1.4447

–0.0877

0.1187

0.0246

–0.1024

1.4456

–0.0875

0.1199

0.0097

–0.0982

–0.0145 –0.0082 –0.0009

–0.0002

–0.0012

0.0149

–0.0042

Distance from the C–G carbon to the adjacent ring atom. b For the molecules with gauche rotamers of the methoxy groups, there are

two different carbon–ring atom distances. c Axial – equatorial values.


Page 29 of 54 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


If one’s focus is directed exclusively to the bond length changes in the heteroatom - carbon G unit, the hyperconjugation model would appear to be validated by the data in Table 6. Indeed, on average, over the nine systems investigated, the axially substituted isomers have longer C–G bonds (~ 0.031 Å longer) and shorter C–heteroatom bonds (~ 0.009 Å shorter) than their equatorial counterparts. However, the unanticipated and rather significant reduction in the charge density at the equatorial hydrogen in the axially substituted heterocycles (on average ~ 0.018 e), coupled with only modest change in the electron density of the ring heteroatom (on average ~ 0.004 e), suggests that more than simple hyperconjugation is at play here. A Unified Paradigm for the Anomeric Effect. A noted above, were hyperconjugation the major factor responsible for the anomeric effect, one would expect a shift in charge density from the ring heteroatom to the axial substituent, a lengthening of the bond from the axial substituent to the carbon to which it is attached, and compression of the bond from that carbon to the ring heteroatom. The shorter C–H bond in the axially substituted isomers is likely attributable to the enhanced p-character of the axial C–G bond resulting from hyperconjugative interaction with the ring heteroatom. As a result, the bond from the C–G carbon to the equatorial hydrogen in the these isomers would be expected to have a higher s-character.32 While the anticipated effects from a hyperconjugative interaction are confirmed by the data summarized in Table 6, these computational observations do not, ipso facto, speak to the etiology of the anomeric effect.10 In particular: (1) why does the equatorial hydrogen in a heterocycle with an axial polar substituent become substantially more positive, and (2), is hyperconjugation connected to the non-classical CH•••G hydrogen bonds between an axial group and the syn-axial hydrogens? We believe the answer to these questions lies in the enhancement of attractive Coulombic interactions engendered by the sizable charge density shifts.



The shift of electron density from an equatorial hydrogen to an axial substituent renders the hydrogen more positive, and the substituent more negative, than is the situation in which the substituent is in the equatorial orientation. In short, the charge density shifts conspire to maximize attractive Coulombic interactions, and minimize repulsive ones, in the axially substituted isomers. Consider, as an example, axial 2-fluoro-1,3-dioxane (Figure 7). The oxygen p-orbitals are roughly parallel to the C–F bond, leading to a repulsive interaction. This repulsion would be lessened by an increase the C–F bond length and such bond lengthening is observed both computationally and experimentally.14 The longer C–F bond requires a carbon orbital with high p-character.32 This then leads to a higher s-character in the bond from that carbon to the hydrogen, resulting in a shorter bond and a larger positive charge at the hydrogen. Thus, the longer C–F bond allows a shift in charge from the hydrogen to the fluorine providing an increase in the attractive Coulombic interaction of the equatorial hydrogen with the neighboring ring oxygens. The axial isomer further benefits energetically from a more negative fluorine capable of participating in a stronger CH•••F hydrogen bond. An analogous analysis appears to be true for all of the substituents in the three hetero-substituted ring systems (9 examples) that were studied. Applying Occam’s razor,33 it appears that the anomeric effect is mainly a result of Coulombic interactions. As a check on these conclusions we also studied 2-fluorotetrahydropyran and again found the major charge shift was from H to F in the H-C-F group.


Page 30 of 54

Page 31 of 54 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


F

H O O

bond length increases by 0.050 Å

K O O

F

H

bond length decreases by 0.016 Å

δ+ H

O O δ–

charge (q) increases by 0.033 e–

F δ–

H O O

K F

O H O δ+ charge (q) decreases by 0.004 e–

F δ–

charge (q) decreases by 0.005 e–

H δ+

two major Coulombic attractions result

charge (q) decreases by 0.024 e–

Figure 7. Interactions in axial 2-fluoro-1,3-dioxane.

As a corollary to this study we suggest that proposals of hyperconjugative interactions in neutral closed shell systems should be checked by calculating the atomic charges to see if the proposed charge transfer is found. We are currently reassessing some of these cases.

CONCLUSIONS The anomeric effect, defined as the difference in conformational free energy between a substituent on a heterocyclic ring and that on cyclohexane, is the result of a composite of a number of different, but interrelated, non-bonded intramolecular interactions. There is a CH•••G attraction between the axial substituent (G) and the syn-axial hydrogen(s) in the heterocycle of the sort advocated by Nishio and coworkers.12 This factor was demonstrated experimentally by 31 ACS Paragon Plus Environment


replacing dimethyl holding groups at the carbons bearing the syn-axial hydrogens with electronwithdrawing CF3 groups and finding that the axial preference is significantly increased. The electrostatic effect, due to the much larger dipole moment of an equatorially substituted isomer vis-à-vis its axially substituted analog, attenuates the magnitude of the anomeric effect in solution. The resultant solvent effects, which are often quite large, make it difficult to compare results from different studies of substituted heterocycles conducted in disparate solvent systems. The hyperconjugation model, frequently proposed as the origin of the anomeric effect, may contribute to bond length changes in the heteroatom - carbon - G unit, but it is likely not uniquely responsible for the axial preference of a substituent that is the hallmark of the anomeric effect. Indeed, in the systems that have been investigated (1,3-dioxanes, 1,3-dithianes, and hexahydropyrimidines) there was no evidence for a large role of such an interaction: the atomic charges on the ring heteroatoms are only slightly altered when the orientation of the substituent is changed from equatorial to axial. Rather, there is a significant charge shift from hydrogen to G in the H–C–G unit that is caused by a combination of repulsion between the ring heteroatom porbital and the substituent, leading to a longer C–G bond, coupled with a decreased C–H bond length and an increased positive charge at H. These charge shifts lead to enhanced Coulombic attraction between the equatorial hydrogen and the negatively charged ring heteroatoms. In the aggregate, the anomeric effect appears to arise mainly from two separate CH•••heteroatom nonbonded Coulombic attractions; in a sense, non-classical hydrogen bonds.

EXPERIMENTAL SECTION General. Spectroscopic and chromatographic procedures and methods used for the purification of reagents and solvents have been previously described.34 Pure meso-2,4-


Page 32 of 54

Page 33 of 54 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


pentanediol was obtained in two steps. A 70:30 mixture of meso and d,l-2,4-pentanediol was obtained from the sodium borohydride reduction of 2,4-pentanedione as described by Pritchard and Vollmer.35 This meso-enriched mixture was then separated following the efficient process described by Zhang and coworkers36 to afford pure meso-2,4-pentanediol. r-2-Methoxy-trans-4,trans-6-dimethyl-1,3-dioxane

(1)

and

r-2-Methoxy-cis-4,cis-6-

dimethyl-1,3-dioxane (2). Following a procedure developed by Eliel and Nader21 with minor modifications, a mixture of 2.621 g of meso-2,4-pentanediol, 2.991 g (27.5 mmol) of trimethyl orthoformate, 116 mg (0.61 mmol) of p-TsOH, and 100 mL of cyclohexane was heated at reflux for 1 h under a 10-mL Dean-Stark trap. After 1 h of reflux, the contents of the trap were discarded and the trap was allowed to refill; this process was repeated twice more allowing for ca. 30 mL of a MeOH/solvent mixture to be discarded. The reaction mixture was allowed to cool to room temperature, 1.50 g of solid, anhydrous K2CO3 was added, and the mixture was stirred for 1.5 h. The solvent was carefully removed by rotary evaporation operating at room temperature and water aspirator pressure to afford 2.578 g (70%) of a clear oil containing a mixture of compounds 1 and 2. The compounds are extremely acid-sensitive and to prevent decomposition due to any adventitious acid, a spatula-tip of anhydrous, solid K2CO3 was added to all glassware to which compounds were transferred. Separation of 1 and 2 was achieved by column chromatography on 200 g neutral alumina (5 → 20% Et2O/hexanes): 50 mL fractions were collected; 863 mg (24%) of pure trans-isomer (1) was collected in fractions 5–9; 101 mg (3%) of pure cis-isomer (2) was collected in fraction 16. Progress of the chromatography was monitored by TLC on neutral alumina (15% Et2O in hexanes) and visualization of 1 and 2 was achieved either by an I2 chamber or staining with a solution of 20% phosphomolybdic acid in EtOH followed by heating. The trans-isomer (1), which streaks on alumina, had an Rf = 0.41 and



the cis-isomer (6) had an Rf = 0.15. The NMR spectra of 1 and 2, detailed below, were identical to those reported for these compounds.21 r-2-Methoxy-trans-4,trans-6-dimethyl-1,3-dioxane (1): 863 mg (24%), clear, colorless oil; 1

H NMR (400 MHz, CDCl3) δ 1.15 (d, J = 6.3 Hz, 6H), 1.32 (dt, J = 13.1 Hz, J = 11.5 Hz, 1H),

1.54 (apparent dtd, J = 13.1, Hz, J = 2.5 Hz, J = 1.4 Hz, 1H), 3.30 (s,12 h 3H), 4.18 (dqd, J = 11.7 Hz, J = 6.1 Hz, J = 2.4 Hz, 2H), 5.37 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 21.6, 40.2, 53.0, 64.2, 109.4. r-2-Methoxy-cis-4,cis-6-dimethyl-1,3-dioxane (2): 101 mg (3%), white, crystalline solid; mp 38.3–38.8 °C (sublimation) (lit.21 38–39 °C); 1H NMR (400 MHz, CDCl3) δ 1.25 (dt, J = 13.0 Hz, J = 11.1 Hz, 1H), 1.26 (d, J = 6.1 Hz, 6H), 1.54 (dt, J = 13.1, Hz, J = 2.4, 1H), 3.50 (s, 3H), 3.85 (dqd, J = 11.1 Hz, J = 6.1 Hz, J = 2.4 Hz, 2H), 5.16 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 21.3, 39.6, 53.2, 71.2, 112.1. d,l- and meso-1,1,1,5,5,5-Hexafluoro-2,4-pentanediol.37 A solution of 400 mL of MeOH and 100 mL of deionized water was prepared in a 2–L two-neck, round-bottomed flask fitted with a mechanical stirrer. The solution was made basic by addition of 0.550 g (13.8 mmol) of solid NaOH, cooled to –78 °C, and then, while stirring, 9.309 g (246 mmol) of solid NaBH4 was added in portions. A solution of 41.612 g (200 mmol) of 1,1,1,5,5,5-hexafluoropentanedione in 100 mL of MeOH was cooled to –10 °C and added to a 200-mL addition funnel. The addition funnel was then fitted to the second neck of the reaction flask and the dione was added at a rate of 50 mL/h to the stirred reaction mixture. The reaction mixture was held at –78 °C for 12 h, and then allowed to warm to room temperature over 18 h. The addition funnel was removed, 400 mL of a 10% aqueous HCl solution was slowly added to the reaction mixture over a period of 20 min to quench the excess NaBH4, and then allowed to stir for an additional 1 h to hydrolyze the 34 ACS Paragon Plus Environment

Page 34 of 54

Page 35 of 54 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


borate ester. The resulting solution was transferred to a round-bottomed flask and the MeOH was removed using a rotary evaporator operating at 35 °C and water aspirator pressure. The remaining solution was transferred to a separatory funnel and extracted with five 100-mL portions of Et2O. The organic layers were combined, 75 mL of hexanes was added and the solvent was removed under reduced pressure; this process was repeated twice to azeotropically remove any excess water or MeOH. The resulting oil was distilled (Kugelrohr, bath temperature = 65–100 °C, 10 mm) to afford 29.560 g (70%) of a mixture (55 : 45; d,l : meso) of the title compounds as a clear oil that partially crystallizes upon standing: 1H NMR (400 MHz, CD2Cl2) δ 1.96–2.05 (m, 3H), 2.16 (dt, J = 14.8 Hz, J = 3.1 Hz, 1H), 2.75 (d, J = 5.8 Hz, 2H), 3.24 (d, J = 3.9 Hz, 2H), 4.25–4.40 (m, 4H); 13C NMR (100 MHz, CD2Cl2) δ 29.3, 29.4, 66.6 (quartet, JC−F = 32.1 Hz), 69.4 (quartet, JC−F = 32.1 Hz), 124.4 (quartet, JC−F = 281.3 Hz), 125.1 (quartet, JC−F = 281.3 Hz); 19F NMR (376 MHz, CD2Cl2) δ –79.7, –80.1; HRMS (DART-TOF) m/z: [M + H]+ Calcd for C5H7F6O2 213.0345; Found 213.0343. r-2-Phenyl-cis-4,cis-6-bis(trifluoromethyl)-1,3-dioxane. A mixture of 29.506 g (139.1 mmol) of 1,1,1,5,5,5-hexafluoro-2,4-pentanediol, consisting of ~ 55% racemic and ~ 45% meso isomers, 9.045 g (59.5 mmol) of benzaldehyde dimethyl acetal, and 120 mg (0.63 mmol) of pTsOH in 150 mL of hexanes was heated at reflux under a Dean–Stark trap38 for 12 h, at which point the reaction mixture was allowed to cool to room temperature. Upon cooling to room temperature, off-white, needle-like crystals formed upon the walls of the reaction flask, and after 3 h of standing, the flask was further cooled to 5 °C in a cold water bath resulting in further crystallization. The contents of the flask were filtered through a Büchner funnel containing a coarse filter paper, and the crystals were rinsed with 50 mL of cold hexanes (the filtrate contained the excess racemic 1,1,1,5,5,5-hexafluoro-2,4-pentanediol), and allowed to air-dry,



affording 17.805 g (95%) of an off-white, crystalline solid (mp 97.0–99.0 °C; hexanes). 1H NMR analysis revealed that the solid was contaminated with ~ 10% by mass of racemic 1,1,1,5,5,5hexafluoro-2,4-pentanediol. Further purification was achieved as follows: the solid was dissolved in CH2Cl2, the solution was extracted with three 100-mL portions of a saturated, aqueous NaHCO3 solution,39 dried over anhydrous Na2SO4, and solvent removed by rotary evaporation to afford 9.737 g (52%) of the title compound as a white, crystalline solid: mp 100.5–101.5 °C (CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 2.00 (dt, J = 12.9 Hz, J = 2.8 Hz, 1H), 2.11 (dt, J = 13.0 Hz, J = 11.6, 1H), 4.35 (dqd, J = 11.6 Hz, J = 5.7 Hz, J = 3.1 Hz, 2H), 5.64 (s, 1H), 7.38– 7.43 (m, 3H) 7.48–7.54 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 22.9, 73.6 (quartet, JC−F = 34.0 Hz), 101.3, 123.1 (quartet, JC−F = 278.9 Hz), 126.5, 128.6, 130.0, 135.8; 19F NMR (376 MHz, CDCl3) δ–79.4; HRMS (DART-TOF) m/z: [M + H]+ Calcd for C12H11F6O2 301.0658; Found 301.0672. meso-1,1,1,5,5,5-Hexafluoro-2,4-pentanediol. A solution of 9.506 g (31.7 mmol) of r-2phenyl-cis,cis-4,6-bis(trifluoromethyl)-1,3-dioxane, 5 mL of deionized water, 10 mL of a 10% aqueous HCl solution, and 150 mL of MeOH were heated at reflux for 48 h. The solution was then allowed to cool to room temperature, 100 mL of hexanes was added, and the solvent was removed under reduced pressure; this process was repeated twice to azeotropically remove any excess water or MeOH. The mixture was diluted with 200 mL of water, transferred to a separatory funnel, and the aqueous layer was extracted with four 75-mL portions of hexanes.40 The organic extracts were discarded and the remaining aqueous solution was extracted with three 100 mL portions of Et2O, the organic layers were combined, dried (Na2SO4), 100 mL of hexanes was added, and the solvent was removed under reduced pressure; this process was repeated twice to azeotropically remove any excess water. The resulting clear oil solidified on cooling to –78 °C 36 ACS Paragon Plus Environment

Page 36 of 54

Page 37 of 54 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


and the last traces of solvent were removed under high vacuum while allowing the flask to warm to ~ 20 °C affording 6.47 g (96%) of the title compound as a white, crystalline solid: mp 24.3– 25.5 °C (Et2O); 1H NMR (400 MHz, CD2Cl2) δ 2.00 (dt, J = 14.8 Hz, J = 9.9 Hz, 1H), 2.15 (dt, J = 14.8 Hz, J = 3.1, 1H), 3.25 (d, J = 3.9 Hz, 2H), 4.26–4.35 (m, 2H);

13

C NMR (100 MHz,

CD2Cl2) δ29.4, 69.4 (quartet, JC−F = 32.1 Hz), 101.3, 124.4 (quartet, JC−F = 281.3 Hz); 19F NMR (376 MHz, CD2Cl2) δ –80.2; HRMS (DART-TOF) m/z: [M + H]+ Calcd for C5H7F6O2 213.0345; Found 213.0349. r-2-Methoxy-trans-4,trans-6-bis(trifluoromethyl)-1,3-dioxane (3) and r-2-Methoxy-cis4,cis-6-bis(trifluoromethyl)-1,3-dioxane (4). A flame-dried, argon-flushed, round-bottomed flask containing a magnetic stir bar was charged with 1.552 g (7.31 mmol) of meso-1,1,1,5,5,5hexafluoro-2,4-pentanediol and 3.753 g (35.4 mmol) of trimethyl orthoformate. The neat mixture was stirred for 5 min to dissolve the diol, then 0.1 mL (ca. 43.5 mg, 0.31 mmol) of a 49 wt/wt% solution of BF3•Et2O in Et2O was added via syringe and the mixture was stirred for 2 h at room temperature. Under a cone of argon gas, ~ 0.50 g of solid, anhydrous K2CO3 was added and the mixture was stirred under a gentle flow of argon until bubbling of the mixture ceased. The mixture was then diluted with 15 mL of pentane, the contents of the flask were transferred to a separatory funnel, diluted with an additional 150 mL of pentane, and rinsed with three portions of a 10% aqueous K2CO3 solution. The pentane layer was checked by GC-MS to ensure no excess diol remained,41 then rinsed with 25 mL of brine, and dried (Na2SO4). The solvent was carefully removed via use of a rotary evaporator operating at ~ 15 °C and water aspirator pressure to afford ~ 1.2 g of a light yellow oil containing a mixture of trimethyl orthoformate, and a mixture of the trans (3) and cis (4) title compounds in a ~5:1 ratio.42 Separation of compounds 3 and 4 was achieved by column chromatography (75 g neutral alumina, 0 → 10%



Et2O/pentane); 20 mL fractions were collected: 286 mg (16 %) of pure trans-isomer (3) was collected in fractions 7–8; 68 mg (4%) of pure cis-isomer (4) was collected in fractions 26–42. Progress of the chromatography was monitored by GC-MS as TLC visualization methods were insufficient. GC-MS analysis on a 25 m × 0.20 mm × 0.33 µm DB-5 5% phenyl / 95% dimethyl polysiloxane column using the following temperature program: 5 min at an initial temperature of 40 °C then a gradual increase in temperature at a rate of 15 °C / min to a final temperature of 240 °C which is held constant for 20 min. A solvent delay of 2 min was used and compounds of interest eluted in the following order: trimethyl orthoformate, 2.60 min; 3, 5.95 min; 4, 6.20 min.; meso-1,1,1,5,5,5-hexafluoro-2,4-pentanediol, 7.30 min. r-2-Methoxy-trans-4,trans-6-bis(trifluoromethyl)-1,3-dioxane (3): clear, colorless oil; 1H NMR (400 MHz, CDCl3) δ1.91 (dtd, J = 12.9 Hz, J = 2.2 Hz, J = 1.0 Hz, 1H), 2.03 (dt, J = 12.5 Hz, J = 12.1, 1H), 3.42 (s, 3H), 4.56 (dqd, J = 11.8 Hz, J = 5.8 Hz, J = 2.9 Hz, 2H), 5.61 (s, 1H);

13

C NMR (100 MHz, CDCl3) δ 22.2, 53.8, 65.5 (quartet, JC−F = 34.4 Hz), 108.8, 123.4

(quartet, JC−F = 278.3 Hz); 19F NMR (376 MHz, CDCl3) δ –79.9; HRMS (DART-TOF) m/z: [M + H]+ Calcd for C7H9F6O3 255.0450; Found 255.0438. r-2-Methoxy-cis-4,cis-6-bis(trifluoromethyl)-1,3-dioxane (4): white, crystalline solid; mp 27.7–28.4 °C (pentane); 1H NMR (400 MHz, CDCl3) δ1.90 (dt, J = 13.0 Hz, J = 3.1 Hz, 1H), 1.98 (dt, J = 12.8 Hz, J = 11.7, 1H), 3.55 (s, 3H), 4.26 (dqd, J = 11.4 Hz, J = 5.6 Hz, J = 3.1 Hz, 2H), 5.38 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 22.1, 52.5, 71,8 (quartet, JC−F = 34.6 Hz), 110.6, 122.8 (quartet, JC−F = 278.8 Hz);

19

F NMR (376 MHz, CDCl3) δ –79.2; HRMS (DART-

TOF) m/z: [M + H]+ Calcd for C7H9F6O3 255.0450; Found 255.0430. N-Phthalimidyl-2-aminoacetaldehyde. A solution of 22.960 g (87.2 mmol) of phthalimidoacetaldehyde diethyl acetal,43 22 mL (132 mmol) of a 6 M aqueous HCl solution, and 38 ACS Paragon Plus Environment

Page 38 of 54

Page 39 of 54 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


175 mL of acetone was heated at reflux for 5 h. The solution was cooled to room temperature, transferred to a separatory funnel, and diluted with 200 mL of water. The solution was extracted with two 200-mL portions of EtOAc, the combined organic layers were dried (MgSO4), and the solvent removed under reduced pressure to yield a brown solid that was recrystallized from CH2Cl2 / pentane to afford 12.351 g (75%) of the title compound as an off-white, crystalline solid: mp 112–113 °C, (sublimation) (lit.44 114 °C); 1H NMR (400 MHz, CDCl3) δ 4.56 (s, 2H), 7.76 (dd, J = 5.5 Hz, J = 3.1 Hz, 2H), 7.89 (dd, J = 5.4 Hz, J = 3.0 Hz, 2H), 9.66 (s, 1H); 13C NMR (100 MHz, CDCl3) δ47.6, 123.9, 132.2, 134.5, 167.7, 193.7. N-((cis-4,cis-6-Dimethyl-1,3-dioxan-2-yl)-r-methyl)-phthalimide. A mixture of 5.730 g (55.0 mmol) of meso-2,4-pentanediol, 10.000 g (52.8 mmol) of N-phthalimidyl-2aminoacetaldehyde, 254 mg (1.33 mmol) of p-TsOH, and 250 mL of benzene was heated at reflux under a Dean-Stark trap for 8 h. The reaction mixture was allowed to cool to room temperature, transferred to a separatory funnel, washed successively with two 100-mL portions of saturated, aqueous Na2CO3 and one 150-mL portion of brine, dried (Na2SO4), and solvent was removed under reduced pressure to give a brown solid. Recrystallization (CH2Cl2/cyclohexane) yielded 12.667 g (88%) of the title compound as a white, crystalline solid: mp 173.8–174.2 °C (CH2Cl2/cyclohexane); 1H NMR (400 MHz, CDCl3) δ 1.18 (d, J = 6.2 Hz, 6H), 1.29 (dt, J = 13.1 Hz, J = 11.2 Hz, 1H), 1.49 (dt, J = 13.1 Hz, J = 2.4 Hz, 1H), 3.68 (dqd, J = 11.1 Hz, J = 6.1 Hz, J = 2.3 Hz, 2H), 3.85 (d, J = 5.4 Hz, 2H), 4.88 (t, J = 5.4 Hz, 1H), 7.71 (dd, J = 5.4 Hz, J = 3.1 Hz, 2H), 7.86 (dd, J = 5.4 Hz, J = 3.1 Hz, 2H) ; 13C NMR (100 MHz, CDCl3) δ 21.6, 40.4, 41.5, 72.7, 97.2, 123.5, 132.4, 134.1, 168.2; HRMS (DART-TOF) m/z: [M + H]+ Calcd for C15H18NO4 276.1230; Found 276.1232.



(cis-4,cis-6-Dimethyl-1,3-dioxan-2-yl)-r-methanamine. A mixture of 12.667 g (46.4 mmol) of N-((cis-4,cis-6-dimethyl-1,3-dioxan-2-yl)-r-methyl)-phthalimide, 3.60 mL (2.375 g, 47.4 mmol) of hydrazine hydrate (64 wt% hydrazine), and 170 mL of EtOH was heated at reflux for 5 h then allowed to cool to room temperature, at which point a white precipitate of 2,3-dihydro1,4-phthalazine formed. The mixture was filtered through a bed of Celite, rinsing with a 100 mL portion of CH2Cl2 to remove the white solid, and the filtrate was then concentrated under reduced pressure to give a brown oil. The oil was triturated with 100 mL of cold CH2Cl2 to further precipitate the byproduct, filtered a second time through a bed of Celite rinsing with cold CH2Cl2, and the solvent was removed under reduced pressure to afford a light orange oil. The crude oil was distilled (Kugelrohr, bath temperature = 85–90 °C, 40 mm) to yield 4.915 g (74%) of the title compound as a clear, colorless oil: nD22 = 1.4445; 1H NMR (400 MHz, CDCl3) δ1.22 (d, J = 6.2 Hz, 6H), 1.24 (dt, J = 13.0 Hz, J = 11.1 Hz, 1H), 1.30 (br s, 2H), 1.52 (dt, J = 13.2 Hz, J = 2.4 Hz, 1H), 2.80 (d, J = 4.5 Hz, 2H), 3.75 (dqd, J = 11.1 Hz, J = 6.2 Hz, J = 2.3 Hz, 2H), 4.52 (t, J = 4.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ21.7, 40.7, 46.0, 72.5, 101.7; HRMS (DART-TOF) m/z: [M + H]+ Calcd for C7H16NO2 146.1176; Found 146.1180. r-2-Cyano-cis-4,cis-6-dimethyl-1,3-dioxane (6). Following the conditions of our previously reported procedure,45 a slurry of 15.995 g (26.0 mmol) of Oxone®, 72 mg (0.45 mmol) of pyridinium bromide, and 100 mL of CH2Cl2 was stirred for 15 min until the solution developed a light yellow color. Then, 4.764 g (60.2 mmol) of dry pyridine was added, the mixture was stirred for 10 min, and 110 mg (0.52 mmol) of 4-acetamido-2,2,6,6-tetramethylpiperidine-1-oxyl catalyst was added. The reaction mixture was stirred for an additional 15 min until the solution returned to a light yellow color. A solution of 1.453 g (10.1 mmol) of (cis-4,cis-6-dimethyl-1,3dioxan-2-yl)-r-methanamine in 20 mL of CH2Cl2 was then added via syringe pump at a rate of


Page 40 of 54

Page 41 of 54 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


10 mL/h and the reaction mixture was allowed to stir for 12 h at room temperature. The reaction mixture was filtered through a short plug of silica gel (~ 50 g) while rinsing with 150 mL of CH2Cl2. The filtrate was concentrated under reduced pressure to give 1.307 g of a light yellow oil, which was distilled (Kugelrohr, bath temperature = 80–100 °C, 10 mm) to yield 1.159 g (82%) of the title compound as a clear, colorless oil: nD23 = 1.4285; 1H NMR (400 MHz, CDCl3) δ1.27 (d, J = 6.2 Hz, 6H), 1.41 (dt, J = 13.5 Hz, J = 11.1 Hz, 1H), 1.58 (dt, J = 13.5 Hz, J = 2.4 Hz, 1H), 3.81 (dqd, J = 11.1 Hz, J = 6.2 Hz, J = 2.4 Hz, 2H), 5.33 (s, 1H); 13C NMR (100 MHz, CDCl3) δ21.3, 39.9, 74.3, 88.6, 114.7; HRMS (DART-TOF) m/z: [M – H]+ Calcd for C7H10NO2 140.0717; Found 140.0712. r-2-Cyano-trans-4,trans-6-dimethyl-1,3-dioxane (5). To an oven-dried, argon-flushed, 5mL vial was added 417 mg (2.96 mmol) of r-2-cyano-cis-4,cis-6-dimethyl-1,3-dioxane (6), 4.5 mL of pentane, 61 mg (0.54 mmol) of potassium tert-butoxide, and a small magnetic stir bar. The vial was tightly sealed with a Teflon-coated cap and to stirred for 24 h, at which point, it was opened and the contents were transferred by pipette and filtered through a bed of Celite into a 5mL vial. The solution was concentrated to ~ 0.3 mL with a gentle stream of N2 gas. Compound 7 was isolated from the concentrated solution by preparative TLC on a 1000 µm SiO2 glassbacked plate using a 10% solution of Et2O in hexanes as eluent to give a clear oil, which crystallized upon cooling to 0 °C to afford 100 mg (24%) of the title compound (Rf = 0.47–0.54) as a crystalline, white solid: mp 27.8 – 28.9 °C (Et2O/pentane); 1H NMR (400 mHz, CDCl3) δ 1.26 (d, J = 6.2 Hz, 6H), 1.40 (dt, J = 13.5 Hz, J = 11.3 Hz, 1H), 1.66 (dt, J = 13.6 Hz, J = 2.0 Hz, 1H), 4.18 (dqd, J = 11.3 Hz, J = 6.1 Hz, J = 2.3 Hz, 2H), 5.74 (s, 1H); 13C NMR (100 mHz, CDCl3) δ21.3, 39.9, 69.2, 87.4, 114.7; HRMS (DART-TOF) m/z: [M + NH4]+ Calcd for C7H15N2O2 159.1128; Found 159.1130. 41 ACS Paragon Plus Environment


Page 42 of 54

N-((cis-4,cis-6-Bis(trifluoromethyl)-1,3-dioxan-2-yl)-r-methyl)-phthalimide. A mixture of 3.679 g (17.3 mmol) of meso-1,1,1,5,5,5-hexafluoro-2,4-pentanediol, 4.572 g (17.3 mmol) of phthalimidoacetaldehyde diethyl acetal,43 239 mg (1.26 mmol) of p-TsOH, and 150 mL of hexanes was heated at reflux under a Dean-Stark trap for 24 h and the reaction mixture was then allowed to cool to room temperature. Upon cooling, a light brown solid precipitated. The reaction mixture was then transferred to a separatory funnel, diluted with 200 mL of CH2Cl2, and the organic layer was rinsed with two 100-mL portions of a saturated, aqueous Na2CO3, dried (Na2SO4), and solvent removed under reduced pressure to afford a brown solid. The crude material was dissolved in 100 mL of EtOAc and adsorbed onto 10 g of SiO2 for flash chromatography. Separation of the title compound was achieved by “double” flash column chromatography (200 g SiO2, 30 → 50% EtOAc/hexanes); 50 mL fractions were collected: 3.469 g (52%) of the title compound of ~ 90% purity was collected in fractions 7–16. This almost pure material was dissolved in 100 mL of EtOAc and was adsorbed onto 8.5 g of SiO2 for additional chromatography (150 g SiO2, 30 → 70% Et2O/hexanes); 50 mL fractions were collected: 3.036 g (46%) of the title compound was collected in fractions 16–26. Progress of the chromatography was monitored by TLC (SiO2, eluent: 50% Et2O in hexanes) and UV-light allowed for visualization of the title compound. The title compound had an Rf = 0.43: white, crystalline solid; mp 196.1–197.0 °C (Et2O/hexanes); 1H NMR (400 MHz, CDCl3) δ1.88 (dt, J = 13.0 Hz, J = 2.6 Hz, 1H), 2.00 (dt, J = 12.8 Hz, J = 11.8, 1H), 4.00 (d, J = 5.3 Hz, 2H), 4.12 (dqd, J = 11.6 Hz, J = 5.6 Hz, J = 2.9 Hz, 2H), 5.08 (t, J = 5.4 Hz, 2H), 7.74 (dd, J = 5.4 Hz, J = 3.0, 2H), 7.87 (dd, J = 5.4 Hz, J = 3.0, 2H); 13C NMR (100 MHz, CDCl3) δ 22.8, 40.4, 73.1 (quartet, JC−F = 34.1 Hz), 97.4, 122.8 (quartet, JC−F = 278.9 Hz), 123.8, 132.0, 134.4, 167.9;


19

F NMR (376 MHz,

Page 43 of 54 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


CDCl3) δ –79.4; HRMS (DART-TOF) m/z: [M + H]+ Calcd for C15H12F6NO4 384.0665; Found 384.0645. (cis-4,cis-6-Bis(trifluoromethyl)-1,3-dioxan-2-yl)-r-methanamine. A mixture of 2.756 g (7.19 mmol) of N-((cis-4,cis-6-bis(trifluoromethyl)-1,3-dioxan-2-yl)-r-methyl)-phthalimide, 0.850 mL (528 mg, 10.5 mmol) of hydrazine hydrate (64 wt% hydrazine), and 100 mL of EtOH was heated at reflux for 5 h then allowed to cool to room temperature, at which point a white precipitate of 2,3-dihydro-1,4-phthalazine formed. An additional 100 mL of a 2:1 mixture of pentane/CH2Cl2 was added to the flask, which was then cooled to 0 °C in an ice/water bath to further precipitate the solid. The mixture was filtered through a bed of Celite, the filtrate was concentrated under reduced pressure resulting in further precipitation of the byproduct, filtered a second time through a bed of Celite rinsing with a cold 2:1 mixture of pentane/CH2Cl2, and the solvent was removed under reduced pressure to afford a light yellow oil. The oil was distilled (Kugelrohr, bath temperature = 120–130 °C, 40 mm) to yield 1.402 g (77%) of the title compound as a crystalline, white solid: mp 36.4–37.2 °C (sublimation); 1H NMR (400 MHz, CDCl3) δ1.30 (br s, 2H), 1.85–2.00 (m, 2H), 2.94 (d, J = 4.1 Hz, 2H), 4.11–4.20 (m, 2H), 4.65 (t, J = 4.1 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 22.9, 45.2, 73.0 (quartet, JC−F = 34.0 Hz), 102.0, 123.0 (quartet, JC−F = 279.0 Hz);

19

F NMR (376 MHz, CDCl3) δ –79.5; HRMS (DART-

TOF) m/z: [M + H]+ Calcd for C7H10F6NO2 254.0610; Found 254.0613. r-2-Cyano-cis-4,cis-6-bis(trifluoromethyl)-1,3-dioxane (8). Following the conditions of our previously reported procedure,45 a slurry of 16.010 g (26.1 mmol) of Oxone®, 71 mg (0.44 mmol) of pyridinium bromide, and 100 mL of CH2Cl2 was stirred for 15 min until the solution developed a light yellow color. Then, 4.754 g (60.1 mmol) of dry pyridine was added, the mixture was stirred for 10 min before the addition of 108 mg (0.51 mmol) of the 4-acetamido43 ACS Paragon Plus Environment


2,2,6,6-tetramethylpiperidine-1-oxyl catalyst, and then stirred for an additional 15 min until the solution returned to a light yellow color. A solution of 582 mg (2.30 mmol) of (cis-4,cis-6bis(trifluoromethyl)-1,3-dioxan-2-yl)-r-methanamine in 20 mL of CH2Cl2 was added to the slurry via syringe pump at a rate of 10 mL/h and following the addition, the reaction mixture was stirred for 12 h at room temperature. The reaction mixture was filtered through a short plug of SiO2 (~ 50 g) while rinsing with 150 mL of CH2Cl2. The filtrate was concentrated under reduced pressure to yield a clear oil, which was triturated with pentane. Upon removal of the solvent 550 mg (96%) of the title compound was isolated as a white solid: mp 30.1–30.8 °C (pentane); 1H NMR (400 MHz, CDCl3) δ2.00 (dt, J = 13.3 Hz, J = 2.7 Hz, 1H), 1.98 (dt, J = 13.3 Hz, J = 11.8, 1H), 4.26 (dqd, J = 11.6 Hz, J = 5.4 Hz, J = 2.7 Hz, 2H), 5.47 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 22.5, 73.5 (quartet, JC−F = 35.5 Hz), 87.9, 112.0, 122.1 (quartet, JC−F = 278.6 Hz); 19F NMR (376 MHz, CDCl3) δ –79.1; HRMS (DART-TOF) m/z: [M – CN]+Calcd for C6H5F6O2 223.0188; Found 223.0217. r-2-Cyano-trans-4,trans-6-bis(trifluoromethyl)-1,3-dioxane (7). To an oven-dried, argonflushed 2-mL ampule was added 68 mg (0.273 mmol) of r-2-cyano-cis-4,cis-6bis(trifluoromethyl)-1,3-dioxane (8), 1.5 mL of Et2O, 11 mg (0.10 mmol) of potassium tertbutoxide, and a small magnetic stir bar. The ampule was flame-sealed and stirred for 1 d, at which point, it was opened and the contents were transferred by pipette into a 3-mL vial containing 1 mL of a saturated, aqueous NH4Cl and shaken. The organic layer was carefully separated from the aqueous layer by pipette, transferred into a separate vial, and the solution was concentrated to ~ 0.3 mL with a gentle stream of N2 gas. Compound 7 was isolated from the concentrated solution by preparative TLC on a 1000 µm SiO2 glass-backed plate using a 10% solution of Et2O in pentane as eluent to afford 32 mg (47%) of the title compound (Rf = 0.58– 44 ACS Paragon Plus Environment

Page 44 of 54

Page 45 of 54 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


0.78) as a crystalline, white solid: mp 33.1–33.7 °C (Et2O); 1H NMR (400 MHz, CDCl3) δ2.04 –2.19 (m, 2H), 4.50–4.60 (m, 2H), 5.97 (s, 1H);

13

C NMR (100 MHz, CDCl3) δ 22.5, 69.9

(quartet, JC−F = 35.5 Hz), 86.4, 111.8, 122.4 (quartet, JC−F = 279.1 Hz);

19

F NMR (376 MHz,

CDCl3) δ –79.2; HRMS (DART-TOF) m/z: [M – CN]+ Calcd for C6H5F6O2 223.0188; Found 223.0187. Equilibrations. For each pair of anancomeric diastereomers, equilibrium was approached independently from pure samples of each isomer. The diastereomers were equilibrated at room temperature (~23 °C) in sealed vials or ampoules as solutions in dry solvent over the specified catalyst (Table 1 and Figure 4) and neutralized prior to GC analysis. The area ratio of the isomers was determined by GC analysis using one of the following columns: a 30 m x 0.25 mm x 0.25 µm Optima-225 50% cyanopropyl / 50% phenylmethyl polysiloxane column or a 30 m x 0.25 mm x 0.25 µm EC-1 100% dimethyl polysiloxane column. The analysis parameters are detailed in the Supporting Information. When the same area ratios were obtained from initially pure samples of each epimer, it was deemed that equilibrium had been attained. Area ratios for each equilibrium were taken as the average of 10 independent determinations from each side, the isomers were assumed to have identical GC response ratios, and the equilibrium constant for each equilibrium was determined from these area ratios. Calculations. All calculations were carried out using Gaussian-16.46 Hirshfeld charges were obtained using the keywords pop=Hirshfeld and density=current. The structures were drawn using CYLview 1.0b.47



ASSOCIATED CONTENT Supporting Information. Appendix titled Atomic Charges; NMR spectra of all products; equilibration data; analytical GC data; a summary of the calculations, including computed energies and coordinates.

ACKNOWLEDGEMENTS We are grateful to Professor Steven R. Kass for providing suggestions on the preparation of meso-1,1,1,5,5,5-hexafluoro-2,4-pentanediol. The work at the University of Connecticut was supported by a grant from Procter & Gamble Pharmaceuticals.

REFERENCES AND NOTES

(1)

Present address: 865 Central Ave., Apt. 404, Needham, MA, 02492.

(2)

Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of Organic Compounds, Wiley: New York, 1994; pp. 686–754.

(3)

Nader, F. W.; Eliel, E. L. Conformational Analysis 22. Conformational Equilibria in 2Substituted 1,3-Dioxanes. J. Am. Chem. Soc. 1970, 92, 3050-3055.

(4)

Wiberg, K. B.; Hammer, J. D.; Castejon, H.; Bailey, W. F.; DeLeon, E. L.; Jarret, R. M. Conformational Studies in the Cyclohexane Series. 1. Experimental and Computational Investigations of Methyl, Ethyl, Isopropyl and tert-Butylcyclohexanes. J. Org. Chem. 1999, 64, 2085-2095.


Page 46 of 54

Page 47 of 54 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(5)

For example, see: (a) Hassel, O.; Ottar, B. The Structure of Molecules Containing Cyclohexane or Pyranose Rings. Acta Chem. Scand. 1947, 1, 929-943. (b) Capon, B. Mechanism in Carbohydrate Chemistry. Chem. Rev. 1969, 69, 407-498.

(6)

(a) Lemieux, R. U.; Chu, N. J. Abstracts of Papers; 133rd National Meeting of the American Chemical Society, San Francisco, CA; American Chemical Society: Washington, DC, April,1958; p. 31N. (b) Chu, N. J. Ph.D. Dissertation University of Ottawa (Canada), 1959.

(7)

Edward, J. T. Stability of Glycosides to Acid Hydrolysis. A Conformational Analysis. Chem. Ind. (London) 1955, 1102–1104.

(8)

Edward, J. T. Anomeric Effect. How it Came to be Postulated. In ACS Symposium Series,Vol. 539; Thatcher, G. R. J, Ed.; American Chemical Society: Washington, DC, 1993, pp 1–5.

(9)

For a short, curated list of reviews, see: Juaristi, E.; Bandala, Y. Anomeric Effect in Saturated Heterocyclic Ring Systems. Adv. Heterocyclic Chem. 2012, 105, 189-222, and references cited therein. Juaristi, E.; Cuevas, G. The Anomeric Effect, CRC Press: Boca Raton, 1995. Kirby, A. J. The Anomeric Effect and Related Stereoelectronic Effects at Oxygen; Springer-Verlag: New York, 1983. Anomeric Effect: Origin and Consequences; Szarek, W. A.; Horton, D., Eds.; ACS Symposium Series, Vol. 87; American Chemical Society: Washington, DC, 1979.

(10) For an intriguing discussion advocating “a clear semantic distinction between cause and effect” when discussing the “anomeric effect”, see: Filloux, C. M. The Problem of Origins and Origin of the Problem: Influence of Language on Studies Concerning the Anomeric Effect. Angew. Chem. Int. Ed. 2015, 54, 8880-8894. 47 ACS Paragon Plus Environment


(11) Lemieux, R. U. Effects of Unshared Pairs of Electrons and Their Solvation on Conformational Equilibria. Pure Appl. Chem. 1971, 25, 527-548. (12) (a) Takahashi, O.; Yamasaki, K.; Kohno, Y.; Ueda, K.; Suezawa, H.; Nishio, M. The Origin of the Generalized Anomeric Effect: Possibility of CH/n and CH/pi Hydrogen Bonds. Carbohydr. Res. 2009, 344, 1225-1229. (b) Takahashi, O.; Yamasaki, K,; Kohno, Y.; Ueda, K.; Suezawa, H.; Nishio, M. The Origin of the Relative Stability of Axial Conformers of Cyclohexane and Cyclohexanone Derivatives: Importance of CH/n and CH/pi Hydrogen Bonds. Bull. Chem. Soc. Jpn. 2009, 82, 272-276. (c) For a comprehensive review of non-classical hydrogen bonds, see: Takahashi, O.; Kohno, Y.; Nishio, M. Relevance of Weak Hydrogen Bonds in the Conformation of Organic Compounds and Bioconjugates: Evidence from Recent Experimental Data and High-Level ab Initio MO Calculations. Chem. Rev. 2010, 110, 6049-6076. (13) (a) Altona, C.; Romers, C.; Havinga, E. Molecular Structure and Conformation of Some Dihalogenodioxanes, Tetrahedron Lett. 1959, 1, 16-20. (b) Romers, C.; Altona, C.; Buys, H. R.; Havinga, E. In Topics in Stereochemistry, Vol. 4; Allinger, N. L.; Eliel, E. L., Eds.; Wiley-Interscience: New York, 1969, pp 39-97 (14) Alabugin, I. V. Stereoelectronic Effects; Wiley: Hoboken, NJ, 2016. (15) (a) Mo, Y. Computational Evidence that Hyperconjugation Interactions are not Responsible for the Anomeric Effect. Nat. Chem. 2010, 2, 666-671. (b) Wang, C.; Chen, Z.; Wu, W.; Mo, Y. How the Generalized Anomeric Effect Influences the Conformational Preference. Chem. Eur. J. 2013, 19, 1436-1444. (c) Wang, C.; Ying, F.; Wu, W.; Mo, Y. How Solvent Influences the Anomeric Effect: Roles of Hyperconjugation verses Steric Interactions on the Conformational Preference. J. Org. Chem. 2014, 79, 1571-1581. 48 ACS Paragon Plus Environment

Page 48 of 54

Page 49 of 54 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(16) Perrin, C. L.; Armstrong, K. B.; Fabian, M. A. The Origin of the Anomeric Effect. Conformational Analysis of 2-Methoxy-1,3-dimethylhexahydropyrimidine. J. Am. Chem. Soc. 1994, 116, 715-722. (17) (a) Bailey, W. F.; Eliel, E. L. Conformational Analysis. 29. 2-Substituted and 2,2Disubstituted 1,3-Dioxanes. Generalized and Reversed Anomeric Effects. J Am. Chem. Soc. 1974, 96, 1798-1806. (b) Wiberg, K. B.; Murcko, M. A. Rotational Barriers. 4. Dimethoxymethane – the Anomeric Effect Revisited. J. Am. Chem. Soc. 1989, 111, 48214828. (c) Wiberg, K. B.; Marquez, M. The Energy Components of the Anomeric Effect for 2-Methoxytetrahydropyran – An Experimental Comparison of the Gas Phase and Solution. J. Am. Chem. Soc. 1994, 116, 2197-2198. (d) Bailey, W. F.; Rivera, A. D. Conformational Change Occasioned by Complexation: Contra-Anomeric Effect Epimerization of 2Methoxy-1,3-dioxanes in the Presence of Magnesium Bromide. J. Org. Chem. 1987, 52, 1559-1562. (e) Bailey, W. F.; Lambert, K. M.; Wiberg, K. B.; Mercado, B. Q. Effect of Remote Substituents on the Conformational Equilibria of 2,2-Diaryl-1,3-dioxanes: Importance of Electrostatic Interactions. J. Org. Chem. 2015, 80, 4108-4115. (18) Lambert, K. M.; Stempel, Z. D; Wiberg, K. B.; Bailey, W. F. Experimental Demonstration of Sizable Nonclassical CH•••G Hydrogen Bond in Cyclohexane Derivatives: Stabilization of an Axial Cyano Group. Org. Lett. 2017,19, 6408 -6411. (19) Signorell, R.; Marquardt, R.; Quack, M.; Suhm, M. A. The Permanent Dipole Moment of CH2D2: FIR Spectroscopy, Centrifugal Distortion Effects and Quantum Monte Carlo Calculations with 9-Dimensioanl Analytic Dipole Moment and Potential Function for Methane. Mol. Phys. 1996, 89, 297-313. (20) Eliel, E. L.; Knoeber, M. C. Conformational Analysis. XVI. 1,3-Dioxanes. J. Am. Chem. 49 ACS Paragon Plus Environment


Soc. 1968, 90, 3444-3458. (21) Eliel, E. L.; Nader, F. W. Conformational Analysis. XX. Stereochemistry of Reaction of Grignard Reagents with Ortho Esters. Synthesis of 1,3-Dioxanes with Axial Substituents at C-2. J. Am. Chem. Soc. 1970, 92, 584-590. (22) Onsager, L. Electric Moments of Molecules in Liquids. J. Am. Chem. Soc. 1936, 58, 14861493 (23) We have found that plots of ∆G° vs the Onsager function, (ε-1)/(2ε+1), usually give a fairly good linear relationship when the solvents were cyclohexane, di-n-butyl ether, THF, acetone and MeCN, and in one case where the experimentally determined gas phase value was available, it fell on the line. The correlation was unsuccessful with Et2O, aromatic solvents and halogenated solvents. See: (a) Wiberg, K. B.; Rush, D. J. Solvent Effects on the Thioamide Rotational Barrier: An Experimental and Theoretical Study. J. Am. Chem. Soc. 2001, 123, 2038-2046. (b) Castejon, H.; Wiberg, K.B. Solvent Effects on Methyl Transfer Reactions. 1. The Menschutkin Reaction. J. Am. Chem. Soc. 1999, 121, 21392146. (24) Juaristi, E.; Valle, L.; Valenzuela, B. A.; Aguilar, M. A. S-C-P Anomeric Interactions. 4. Conformational Analysis of 2-(Diphenylphosphinoyl)-1,3-dithiane. J. Am. Chem. Soc. 1986, 108, 2000-2005. (25) (a) Stolow. R. D.; Giants, T. W.; Roberts, J. D. Fluorine and Proton NMR Studies of the Conformation of 4,4-Difluorocyclohexanol. Tetrahedron Lett. 1968, 5777-5780. (b) Stolow, R. D.; Lewis, D. I.; D’Angelo, P. A. Conformational Studies. XV. Transannular Electrostatic Interaction in 4-Substituted 1,1-Dimethylpiperidinnium Cations. Tetrahedron 1970, 26, 5831-5844. 50 ACS Paragon Plus Environment

Page 50 of 54

Page 51 of 54 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(26) Kleinpeter, E.; Heydenreich, M.; Koch, A.; Linker, T. Synthesis and NMR Spectroscopic Conformational Analysis of Esters of 4-Hydroxycyclohexanone: the More Polar the Molecule the More Stable the Axial Conformer. Tetrahedron 2012, 68, 2363-2373 and references therein. (27) Wiberg, K. B.; Castejon, H.; Bailey, W. F.; Ochterski, J. Conformational Studies in the Cyclohexane Series. 2. Phenylcyclohexane and 1-Methyl-1-phenylcyclohexane. J. Org. Chem. 2000, 65, 1181-1187. (28) (a) Hirshfeld, F. L. Bonded Atom Fragments for Describing Molecular Charge Densities. Theor. Chim. Acc. 1977, 44, 129-138. (b) Marenich, A, V.; Jerome, S. V.; Cramer, C. J.; Truhlar, D. G. Charge Model 5. An Extension of Hirshfeld Population Analysis for the Accurate Description of Molecular Interactions in Gaseous and Condensed Phases. J. Chem. Theory Comput. 2012, 8, 527-541. (29) Tomasi, J,; Mennucci, M.; Cammi, R. Quantum Chemical Continuum Solvation Models. Chem. Rev. 2005, 105, 2999-3094. (30) Jorgensen, W. L.; Thomas, L. L. Perspective on Free-Energy Perturbation Calculations for Chemical Equilibria. J. Chem. Theory Comput. 2008, 4, 869-876. (31) The orientation of the dipole is readily found as follows. After a geometry optimization that also gives the components of the dipole moment, one requests a new .com file with just the energy requested. This file is edited to add two new entries after the coordinates. The first has H 0.0 0.0 00 and the second has H followed by the components of the dipole moment. The connection table is edited to add a bond between the two entries above. Now, if this file is opened in Gaussview, the dipole vector can be seen, and it will rotate with the molecule. 51 ACS Paragon Plus Environment


(32) Bent, H. A. An Appraisal of Valence Bond Structures and Hybridization in Compounds of the 1st Row Elements. Chem. Rev. 1961, 61, 275 -311. (33) "Entities are not to be multiplied without necessity" (Non sunt multiplicanda entia sine necessitate). (34) Bailey, W. F.; Lambert, K. M.; Stempel, Z. D.; Wiberg,K. B.; Mercado, B. Q. C. Controlling the Conformational Energy of a Phenyl Group by Tuning the Strength of a Nonclassical CH•••O Hydrogen Bond. The Case of 5-Phenyl-1,3-Dioxane. J. Org. Chem. 2016, 81, 12116-12127. (35) Pritchard, J. G.; Vollmer, R. L. Conversion of Acetates into Alcohols in 1,3-Diol Systems. J. Org. Chem. 1963, 28, 1545–1549. (36) Pan, H.; Tu, S.; Zhang, C.; Young, A.; Fontaine, P. P. Efficient Separation of Diastereomeric Mixtures of syn- and anti-Pentanediol. Org. Process Res. Dev. 2015, 19, 463–469. (37) (a) Shokri, A.; Kass, S. R. Solvent Effects on the Molecular Recognition of Anions. Chem. Commun. 2013, 49, 11674–11676. (b) Shokri, A.; Wang, X. B.; Kass, S. R. Electron Withdrawing Trifluoromethyl Groups in Combination with Hydrogen Bonds in Polyols: Bronsted Acids, Hydrogen Bond Catalysts, and Anion Receptors. J. Am. Chem. Soc. 2013, 135, 9525–9530. (38) An azeotrope of unknown composition sometimes arises leading to removal of the diol from the reaction mixture. This can be detected by the appearance of a milky, turbid lower layer in the Dean-Stark trap within 1 h of reflux. This is easily dealt with by cooling the reaction mixture to room temperature, emptying the contents of the Dean-Stark trap into


Page 52 of 54

Page 53 of 54 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


the reaction flask, and adding 2–3 mL of deionized water to the reaction mixture before continuing. (39) The aqueous layers were extracted with two 100-mL portions of Et2O, dried over Na2SO4, and solvent removed to afford the racemic 1,1,1,5,5,5-hexafluoro-2,4-pentanediol as a white crystalline solid. This diol was not of interest in the present study, however, it had the following properties: mp 75.1–76.0 °C (Et2O); 1H NMR (400 MHz, CDCl3) δ 1.99 (dd, J = 7.5, Hz, J = 5.7, 2H), 2.69 (d, J = 5.8 Hz, 2H), 4.30–4.40 (m, 2H); 13C NMR (100 MHz, CD2Cl3) δ 29.3, 66.6 (quartet, JC−F = 32.1 Hz), 125.1 (quartet, JC−F = 281.3 Hz); 19F NMR (376 MHz, CD2Cl2) δ –79.7; HRMS (DART-TOF) m/z: [M + H]+ Calcd for C5H7F6O2 213.0345; Found 213.0366. (40) The hexane extraction facilitates the removal of benzaldehyde; the meso diol is not significantly soluble in hexanes and remains in the aqueous layer. (41) It is essential to ensure no excess diol remains as its separation from the title compounds is unsuccessful through column chromatography. If excess diol remained, additional aqueous K2CO3 washings are necessary. (42) The boiling point of the title compounds appears to be extremely low and care has to be taken during solvent removal to prevent loss of the product. (43) Anderson, M. A.; Shim, H.; Raushel, F. M.; Cleland, W. W. Hydrolysis of Phosphotriesters: Determination of Transition States in Parallel Reactions by Heavy-Atom Isotope Effects. J. Am. Chem. Soc. 2001, 123, 9246–9253. (44) Alvarez, M.; Fernandez, D.; Joule, J. A. Synthesis of Deoxyvariolin B. Tetrahedron Lett. 2001, 42, 315–317.



(45) Lambert, K. M.; Bobbitt, J. M.; Eldirany, S. A.; Kissane, L. E.; Sheridan, R. K.; Stempel, R. D.; Sternberg, F. H.; Bailey, W. F. Metal-Free Oxidation of Primary Amines to Nitriles through Coupled Catalytic Cycles. Chem. Eur. J. 2016, 22, 5156 - 5159. (46) Gaussian 16 Revision A.03. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Peterson, G. A.; Nakatsuji, H.; Li, X.; Caricto. M.; Marenich, A. V.; Bloino, J.; Janesko, B. G.; Gomperts, R; Mennucci, B.; Hratchian, H. F.;.Ortiz, J. V.; Izmayiov, A. F.; Sonnenberg, J. L.; Williams-Young, D.; Ding, F.; Lipparini, F.; Egidi, F.;

Goings, I.; Peng, B.; Petrone, A.; Henderson, T;

Ranasinghe, D.; Zakrzewski, V. G.; Gao, J.; Rega, N.; Zheng, G.; Liang, W.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Throssell, E.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.J.; Heyd, J. J.; Brothers, E. N.; Kudin, K. N.; Staroverov, V. N.; Keith, T. A.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A. P.; Burant, J. C.; Iyengar, S.S.; Tomasi, J.; Cossi, M.; Millam, J.M.; Klene, M.; Adamo, C.; Cammi, R.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Farkas, O.; Foresman, J. B.; Fox, D. J. Gaussian, Inc., Wallingford, CT, 2016. (47) Legault, C. Y. CYLview 1.0b; Université de Sherbrook: Sherbrook, QC, Canada, 2009; http://www.cylview.org.


Page 54 of 54

The Anomeric Effect - It's Complicated - The Journal of Organic

Recommend Documents