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Chiral Superbases with Extended Hydrogen Bond Networks Steven M. Bachrach J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00048 • Publication Date (Web): 22 Feb 2019 Downloaded from http://pubs.acs.org on February 24, 2019

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The Journal of Organic Chemistry

Chiral Superbases with Extended Hydrogen Bond Networks Steven M. Bachrach* Department of Chemistry and School of Science, Monmouth University, 400 Cedar Avenue, West Long Branch, NJ 07764 USA [email protected] revised manuscript jo-2019-00048u

Abstract Extended hydrogen bond networks can substantially increase basicity through stabilization of the resultant conjugate acid. In this study, the chiral superbases (9-11) having anilinyl substituents attached to the prototype superbase 1,8-bis(dimethylamino)naphthalene 1 are examined using DFT methods (PBE1PBE/6-311+G(d,p). While in the gas phase, these are more basic than 1, in THF solution they are slightly weaker bases than 1. While 9-11 are chiral, their rotational barrier about the Caryl-Caryl bond is about 20 kcal mol-1. Aminonaphthyl substituents (18-20) increase the rotational barrier by about 10 kcal mol-1. As a proof-ofconcept, deprotonation of propanal by the chiral bases 9-11 is predicted to have ee’s ranging from 58% (with 9) to 95% (with 11). The deprotonation of 4-t-butylcyclohexanone and cyclohexanoxide by 9 are predicted to have modest (23%) and excellent (97%) ee’s, respectively.

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NR'2

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R'2N

NRH NRH

9: R = R' = H 10: R = H, R' = Me 11: R = Me, R' = H


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Introduction Organic bases that are stronger than the basicity of 1,8-bis(dimethylamino)naphthalene 1 (DMAN)1 have been termed “superbases”. Many different approaches to superbases have been explored. Scaffolds were developed that exploit the key components that lead to 1 being a strong base, namely destabilizing the base by forcing amine groups to be near each other and/or stabilizing the conjugate acid through hydrogen bonding, such as 4.2-8 Another approach is to utilize nitrogen oxides,9 phosphazenyl,10-15 cyclopropenimino,16,17 or guanidinyl18-20 groups. We have explored the idea proposed by Kass21-23 to utilize a network of hydrogen bonds to stabilize the conjugate acid. A few of our better examples are 5-8.24-26 These and other examples of superbases are the subjects of a number of reviews.27-30 R1R2 N

NR1R2

1: R1 = R2 = Me

4

2: R1 = R2 = H

NMe2 NMe2

3: R1 = Me, R2 = H

N H2 N H2 N H2 N H2

H

5

N H2

N H2

H 2N

N H2

H 6

N H2 N H2 N H2 N H2

Me2N N Me2 N H2 N H2

N H2 H 7

8

Inspection of the structure of 8 and its conjugate acid 8H+ reveals its chiral nature, most notably the near C2 symmetry of 8H+ (Figure 1). A number of chiral superbases have been 3 ACS Paragon Plus Environment


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explored, including chiral guanidines,31-33 phosphazenes,34-36 and iminophosphoranes.37,38 None of these builds off the bisaminonaphthalene scaffold of 1. 8 itself is dynamically achiral as rotation about the Caryl-Cethylamine bond passes through a very small barrier, and this will lead to racemization. To impede this rotation, the remote amino group can be affixed to a phenyl group (2,7-bis(2-aminophenyl)naphthalene-1,8-diamine 9), which has hindered rotation about the Caryl-Caryl bond. The design places the remote amino groups in similar proximity to the interior amino groups as in 8, but should diminish stereomutation. Density functional computations are used here to assess the basicity of 9 and two methylated analogues 10 and 11. The enantioselectivity of these bases is first evaluated on their ability to selectively deprotonate propanal 12, followed by a couple of more pertinent examples. NR'2

R'2N

NRH NRH

9: R = R' = H 10: R = H, R' = Me 11: R = Me, R' = H

2nd layer

2nd layer

2nd layer

2nd layer

1st layer

1st layer

11H+

8H+

Figure 1. PBE1PBE/6-311+G(d,p) optimized geometries of 8H+ and 11H+. The dashed lines indicate hydrogen bonds. 4 ACS Paragon Plus Environment

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Computational Methods In our previous studies of organic superbases24-26 we employed a number of density functionals and basis sets, most recently with ωB97X-D/6-311+G(2d,p) but also finding good results with PBE1PBE/6-311G(d,p). Since this study examines the deprotonation of propanal, diffuse functions will be required, and since bases 9-11 are fairly large and multiple transition states will need to be located, some consideration of basis set size is warranted. Therefore, two methods, PBE1PBE/6-311+G(d,p) and ωB97X-D/6-311+G(d,p), were benchmarked against 20 nitrogen bases whose gas phase proton affinities (PA) are available from the NIST Webbook database.39 The computed PAs are listed in the Supporting Materials. Both methods provide excellent linear correlations (r2 greater than 0.996) of the predicted PAs with the experimental values, with PBE1PBE providing a slightly better model (see Figures S1 and S2), having a slope closer to unity and a smaller intercept than with the ωB97X-D results. All PBE1PBE results are reported here along with some ωB97X-D results. All computations were performed using PBE1PBE/6-311+G(d,p)40,41 and some were repeated with ωB97X-D/6-311+G(d,p).42 The structures of 9-11 and their conjugate acids 9H+11H+ were fully optimized in both the gas- and solution phase. The transition states for the deprotonation of propanal by bases 9-11 were fully optimized in the solution phase only. Solution phase computations were performed using the SMD43 procedure with THF as the solvent. A number of different configurations for the transition states were explored for both deprotonation of the pro-R and pro-S hydrogen atoms with all three bases. Analytical frequencies were computed to confirm the nature of the stationary points. The unscaled zero-point vibrational frequencies were used to compute the enthalpy and free 5 ACS Paragon Plus Environment


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energies employing the quasiharmonic approximation44 whereby frequencies less than 100 cm-1 were raised to 100 cm-1 for the vibrational partition functions. The corrected enthalpies and free energies were evaluated at 298 K. All computations were performed using the Gaussian0945 or Gaussian-1646 suite.

Results Structures and proton affinities of 9-11 To begin, the gas- and solution-phase proton affinities of DMAN 1, and its analogues missing two (3) or all four methyl groups (2) were computed. The structures of 2 and 3 exhibit an internal hydrogen bond between the two amino groups; this is not present in 1 since it has no hydrogens directly bonded to nitrogen. Their conjugate acids all show the added proton between the two nitrogens, forming a N-H…N hydrogen bond. Removal of pairs of methyl groups from 1 diminishes the proton affinity: 3 is less basic than 1 by 14.3 kcal mol-1 and 2 is nearly 6 kcal mol-1 less basic than 3 (see Table 1). This trend can be attributed to two factors: (a) the internal hydrogen bonds of 2 and 3 make them less basic and (b) the general trend47 that 3° amines are more basic than 2° amines which are more basic than 1° amines. All of these observations hold for these bases in solution as well, with a compression of the range of PAs from 20 kcal mol-1 in gas phase to 15 kcal mol-1 in THF.


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Table 1. PBE1PBE/6-311+G(d,p) Proton Affinities (PA, kcal mol-1) relative to DMAN 1. Gas

Solution

1

0.0

0.0

2

-20.1

-14.6

3

-14.3

-13.3

8

1.5

-4.9

9

-3.4

-8.9

10

1.9

-6.0

11

5.5

-2.1

In our previous exploration of amine bases that benefit from extended hydrogen bonding networks, we found that addition of 2-(dimethylamino)ethyl groups at the 2 and 7 positions of 2 led to a substantial increase in basicity, with the difference in PA of 8 and 2 of about 19 kcal mol-1. This increase in basicity can be attributed to stabilizing the conjugate acid through second-layer hydrogen bonding (see Figure 1). While 8 is potentially chiral, the rotational barrier about the Caryl-Cethyl bond is small, leading to racemization. Since rotation about Caryl-Caryl bonds is more restricted, especially if substituents are in an ortho position, a chiral superbase might come about when o-anilinyl groups are attached at the 2 and 7 positions of 2 or 3. Therefore, the structures of 9-11 and their conjugate acids were optimized. These geometries are shown in Figure S3, and the structure of 11H+, the conjugate acid of 11 is drawn in Figure 1. The structures of the three bases have C2 symmetry, and their conjugate acids involve first and second-layer hydrogen bonds, the latter involving the anilinyl amines as proton



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acceptors. (The anilinyl analogue of 1 was not examined because it lacks protons on the central nitrogen atoms and cannot participate in second-layer hydrogen bonding.) The PAs of 9-11 are listed in Table 1. The remote amino groups do act to increase the basicity of the 1,8-diaminonaphthalene core. While 9 is not as basic as DMAN 1, the anilinyl groups do increase the PA, relative to 2 by nearly 17 kcal mol-1 (gas phase) and 5 kcal mol-1 (THF). Adding methyl groups to the anilinyl amines further increases the basicity, with the PA of 10 now greater than that of 1 in the gas phase. Lastly, the anilinyl groups dramatically increase the basicity of 11 over 3, by 24 kcal mol-1 in the gas phase and 15 kcal mol-1 in solution. 11 is predicted to be a stronger base than 1 in both gas phase, but just slightly weker than 1 in solution. Very similar results are obtained with ωB97X-D/6-311+G(d,p) calculations (see Table S2). To test the assumption that chiral bases 9-11 will not readily racemize, the rotational transition states converting them into their achiral meso-like conformers (9meso-11meso) were optimized. In other words, the racemization is from the P,P-enantiomer to the meso, P,Misomer to the M,M-enatiomer. There are two different TSs corresponding to whether the amino groups pass near each other (TSsyn) or are far apart (TSanti), as shown in Scheme 1. The chiral and meso isomers for all three bases are very similar in relative enthalpy. As expected, rotation through TSanti is easier than through TSsyn, and these barriers are sizable (17-19 kcal mol-1, see Table 2) for all three bases. As long as deprotonation reactions are carried out at moderate temperatures, the chiral forms of the bases will persist. Racemization can also occur in the protonated forms 9H+-11H+ through an analogous pathway as the bases. The rotational free energy barriers for the conjugate acids are listed in 8 ACS Paragon Plus Environment

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Table 2. In contrast to the rotation of the bases, rotation through TSsyn is easier than through TSanti. Though the syn transition states are more congested, it does bring another amine close to the ammonium center and additional hydrogen bonds can form. Nonetheless, the barriers for racemization of the conjugate acids are comparable to those of the free bases.

Scheme 1. NR'2

R'2N

NRH NRH

NR'2

R'2N

NRH NRH

9: R = R' = H 10: R = H, R' = Me 11: R = Me, R' = H

NR'2

9-TSsyn 10-TSsyn 11-TSsyn

R'2N

NRH NRH

NR'2

9meso 10meso 11meso

NRH NRH

NR'2 9-TSanti 10-TSanti 11-TSanti



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Table 2. PBE1PBE/6-311+G(d,p) relative gas phase free energies (kcal mol-1) of the chiral (P,P) and meso (P,M) isomers and rotational TSs for 9-11, 18 and 20. X

Xmeso

X-TSanti

X-TSsyn

9

0.0

-0.2

19.4

21.3

10

0.0

-0.2

17.4

17.4

11

0.0

-0.7

19.1

21.4

9H+

0.0

0.2

24.9

21.4

10H+

0.0

0.0

23.6

17.0

11H+

0.0

1.4

28.6

22.4

18

0.0

-0.5

34.2

30.3

20

0.0

0.6

37.0

31.5

18H+

0.0

0.1

37.0

29.0

20H+

0.0

1.0

37.3

28.3

Deprotonation of propanal by 9-11 To test the ability of these chiral bases 9-11 to selectively remove prochiral protons, the deprotonation of propanal (12) was explored as a proof-of-concept. Propanal provides a suitable test as it is a small molecule with a prochiral center and is reasonably acidic. However, deprotonation of propanal lacks an obvious experimental test for verification of any enantioselectivity. Therefore, two cases where enantioselective deprotonation can be experimentally verified are presented in a later section. The transition state search was performed manually by careful selection of initial geometries. General patterns were followed, specifically that the propanal oxygen atom must be hydrogen bonded to one of the amines and the proton is removed by a different amine. A large number of orientations sampling these two conditions were created as initial geometries. 10 ACS Paragon Plus Environment

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When a TS was located, a new search was initiated from that geometry by interchange of the methyl and hydrogen attached to C2 (the prochiral carbon) of propanal. In this way, a good sampling of the potential space of the transition states was explored. While this is not an exhaustive search, it is likely that all reasonable initial conditions were sampled. As a reference, the transition states for the reaction of 2 with propanal were located. The six lowest energy transition states, labeled 13-1 to 13-6 by increasing free energy, are shown in Figure 2. These TSs present a few commonalities that are observed in the reactions of propanal with the chiral bases 9, 10, and 11. 13-1 and 13-2 differ in which proton is removed from the prochiral center: the pro-R proton is removed in 13-1 and the pro-S proton is removed in 13-2. The 13-3 and 13-4 pair and the 13-5 and 13-6 differ in this same way. The relative orientation of propanal to the base can be viewed as which aldehyde face (Si or Re) is nearer the base. The Re face of propanal approaches 2 in 13-1 while the propanal Si face approaches 2 in 13-3. The 13-2 and 13-4 pair differ in this way as well. The incipient enolate oxygen atom is stabilized by forming a hydrogen bond to the neighboring amine group in 13-1 to 13-4. This NH…O hydrogen bond is absent in 13-5 and 13-6, and this absence accounts for the higher energy of these two TSs. Lastly, all six of these TSs benefit from an internal N-H…H hydrogen bond that aids in stabilizing the forming ammonium cation.



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1.773 1.793

1.630

1.633 1.159

1.164

13-1 36.6

13-2 37.3

1.769 1.629

1.823

1.655 1.163

1.164

13-3 37.3

13-4 37.7

1.670 1.146

1.671 1.143

13-5 41.8

13-6 42.2

Figure 2. PBE1PBE/6-311+G(d,p) optimized geometries of the six lowest free energy transition states (13-1 to 13-6) for the deprotonation reaction of propanal by 2. Free energy of activation in kcal mol-1 and distances in Å.


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For further reference, the transition states for the reaction of DMAN 1 with propanal were optimized (14), and two representative structures are shown in Figure 3. Notably, since no N-H bonds are present, these transition states lack the internal N-H…H hydrogen bond and a hydrogen bond to the oxygen of propanal as seen in 13. The internal N-H…H hydrogen bond that is a major contributor to the superbasicity of 1 is formed well after the transition state. This results from the four methyl groups blocking access by the acid (propanal) to both of the amine nitrogens. The favored TS has propanal attacking one amine from the exterior, with no interaction of the transferring proton with the remote amine at all. The lowest energy TS where propanal interact between the two amines is 14-5, but this more congested TS is 2.8 kcal mol-1 higher in energy than 14-1. Even though 1 is significantly more basic than 2, the steric congestion and lack of stabilizing hydrogen bonds results in a higher activation free energy for the reaction of propanal with 1 (43.8 kcal mol-1) than with 2 (36.6 kcal mol-1).

1.681

1.741 1.170 1.127

14-1 43.8

14-5 46.6

Figure 3. PBE1PBE/6-311+G(d,p) optimized geometries of two transition states (14-1 and 14-5) for the deprotonation reaction of propanal by 1. Free energy of activation in kcal mol-1 and distances in Å. 13 ACS Paragon Plus Environment


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With the use of a chiral base, the removal of the pro-R or pro-S hydrogen of propanal proceeds through diastereomeric transition states. A total of 31 different transition states were located for the deprotonation of propanal by 9 (the P,P-enantiomer), 15 removing the pro-R proton (labeled as 15-Rn) and 16 TSs for removing the pro-S proton (labeled as 16-Sn). Six representative TSs are drawn in Figure 4 that demonstrate the range of conformational and configurational possibilities that were explored. Transition states 15-R1 and 15-S1 resemble the TS for the deprotonation of propanal by 2: the proton is abstracted by the amine on N1 while the incipient oxyanion is stabilized by a hydrogen bond from the N8 amine. An internal N-H…N hydrogen bond exists between the two central amine groups, and the C2 anilinyl nitrogen accepts a hydrogen bond from the N1 amine, further stabilizing this incipient cation. The amine of the aniline at C7 (referred to below as the N7 amine), while on the same face of the naphthyl moiety, is slightly too far away from the oxygen to form a true hydrogen bond, but can stabilize the anion through a weak electrostatic interaction. These two TSs differ in which prochiral proton is removed. 15-1 and 15-3 differ in which aldehyde face approaches 8, Re in the former and Si in the latter. In 15-S5, the orientation of the propanal is opposite that in 15-S1; the oxygen is directed away from the aniline that lies on the same face of the naphthyl moiety and so no additional electrostatic or hydrogen bond stabilization of the oxyanion is provided. While deprotonation of propanal occurs on the N1 amine in 15-R5, just like in 15-1R, the oxyanion is stabilized by a hydrogen bond to the C7 aniline amine group, and the N8 amine acts as a proton donor to the C7 aniline amine group. 15-S5 and 15-S7 differ by which aldehyde face approaches the base. TS 15-S8 has the aniline amine acting as the base, rather than either of the internal amines on the naphthyl 14 ACS Paragon Plus Environment

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ring. The last motif is represented by 15-S9, whereby N8 abstracts the proton from propanal while the oxygen is hydrogen-bonded to the amine of the N7 anilinyl ring. The lowest energy TS is 15-R1, having an activation energy of 34.4 kcal mol-1. There are seven other TSs within 3 kcal mol-1 of 15-R1; their energies are listed in Table 3, and the free energies of activation for all 31 TSs are listed in Table S3. The lowest energy TS that removes the pro-S proton (third lowest energy overall) is 15-S1 and it lies 0.9 kcal mol-1 above 15-R1. These two TSs (15-R1 and 15-S1) are structurally very similar – N1 removes the proton from propanal, the oxygen is hydrogen-bonded to N8, and the Re aldehyde face is nearer to the base – and their principle difference is which of the prochiral protons are removed.



1.549

1.832

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1.804

1.557

1.207

1.205

15-R1 34.4

15-S1 35.3

1.786

1.561

1.633

1.767

1.165

1.202

15-R3 35.7

15-S5 37.8

1.890

1.612 1.165

1.750

1.632 1.164

15-R5 38.2

15-S7 38.8

1.701 1.769

1.138

1.666 1.141

15-S8 39.8

1.840

15-S9 40.2

Figure 4. PBE1PBE/6-311+G(d,p) optimized geometries of representative transition states for the deprotonation reaction of propanal by 9. Free energy of activation in kcal mol-1 and distances in Å. 16 ACS Paragon Plus Environment

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Table 3. Free energy of activation (kcal mol-1) for the lowest energy TSs (within 3 kcal mol-1) for the reactions of propanal with 9-11. ΔG‡

ΔG‡

ΔG‡

15-R1

34.4

16-R1

33.0

17-R1

31.1

15-R2

34.8

16-R2

33.4

17-R2

32.4

15-S1

35.3

16-S1

33.9

17-S1

33.6

15-S2

35.6

16-R3

34.5

17-S2

34.0

15-R3

35.7

16-S2

34.9

15-R4

35.9

15-S3

36.2

15-S4

36.6

For the reaction of P,P-10 with propanal, 14 different TSs were obtained, half removing the pro-R proton and half removing the pro-S proton. The structures of the four lowest energy TS are shown in Figure 5. These four TSs share a number of common features. The N1 amine abstracts the proton while the N8 amine is the donor in a hydrogen bond to the oxygen. The two hydrogen atoms on the N1 amine act as donors in hydrogen bonds to the N8 and N2 anilinyl amines. Since there are no donor hydrogens on the C2 and C7 anilinyl nitrogens, these nitrogens can only participate in hydrogen bonding as acceptors, and cannot stabilize the forming oxyanion. 16-R1 and 16-R2 differ in the dihedral angle about the C7-Caniline bond, with the anilinyl nitrogen farther away from propanal in the former than in the latter. 16-R1 and 16-S1 differ in which prochiral proton is removed, while 16-R1 and 16-R3 differ in which aldehyde face approaches the base.



1.543 1.212

1.828

1.549

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1.864

1.208

16-R1 33.0

1.795

1.550

16-R2 33.4

1.844

1.555 1.207

1.208

16-S1 33.9

16-R3 34.5

Figure 5. PBE1PBE/6-311+G(d,p) optimized geometries of the four lowest energy transition states for the deprotonation reaction of propanal by 10. Free energy of activation in kcal mol-1 and distances in Å. There are five TSs within 3 kcal mol-1 of the lowest energy one, that being 16-R1 with an activation energy of 33.0 kcal mol-1 (see Table 3). There are two transition states that remove the pro-R proton with energies lower than 16-S1, the lowest energy TS for removing the pro-S proton. The four lowest energy TSs, of the 12 located, for the reaction of P,P-11 with propanal are shown in Figure 6. The two lowest energy TS, 17-R1 and 17-R2, involve removal of the pro-R hydrogen from propanal by the N1 amine. They both have hydrogen bonds between the N1 and N8 amines and between the N8 and N7 amines, while the oxygen hydrogen bonds to the N7 amine. They differ in which aldehyde face approaches the base. The next two lowest TSs, 17-S1 18 ACS Paragon Plus Environment

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and 17-S2, have the pro-S proton removed from propanal, supported by only the N1-H…N8 hydrogen bond and the N7-H…O hydrogen bond. They differ in which aldehyde face is nearer the base. A key geometric feature of the transition states with 11 as the base (TSs 17) is that the methyl groups of the central amines must be on the face opposite the approach of propanal, in order to allow this acid to get close to the nitrogen atom. In order to maintain a hydrogen bond to an anilinyl amine, propanal approaches such that its proton will be abstracted by N1 and the oxygen hydrogen bonds to the N8 amine. This forces the N1 methyl to be on the same side as the N8 methyl, and this means a loss of the potential hydrogen bond between N1 and N2. After fully abstracting the proton, the resulting conjugate acid 11H+ will not be in its most stable conformation (see Figure 1), which will necessitate either internal rotation(s) or intermolecular proton transfers to achieve the lowest energy conformation. The four TSs shown in Figure 6 are the only ones within 3 kcal mol-1 of the lowest energy configuration 17-R1, with an activation energy of 31.1 kcal mol-1. The two lowest energy TS correspond to removal of the pro-R proton, and the next two lowest energy TS remove the proS proton.



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1.912 1.623 1.167

1.191

17-R1 31.1

17-R2 32.4

1.893

1.584

1.882

1.587

2.064

1.628 1.175

1.198

17-S1 33.6

17-S2 34.0

Figure 6. PBE1PBE/6-311+G(d,p) optimized geometries of the four lowest energy transition states for the deprotonation reaction of propanal by 11. Free energy of activation in kcal mol-1 and distances in Å.

Discussion The goals for this work were to identify stable, chiral superbases structurally related to 1 that would be enantioselective in deprotonation of propanal. Building on our previous studies2426

of positioning remote amino groups to establish a hydrogen bonding network that stabilizes

the conjugate acid, candidate bases 9-11 were selected for study. These bases lack the methyl groups on the amines of 1, which will reduce its basicity. However, the neighboring aniline groups will aid in stabilizing the conjugate acid. The net result is that in the gas phase 10 and 11 are stronger bases than 1 (see Table 1). In solution, the three chiral bases are weaker than 1, 20 ACS Paragon Plus Environment

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but the proton affinity of 11 is only 2.1 kcal mol-1 less than that of 1. Solvent tends to preferentially stabilize concentrated charge. Since the aniline groups delocalize the positive charge on the conjugate acids 9H+-11H+ relative to 1H+, these acids are stabilized less by solvent than is 1H+. This leads to a diminished proton affinity. Technically, while these bases are not superbases, they are certainly quite strong. In addition to being strong bases, it is necessary that the barriers to rotation about the C-C bonds between the rings preclude racemization. The computed barrier for rotation for the racemization process of 9-11 are about 17-19 kcal mol-1. This is large enough to restrict the rotation at lower temperatures, but at higher temperatures, racemization will occur. Since the activation barriers for the deprotonation of propanal is greater than this rotation barrier, these bases will not remain enantiomerically pure. The rotational barrier can be significantly increased by using aminonaphthyl groups instead of anilinyl groups, such as 18-20. The computed proton affinity of 18 is 1.6 kcal mol-1 less than that of 9, and the proton affinity of 20 is 0.8 kcal mol-1 less that of 11. This slight reduction in base strength is due to the bulkier naphthyl ring pushing the ring farther from planarity with the central naphthalene. This reduces the hydrogen bond strength to the more remote amines. The computed free energy rotational barrier of 18 is 30.3 kcal mol-1 through the syn transition state and 34.2 kcal mol-1 through the anti TS (see Table 2). The rotational barriers are higher still for 20: 31.5 kcal mol-1 through the syn path and 37.0 kcal mol-1 through the anti path. Similarly, the rotational barriers for the conjugate acids 18H+ and 20H+ are about 29 kcal mol-1. Thus, 18-20 will provide strong basicity while being chirally stable. With the added bulk physically remote from the reaction centers, it



Page 22 of 39

is expected that the reactivity of 18-20 will mirror that of 9-11. Nonetheless, computations of the deprotonation of propanal by 18 were carried out and discussed below. NR'2

R'2N

NRH NRH

18: R = R' = H 19: R = H, R' = Me 20: R = Me, R' = H

The lowest energy transition state for the deprotonation of propanal by chiral bases 911 each involve removal of the pro-R proton. These three lowest TSs (15-R1, 16-R1, and 17-R1) are quite similar in structure. In all three, the pro-R proton is removed by the N1 amine, while the oxygen is hydrogen bonded to either the N8 amine (15-R1 and 16-R1) or the N7 aniline (17R1). A hydrogen bond exists between N1 and N8, and in 15-R1 and 16-R1 a hydrogen bond exists between N1 and the N2 aniline. These hydrogen bonds aid in delocalizing the charge across many atoms, thereby stabilizing the TS. The Re face of the aldehyde approaches the base. The lowest energy transition states that remove the pro-S proton (15-S1, 16-S1, and 17S1) express the same geometric attributes as their R counterparts as described above, except for the removal of the different enantiotopic proton. The network of hydrogen bonding along with the approach of the Re face of propanal to the base provides optimal stabilization of the incipient enolate and ammonium cation. The lower energy of the TSs that remove the pro-R proton can be attributed to their positioning the terminal methyl group of propanal away from the base, positioning the smaller C2 hydrogen towards the base.


Page 23 of 39 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


Contributing to the overall enantioselectivity of these bases is that for all three of them, the second lowest energy TS also removes the pro-R proton. These TSs (15-R2, 16-R2, and 17R2) share many geometric attributes of the lowest energy TSs. With the lowest energy TSs for removal of the pro-S proton lying 0.9 kcal mol-1 higher than that for the removal of the pro-R proton for the reaction with 15 and 16, and 2.5 kcal mol-1 for the reaction with 17, these lowest energy pro-R-removing TSs should dominate the overall enantioselectivity. The Arrhenius equation was employed to assess the enantioselectivity of the deprotonation by 9-11. The relative rates of reaction through two different TSs is given by Eqn 1. For these reactions, of interest is the ratio of the deprotonation of the pro-R proton relative to the removal of the pro-S proton. A reasonable approximation is that the Arrhenius prefactor will be essentially identical for all TSs with a given base, leading to the approximate result on the right hand side of Eqn 1. Here, ΔG is the activation free energy and we assume a temperature of 298 K. Summing up the relative rates for all of the reactions through all of the TSs for removal of the pro-R proton and dividing by the sum of the relative rates of the reactions through the all of TSs for removal of the pro-S proton gives the selectivity. This can then be translated into an enantiomeric excess (ee) for the reaction with each base; these are presented in Table 4.

𝑟𝑎𝑡𝑒1 𝑟𝑎𝑡𝑒2

=

𝐴1𝑒 ―(

∆𝐺1 𝑅𝑇) ∆𝐺2 𝑅𝑇)

𝐴2𝑒 ―(

∆𝐺1 𝑅𝑇)

≈

𝑒 ―(

∆𝐺2 𝑅𝑇)

𝑒 ―(

Eqn 1



Page 24 of 39

Table 4. Enantiomeric excess (ee) for the preferential deprotonation of the pro-R proton of propanal by bases 9-11. Base

ee

9

57.6

10

72.8

11

95.0

18

65.9

The ee for deprotonation of propanal by 9 is a respectable 58%. (The predicted ee with the ωB97X-D functional is slightly reduced to 43%.) Increasing the steric bulk, along with making the base stronger, leads to increased enantioselectivity. The ee with 10 is 73%, and it is even larger, 95%, with 11. Enantioselective deprotonation of propanal by the larger base 18 is likely to be similar to that by base 9. To confirm this, the eight lowest energy transition states for the reaction of 9 with propanal (15-R1 through 15-R4 and 15-S1 through 15-S4) were used as models for 21, the transition states for the reaction of 18 with propanal. The structures, which are little changed from their 15 analogs, and energies of these transition states are shown in the Supporting Materials. Applying Eqn 1 and summing over these eight TSs gives an expected ee of 66%. Thus, we expect that all these bases (9-11 and 18-20) can provide significant enantioselective deprotonation. To demonstrate that these new bases can have enantioselective utility, we examined the reaction of 9 with 4-t-butylcyclohexanone 22 (rxn 1) and cyclohexanoxide 25 (rxn 2).


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Deprotonation of 22 gives the enantiomers (R)-24 and (S)-24, while deprotonation of 25 leads to the ring-opened enolates (R)-27 and (S)-27.

O

O

–

O

–

9

Rxn 1

+

t-Bu 22

O

t-Bu (S)-24

t-Bu (R)-24

O

9

Rxn 2

+

O 25

–

(S)-27

–

(R)-27

Enantioselective deprotonation reactions are widely applicable in synthesis.48,49 Experimental examples of the Rxns 1 and 2 with other chiral bases are listed in Scheme 2, and these demonstrate that large enantiomeric excesses can be readily achieved.



Page 26 of 39

Scheme 2. OTMS

O chiral base

OTMS

+

TMSCl

t-Bu

t-Bu

Chiral base

t-Bu

ee

Ref.

>80%

50

88%

51

86%

52

>80%

53

Ph N

N Li

N

Ph

N Li

Ph

Ph

Ph

N Li

N

Ph

O

2

Mg

OH

chiral base +

OH

NH N

, 2 eq LDA

H N , n-BuLi

96%

54

>80%

55


Page 27 of 39 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


Using the results for the deprotonation of propanal as a guide, four transition states were located for Rxn 1 and for Rxn 2, two TSs for the removal of the proton leading to the R isomer and two TSs leading to the S isomer. For each pair of TSs, the two TSs differ by removing either the axial or the equatorial proton. In all of these transition states, oxygen of the acid is hydrogen bonded to the N8 amine and the N1 amine removes the proton. The lower energy TS leading to the R and S products for both Rxns 1 and 2 are shown in Figure 7, and the activation free energies for all of the computed TSs are listed in Table 5. The four TSs for Reaction 1 place the t-butyl group in the equatorial position. The lowest energy TS 23-S1 removes the axial proton with the bulk of the acid positioned away from the C2-anilinyl group. The lowest TS leading to the R isomer also has the bulk of the base away from the C2-anilinyl group, but it removes the axial proton, which is less sterically accessible. 23-S2 has the base remove the axial proton and the bulk of the acid faces the C2-anilinyl group, which explains its higher energy.



1.607 1.178

1.739

1.729

1.595 1.180

23-S1

23-R1

1.702

1.656

1.322 1.403

Page 28 of 39

1.342 1.395

26-S1

26-R1

Figure 7. PBE1PBE/6-311+G(d,p) optimized geometries of the two lowest energy transition states for Reactions 1 and 2. Distances in Å.

In order to establish the hydrogen bond from the N8 amine to the oxygen of 25, only the protons on the same face as the oxygen atom are accessible to the base. The lowest energy TS (26-S1) has the bulk of the acid away from the C2-anilinyl group and the cyclohexyl ring is in a chair-like conformation. 26-S2 is higher in energy because it is in a boat-like conformation. 26R1 brings the bulk of the base near the C2-anilinyl group, which destabilizes it relative to 26-S1.


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The activation barrier for Reaction 1 is a 39 kcal mol-1, a few kcal mol-1 higher than for the deprotonation of propanal. This is likely associated with solvation, with the larger acid pushing the solvent farther from the site of the charge build-up. The much larger barrier associated with Reaction 2 (48.8 kcal mol-1) reflects the diminished acidity of 24 relative to the carbonyl compounds. The main point here is whether deprotonation using the chiral base 9 leads to any significant enantiomeric excess. For Reaction 1, the predicted ee is relatively small, only 23%, with the four TSs clustered closely together in energy. On the other hand, for Rxn 2, the predicted ee is very large, 97%, as TS 26-S1 is 2.5 kcal mol-1 lower in energy than any other transition state. These results indicate that the chiral bases 9-11 and 18-20 can induce significant chirality through deprotonation.

Table 5. Activation free energies (kcal mol-1) and predicted ee for Rxns 1 and 2. ΔG‡

ΔG‡

23-S1

39.2

26-S1

48.8

23-R1

39.7

26-R1

51.3

23-R2

39.8

26-S2

51.9

23-S2

39.9

26-R2

54.1

ee

22.8%

96.8%

Conclusion Building upon the concept of enhanced basicity enabled by extended hydrogen bonding networks,24-26 the goal here is to develop potential chiral superbases. To fit this need, the



Page 30 of 39

proposed bases must (1) be very strong bases, (2) be chirally stable, and (3) selectively remove enantiotopic protons. The aniline-substituted 1,8-bis(dimethylamino)naphthalene analogues 911 are very basic, with gas phase proton affinities that exceed that of the benchmark superbase 1, while their solution phase basicities are slightly less than that of 1. In order to act as chiral bases, rotation about the bonds between the aryl rings must be suppressed. The computed rotational barriers for 9-11 are 17-20 kcal mol-1, which is likely to be too small to preserve chirality at the temperatures needed for deprotonation. The rotational barriers can be substantially increased through expanding the anilinyl substituents to aminonaphthyl groups, as in 18-20. For example, the rotational barrier is 30.3 kcal mol-1 for 18 and 31.5 kcal mol-1 for 20. Even larger rotational barriers will be found in analogues such as shown in Scheme 3. Scheme 3. Potential chiral bases with large rotational barriers. NR'2

R'2N

NR'2

NRH NRH

Me

Me NR'2

R'2N

R'2N

NRH NRH

Me

Me

NR'2

NRH NRH

R'2N

NRH NRH

The lowest energy transition states for the deprotonation of propanal by bases 9-11 are for the removal of the pro-R proton. This translates into a predicted ee of 58% with 9, 73% with 10 and 95%, with 11. Deprotonation of propanal by 18 is predicted to have an ee of 66%.


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Deprotonation of 4-t-butylcyclohexanone 22 and cyclohexanoxide 25 with 9 represents test cases that can be experimentally verified; both show enentioslectivity, with a modest ee of 23 for the former and a significant ee of 97% for the latter. Therefore, the bases 9-11 (and by analogy 18-20) meet the criteria for chiral superbases. Methods for synthesis of axially chiral compounds, especially aryl-aryl chiral systems, are flourishing.56 The proposed chiral superbases should make for excellent synthetic targets, having interesting potential application in a variety of enantioselective process including catalysis.

Acknowledgements Preliminary computations were performed by Ann Andrews and Clemente Guzman at Trinity University. The author thanks Monmouth University for the computational resources used in the project, and referees for helpful suggestions

Supporting Materials: Tables and figures for benchmarking the computational methods (Tables S1-S2, Figures S1-S2), activation free energies for the reactions of propanal with 8-11 (Table S3-S5), views of selected transition states (Figures S3-S4), and optimized coordinates of all compounds and transition states.



Page 32 of 39

References

(1)

Alder, R. W.; Bowman, P. S.; Steele, W. R. S.; Winterman, D. P. The remarkable

basicity of 1,8-bis(dimethylamino)naphthalene. Chem. Commun. 1968, 723-724. (2)

Schwesinger, R.; Missfeldt, M.; Peters, K.; von Schnering, H. G. Novel, Very

Strongly Basic, Pentacyclic "Proton Sponges" with Vinamidine Structure. Angew. Chem. Int. Ed. 1987, 26, 1165-1167. (3)

Zirnstein, M. A.; Staab, H. A. 1. New proton sponges. 4. Quino[7,8-h]quinoline, a

new type of proton sponge. Angew. Chem. Int. Ed. 1987, 26, 460-462. (4)

Estrada, E.; Simón-Manso, Y. Rational Design and First Principles Studies Toward

the Discovery of a Small and Versatile Proton Sponge. Angew. Chem. Int. Ed. 2006, 45, 17191721. (5)

Singh, A.; Ganguly, B. Rational Design and First-Principles Studies toward the

Remote Substituent Effects on a Novel Tetracyclic Proton Sponge. J. Phys. Chem. A 2007, 111, 6468-6471. (6)

Bühl, M. Dodeka(ethylene)octamine. Chem. Eur. J. 2011, 17, 3575-3578.

(7)

Galeta, J.; Potáček, M. Substituted Diazatetracyclo[4.4.0.13,10.15,8]dodecanes

as Stable Caged Proton Sponges. J. Org. Chem. 2012, 77, 1010-1017. (8)

Sanchez-Sanz, G.; Trujillo, C.; Alkorta, I.; Elguero, J. Modulating intramolecular

P[three dots, centered]N pnictogen interactions. Phys. Chem. Chem. Phys. 2016, 18, 9148-9160. (9)

Despotovic, I.; Vianello, R. Engineering exceptionally strong oxygen superbases

with 1,8-diazanaphthalene di-N-oxides. Chem. Commun. 2014, 50, 10941-10944. 32 ACS Paragon Plus Environment

Page 33 of 39 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)

Schwesinger, R.; Schlemper, H. Peralkylated Polyaminophosphazenes -

Extremely Strong, Neutral Nitrogen Bases. Angew. Chem. Int. Ed. 1987, 26, 1167-1169. (11)

Schwesinger, R.; Schlemper, H.; Hasenfratz, C.; Willaredt, J.; Dambacher, T.;

Breuer, T.; Ottaway, C.; Fletschinger, M.; Boele, J.; Fritz, M.; Putzas, D.; Rotter, H. W.; Bordwell, F. G.; Satish, A. V.; Yi., G. Z.; Peters, E.-H.; Peters, K.; von Schnering, H. G.; Walz, L. 5. Extremely strong, uncharged auxiliary bases. Monomeric and polymer-supported polyaminophosphazenes (P2-P5) Liebigs Ann. 1996, 1055-1081. (12)

Raab, V.; Gauchenova, E.; Merkoulov, A.; Harms, K.; Sundermeyer, J.; Kovacevic,

B.; Maksic, Z. B. 1,8-Bis(hexamethyltriaminophosphazenyl)naphthalene, HMPN: A Superbasic Bisphosphazene "Proton Sponge". J. Am. Chem. Soc. 2005, 127, 15738-15743. (13)

Barić, D.; Kovačević, B. Designing a next generation of proton sponges:

cyclopropeniminophosphazenes as the strongest pincer ligands. Tetrahedron Lett. 2016, 57, 442-445. (14)

Kaljurand, I.; Koppel, I. A.; Kütt, A.; Rõõm, E.-I.; Rodima, T.; Koppel, I.; Mishima,

M.; Leito, I. Experimental Gas-Phase Basicity Scale of Superbasic Phosphazenes. J. Phys. Chem A 2007, 111, 1245-1250. (15)

Despotovic, I.; Kovacevic, B.; Maksic, Z. B. Hyperstrong Neutral Organic Bases:

Phosphazeno Azacalix[3](2,6)pyridines. Org. Lett. 2007, 9, 4709-4712. (16)

Belding, L.; Stoyanov, P.; Dudding, T. Synthesis, Theoretical Analysis, and

Experimental pKa Determination of a Fluorescent, Nonsymmetric, In–Out Proton Sponge. J. Org. Chem. 2016, 81, 6-13.



(17)

Page 34 of 39

Barić, D.; Kovačević, B. Cyclopropenimine as pincer ligand and strong electron

donor in proton sponges. J. Phys. Org. Chem. 2016, 29, 750-758. (18)

Maksić, Z. B.; Kovačević, B. Absolute Proton Affinity of Some Polyguanides. J.

Org. Chem. 2000, 65, 3303-3309. (19)

Kovacevic, B.; Despotovic, I.; Maksic, Z. B. In quest of strong neutral organic

bases and superbases--supramolecular systems containing four pyridine subunits. Tetrahedron Letters 2007, 48, 261-264. (20)

Barić, D.; Dragičević, I.; Kovačević, B. Design of Superbasic Guanidines: The Role

of Multiple Intramolecular Hydrogen Bonds. J. Org. Chem. 2013, 78, 4075-4082. (21)

Tian, Z.; Fattahi, A.; Lis, L.; Kass, S. R. Neutral Intramoleuclar Hydrogen-Bonded

Bases. Croat. Chem. Acta 2009, 82, 41-45. (22)

Shokri, A.; Abedin, A.; Fattahi, A.; Kass, S. R. Effect of Hydrogen Bonds on pKa

Values: Importance of Networking. J. Am. Chem. Soc. 2012, 134, 10646-10650. (23)

Shokri, A.; Schmidt, J.; Wang, X.-B.; Kass, S. R. Hydrogen Bonded Arrays: The

Power of Multiple Hydrogen Bonds. J. Am. Chem. Soc. 2011, 134, 2094-2099. (24)

Bachrach, S. M. Extended Hydrogen Bond Network Enabled Superbases. Org.

Lett. 2012, 14, 5598-5601. (25)

Bachrach, S. M. Amine Superbases Stabilized by Extended Hydrogen Bond

Networks. J. Org. Chem. 2013, 78, 10909-10916. (26)

Bachrach, S. M.; Wilbanks, C. C. Using the Pyridine and Quinuclidine Scaffolds for

Superbases: A DFT Study. J. Org. Chem. 2010, 75, 2651-2660.


Page 35 of 39 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


(27)

Schlosser, M. Superbases for organic synthesis. Pure Appl. Chemistry 1988, 60,

1627-1634. (28)

Raczyńska, E. D.; Gal, J.-F.; Maria, P.-C. Enhanced Basicity of Push–Pull Nitrogen

Bases in the Gas Phase. Chem. Rev. 2016, 116, 13454-13511. (29)

Maksić, Z. B.; Kovačević, B.; Vianello, R. Advances in Determining the Absolute

Proton Affinities of Neutral Organic Molecules in the Gas Phase and Their Interpretation: A Theoretical Account. Chem. Rev. 2012, 112, 5240-5270. (30)

Superbases for Organic Synthesis: Guanidine, Amidines, Phosphazenes and

Related Organocatalysts; Iskikawa, T., Ed.; John Wiley: Chichester, UK, 2009. (31)

Isobe, T.; Fukuda, K.; Araki, Y.; Ishikawa, T. Modified guanidines as chiral

superbases: the first example of asymmetric silylation of secondary alcohols. Chem. Commun. 2001, 243-244. (32)

Isobe, T.; Fukuda, K.; Tokunaga, T.; Seki, H.; Yamaguchi, K.; Ishikawa, T. Modified

Guanidines as Potential Chiral Superbases. 2. Preparation of 1,3-Unsubstituted and 1Substituted 2-Iminoimidazolidine Derivatives and a Related Guanidine by the 2-Chloro-1,3dimethylimidazolinium Chloride-Induced Cyclization of Thioureas. J. Org. Chem. 2000, 65, 77747778. (33)

Isobe, T.; Fukuda, K.; Yamaguchi, K.; Seki, H.; Tokunaga, T.; Ishikawa, T. Modified

Guanidines as Potential Chiral Superbases. 3. Preparation of 1,4,6-Triazabicyclooctene Systems and 1,4-Disubstituted 2-Iminoimidazolidines by the 2-Chloro-1,3-dimethylimidazolinium Chloride-Induced Cyclization of Guanidines with a Hydroxyethyl Substituent. J. Org. Chem. 2000, 65, 7779-7785. 35 ACS Paragon Plus Environment


(34)

Page 36 of 39

Koegel, J. F.; Kovacevic, B.; Ullrich, S.; Xie, X.; Sundermeyer, J. Chelating P2-Bis-

phosphazenes with a (R,R)-1,2-Diaminocyclohexane Skeleton: Two New Chiral Superbases. Chem. - Eur. J. 2017, 23, 2591-2598. (35)

Koegel, J. F.; Kneusels, N.-J.; Sundermeyer, J. Two C2-symmetric chelating P2-

bisphosphazene superbases connected via a binaphthyl backbone - synthesis, structural features and preparation of a cationic alkyl aluminum complex. Chem. Commun. 2014, 50, 4319-4321. (36)

Lo, R.; Ganguly, B. Exploiting propane-1,3-diimines as building blocks for

superbases: a DFT study. New J. Chem. 2011, 35, 2544-2550. (37)

Krawczyk, H.; Dziegielewski, M.; Deredas, D.; Albrecht, A.; Albrecht, L. Chiral

Iminophosphoranes-An Emerging Class of Superbase Organocatalysts. Chem. - Eur. J. 2015, 21, 10268-10277. (38)

Azusa, K.; Shiori, A.; Masafumi, O.; Masahiro, T. Enantioselective Formal [3+2]

Cycloaddition of Epoxides with Imines under Brønsted Base Catalysis: Synthesis of 1,3-Oxazolidines with Quaternary Stereogenic Center. Angew. Chem. Int. Ed. 2018, 57, 62996303. (39)

Linstrom, P. J.; Mallard, W. G.; NIST: 2009, p URL: http://webbook.nist.gov.

(40)

Perdew, J. P.; Burke, K.; Ernzerhof, M. Generalized Gradient Approximation

Made Simple. Phys. Rev. Lett. 1996, 77, 3865-3868 (errata 1997, 3878 , 1396). (41)

Adamo, C.; Barone, V. Toward reliable density functional methods without

adjustable parameters: The PBE0 model. J. Chem. Phys. 1999, 110, 6158-6170.


Page 37 of 39 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


(42)

Chai, J.-D.; Head-Gordon, M. Long-range corrected hybrid density functionals

with damped atom-atom dispersion corrections. Phys. Chem. Chem. Phys. 2008, 10, 6615-6620. (43)

Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. Universal Solvation Model Based on

Solute Electron Density and on a Continuum Model of the Solvent Defined by the Bulk Dielectric Constant and Atomic Surface Tensions. J. Phys. Chem. B 2009, 113, 6378-6396. (44)

Ribeiro, R. F.; Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. Use of Solution-Phase

Vibrational Frequencies in Continuum Models for the Free Energy of Solvation. J. Phys. Chem B 2011, 115, 14556-14562. (45)

Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, J. A.;

Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery Jr., J. A.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, J. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J.; Gaussian-09, rev. D.01, Gaussian, Inc.: Wallingford CT, 2009. (46)

Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Rob, M. A.;

Cheeseman, J. R.; Scalmani, G.; Barone, V.; Petersson, G. A.; Nakatsuji, H.; Li, X.; Caricato, M.; 37 ACS Paragon Plus Environment


Page 38 of 39

Marenich, A. V.; Bloino, J.; Janesko, B. G.; Gomperts, R.; Mennucci, B.; Hratchian, H. P.; Ortiz, J. V.; Izmaylov, A. F.; Sonnenberg, J. L.; Williams-Young, D.; Ding, F.; Lipparini, F.; Egidi, F.; Goings, J.; 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, K.; Jr., J. A. M.; 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, M.; Klene, M.; Adamo, C.; Cammi, R.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Farkas, O.; Foresman, J. B.; Fox, D. J.; Gaussian-16, rev. B.01Gaussian, Inc.: Wallingford CT, 2016. (47)

Carroll, F. A. Perspectives on Structure and Mechanism in Organic Chemistry; 2nd

ed.; John Wiley & Sons: Hoboken, NJ USA, 2010. (48)

Beak, P.; Basu, A.; Gallagher, D. J.; Park, Y. S.; Thayumanavan, S. Regioselective,

Diastereoselective, and Enantioselective Lithiation−Substitution Sequences: Reaction Pathways and Synthetic Applications. Acc. Chem. Res. 1996, 29, 552-560. (49)

Organolithiums in Enantioselective Synthesis; Hodgson, D. M., Ed.; Springer-

Verlag: Berlin, 2003. (50)

Shirai, R.; Tanaka, M.; Koga, K. Enantioselective deprotonation by chiral lithium

amide bases: asymmetric synthesis of trimethylsilyl enol ethers from 4-alkylcyclohexanones. J. Am. Chem. Soc. 1986, 108, 543-545.


Page 39 of 39 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


(51)

Cain, C. M.; Cousins, R. P. C.; Coumbarides, G.; Simpkins, N. S. Asymmetric

deprotonation of prochiral ketones using chiral lithium amide bases. Tetrahedron 1990, 46, 523-544. (52)

Simpkins, N. S. Recent advances in asymmetric synthesis using chiral lithium

amide bases. Pure Appl. Chem. 1996, 68, 691-694. (53)

Henderson, K. W.; Kerr, W. J.; Moir, J. H. Enantioselective deprotonation

reactions using a novel homochiral magnesium amide base. Chem. Commun. 2000, 479-480. (54)

Södergren, M. J.; Andersson, P. G. New and Highly Enantioselective Catalysts for

the Rearrangement of meso-Epoxides into Chiral Allylic Alcohols. J. Am. Chem. Soc. 1998, 120, 10760-10761. (55)

Malhotra, S. V. Lithium diisopinocampheylamide: a new and highly effective

chiral catalyst in the enantioselective deprotonation of meso-epoxides. Tetrahedron Asym. 2003, 14, 645-647. (56)

Wang, Y.-B.; Tan, B. Construction of Axially Chiral Compounds via Asymmetric

Organocatalysis. Acc. Chem. Res. 2018, 51, 534-547.


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