Investigation of the C–N bond rotation of spirophosphorane carbamates by dynamic NMR and DFT calculation

Accepted Manuscript Investigation of the C-N bond rotation of spirophosphorane carbamates by dynamic NMR and DFT calculation Pei Zhao, Shuxia Cao, Yanchun Guo, Peng Gao, Yanyan Wang, Miaomiao Peng, Yufen Zhao PII:

S0040-4020(15)30080-6

DOI:

10.1016/j.tet.2015.09.052

Reference:

TET 27149

To appear in:

Tetrahedron

Received Date: 25 June 2015 Revised Date:

20 September 2015

Accepted Date: 22 September 2015

Please cite this article as: Zhao P, Cao S, Guo Y, Gao P, Wang Y, Peng M, Zhao Y, Investigation of the C-N bond rotation of spirophosphorane carbamates by dynamic NMR and DFT calculation, Tetrahedron (2015), doi: 10.1016/j.tet.2015.09.052. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Graphical Abstract To create your abstract, type over the instructions in the template box below.

Leave this area blank for abstract info.

RI PT

Investigation of the C-N bond rotation of spirophosphorane carbamates by dynamic NMR and DFT calculation

AC C

EP

TE D

Fonts or abstract dimensions should not be changed or altered.

M AN U

SC

Pei Zhaoa, Shuxia Caoa,∗, Yanchun Guoa, Peng Gaoa, Yanyan Wanga, Miaomiao Penga and Yufen Zhaoa,b a The College of Chemistry and Molecular Engineering, The Key Laboratory of Chemical Biology and Organic Chemistry of Henan Province, Zhengzhou University, Zhengzhou, 450052, P. R. China b Department of Chemistry, the College of Chemistry and Chemical Engineering, The Key Laboratory for Chemical Biology of Fujian Province, Xiamen University, Xiamen, 361005, P. R. China

1

ACCEPTED MANUSCRIPT

Tetrahedron journal homepage: www.elsevier.com

RI PT

Investigation of the C-N bond rotation of spirophosphorane carbamates by dynamic NMR and DFT calculation Pei Zhaoa, Shuxia Caoa,∗, Yanchun Guoa, Peng Gaoa, Yanyan Wanga, Miaomiao Penga and Yufen Zhaoa,b a

SC

The College of Chemistry and Molecular Engineering, The Key Laboratory of Chemical Biology and Organic Chemistry of Henan Province, Zhengzhou University, Zhengzhou, 450052, P. R. China b Department of Chemistry, the College of Chemistry and Chemical Engineering, The Key Laboratory for Chemical Biology of Fujian Province, Xiamen University, Xiamen, 361005, P. R. China

ABSTRACT

Article history: Received Received in revised form Accepted Available online

Spirophosphorane carbamates are a new type of pentacoordinate phosphorus compounds. In order to explore internal rotation, the dynamic 1H NMR, 31P NMR and molecular theory calculations were employed to investigate the rotation barriers of the N-C(=O) bond of symmetrical and asymmetrical spirophosphorane carbamates. The Gibbs free activation, ∆G≠, was calculated by Eyring equation. The results showed that the rotation barriers of spirophosphorane carbamates were about 16-18 kcal/mol, and the rotation isomers coexisted at room temperature. Moreover, it was found that the benzyl group attached to amide nitrogen increased the C-N bond rotation barriers of spirophosphorane carbamates. Furthermore, the preferred conformation of spirophosphorane carbamates was presumed by density functional theory (DFT), and the conformation of solid state were also confirmed by X-ray diffraction analysis.

1. Introduction

TE D

Keywords: Spirophosphorane carbamates Dynamic NMR Rotation barrier X-ray analysis DFT calculations

M AN U

ARTICLE INFO

AC C

EP

In recent years, the rotation of C-N bond is an on-going topic in conformational stereochemistry that has attracted the interest of many investigators.1 Previous studies on indole derivatives2, 3 and carbamates4 bearing N-C(=O) group testified the restricted rotation of C-N bond. The dynamic processes due to restricted intramolecular rotation have been extensively explored by dynamic NMR methods,5 and the results show that the rotational free energies (G) are largely governed by substituents around the N-C(=O) bond. Now the investigation of C-N bond rotation is considered to be a commendable method to study the conformation and internal rotation of the molecule bearing NC(=O) group. Pentacoordinate phosphorus compounds play a crucial role in numerous biological processes such as hydrolyses of RNA or phosphoryl transfer reactions. Many phosphoryl transfer reactions such as energy transfer and DNA formation via ATP are assumed to go through pentacoodinate phosphorus intermediates. Therefore, the investigation of the character of pentacoordinate phosphorus compounds is important to the research of biochemistry. Recently, we reported a one-pot practical method for the synthesis of a novel spirophosphorane carbamate,6 which involves steric hindrance adjacent to the nitrogen atom of the N-C(=O) bond. Although the first pentacoordinate phosphorane containing a carbamato substituent was synthesized by Stephan’s group as shown in Scheme 1,7 the N-C(=O) bond was in the ring structure. The spirophosphorane

2009 Elsevier Ltd. All rights reserved.

carbamate synthesized by our group is the second kind of pentacoordinate spirophosphorane carbamate, which has a chain carbamate substituent. Therefore, the new-type spirophosphorane carbamate is a good model to observe and investigate the rotational barriers of the N-C(=O) bond of pentacoordinate phosphorane compounds. The dynamic NMR is a branch of NMR with wide application in the elucidation of rotation barriers in the stereodynamics of ortho-disubstituted biaryls,8 hindered heterocyclic systems,9 and molecular rotors systems.10 The NMR signals in solution always show the averaged state of molecular conformations, which varies with magnetic strength, on the time scale of measurement. For the new type of asymmetrical spirophosphorane carbamates, the 31P nucleus is found to be a very sensitive probe for structural studies. Therefore, both dynamic 31P NMR and dynamic 1H NMR can be used to investigate the rotation of the C-N bond. In order to study the stereochemical character of pentacoordinate phosphorus compounds, the investigation of the rotation of the N-C(=O) bond of new spirophosphorane carbamates was carried out by dynamic 1H NMR, 31P NMR and theoretical calculations. In addition, the Gibbs free activation, ∆G≠, was calculated by Eyring equation. The density functional theory (DFT) method and X-ray diffraction analysis were used to study the preferred conformations of the spirophosphorane carbamates.

2

Tetrahedron

spectra confirmed that two signals in Fig. 1 were produced from ACCEPTED MANUSCRIPT

2.1. Synthesis The spirophosphorane carbamates 3a-h were synthesized from hydrospirophosphorane 1 and secondary amines 2 in CO2 atmosphere as showed in Scheme 2.6 O

O R

NH NH

R +

H P O

3a R = i-Pr, R1 = R2 = Et

H H

O

R1R2NH

H

R O 1 ?P

2

CCl4 , CO2 Cs2CO3

3b R = i-Pr, R1 = R2 = n-Pr

O

O R1 P O C N HN R2 R O H O HN

3 ?P

3c R = i-Pr, R1 = R2 = n-Bu 3d R = i-Pr, R1 = Me, R2 =n-Pr 3e R = i-Pr, R1 = Me, R2 = Bn 3f R = i-Pr, R1 = Bn , R2 = i-Pr 3g R = s-Bu, R1 = Me, R2 =n-Pr 3h R = s-Bu, R1 = Bn, R2 = i-Pr

Scheme 2. The synthesis of spirophosphorane carbamates

TE D

M AN U

Here the spirophosphorane carbamates 3 are divided into symmetrical carbamates (3a-3c) and asymmetrical carbamates (3d-3h) according to the substituent groups to nitrogen atom. The synthesis of spirophosphorane carbamates 3a-3f has been reported,6 while 3g-3h were first synthesized under similar conditions for further investigation of substituent effect. As shown in Scheme 2, the symbols, ∆P and ΛP, were used to name two different diastereoisomers of pentacoordinate spirophosphorane derivatives based on coordination stereochemistry.11 For the reactant hydrospirophosphoranes with ∆P configuration, all the products were obtained with inversion of configuration at phosphorus.6 The structures of the spirophosphorane carbamates 3 were characterized by 1H-NMR, 13 C-NMR, 31P-NMR, ESI-MS/MS, HR-ESI-MS and IR spectra. The absolute configurations of 3c and 3f were confirmed by Xray single crystal diffraction analysis, and other configurations of products were deduced by the chemical shift in 31P NMR and coupling constant in 13C NMR.12

RI PT

2. Results and discussion

SC

Scheme 1. The first pentacoordinate phosphorane carbamates synthesized by Stephan's group

conformational isomers because of the restricted rotation of the C-N bond instead of the diastereoisomers of ΛP and ∆P configurations. By increasing the temperature of measurement, the C-N bond of conformational isomers B’ and C’ possessed sufficient energy to overcome the barriers to rotate rapidly and the conformational isomerization receded. Thus, conformational isomers B’ and C’ transformed into averaged conformer A (Scheme 3) at high temperature, and the coalescing process could be observed clearly by 31P NMR. Therefore, the results indicate that 31P nucleus is a good NMR probe for the investigation on the restricted rotation phenomena of the C-N bond for spirophosphorane carbamates. Similar related dynamic processes were also observed in the dynamic 1H NMR spectra of the asymmetrical spirophosphorane carbamates. For example, the variable temperature 1H NMR spectra of 3e (R1=Me, R2=Bn) in DMSO-d6 recorded between 293K and 363K are given in Fig. 2. The two signals at 2.77 and 2.83 ppm were separately assigned to the hydrogens of the Nmethyl group corresponding to conformational isomers B’ and C’ as shown in Scheme 3, which were not equivalent on the NMR time scale and exhibited two signals at room temperature. In the dynamic 1H NMR spectra, the two peaks at 2.77 and 2.83 ppm came closer and finally coalesced at 343K. At the same time, the methylene protons at the nitrogen atom of conformational isomers B’ and C’, which gave signals at 4.30-4.54 ppm, did not coalesce until 343K. The signals exhibited multiplet at room temperature, and they looked like to coalesce at 343K. Above this temperature, the rotation of C-N bond became fast. When the temperature reached 363K, the signals of N-methylene protons of benzyl coalesced into a double doublet due to the nonequivalent hydrogens of methylene groups. On the other hand, the signals at 6.15-6.22 ppm were assigned to the hydrogens of nitrogen atoms in the five-membered ring. When temperature increased, they gradually moved towards upfield, and coalesced at 343K. It was presumed that the high temperature weakened the hydrogen bond of the active hydrogen of nitrogen atoms and led the signals move towards upfield. On the whole, all three signals broadened and began to merge as temperature increased. At about 333 K, coalescence occurred simultaneously for all three signals and finally completed at 343 K, leaving three broad single peaks at 2.83, 4.84 and 5.96 ppm separately (Fig. 2). Therefore, the rotational hindrance of the C-N bond was presumed to be the main factor in splitting the signals of phosphorus atom and protons. The phenomena also indicated that it was the conformational isomerization around N-C(=O) bond to produce the nonequivalent signals, and the signals coalescence came from the rapid C-N bond rotation. Unlike the asymmetrical spirophosphorane carbamates, symmetrical spirophosphorane carbamates 3a-3c don’t have E/Z conformers because of the same N-substituted group. In the 31P NMR spectrum, the symmetrical spirophosphorane carbamates gave only one signal corresponding to the conformational isomers B’(C’) in Scheme 3. However, they still exhibited nonequivalent N-alkyl signals in the 1H NMR spectrum. Therefore, the dynamic process was also investigated for N-alkyl groups by dynamic 1H NMR instead of 31P NMR. For instance, the dynamic 1H NMR spectra of 3a (R1=R2=Et) in DMSO-d6 are given in Fig. 3. The signals at 6.07-6.12 ppm were assigned to the hydrogens of nitrogen atoms in the five-membered ring. The signal of N-methylene at about 3.20 ppm exhibited a quartet peak. The quartet peak was produced by the adjacent methyl instead of the restricted rotation of C-N bond in DMSO-d6, hence there was no coalescence for this signal at high temperature. The signals at 1.03-1.11 ppm exhibiting multiplet corresponded to the

EP

2.2. Dynamic NMR experiments

AC C

In view of symmetrical spirophosphorane carbamates (3a-3c), they presented only one signal in 31P NMR spectra at room temperature. On the other hand, there were two signals in the 31P NMR spectra of asymmetrical carbamates (3d-3h). To investigate the signals of asymmetrical spirophosphorane carbamates further, the variable temperature 31P NMR spectra of asymmetrical spirophosphoranecarbamates were recorded. For example, the variable temperature 31P NMR spectra of carbamates 3e recorded between 293K and 363K in DMSO-d6 are given in Fig. 1. In the studied temperature range and on the NMR time scale, the 31P NMR spectra of 3e showed two signals at -55.03 and -54.54 ppm with the integral ratio about 1.3:1 at room temperature (293K), which may be ascribed to the conformational isomerization around the C-N bond. Then the two signals in the 31P NMR spectra got close with increasing temperature and began to coalesce at 333K as shown in Fig. 1. Finally, they gradually coalesced into a broad signal at -54.58 ppm at about 363K. It was presumed that there was conformational isomerization for the asymmetrical spirophosphorane carbamate because of the restricted rotation of the C-N bond as shown in Scheme 3. The dynamic 31P NMR

3

SC

RI PT

protons of methyl in N-ethyl group. With temperature increasing, MANUSCRIPT ACCEPTED they

Fig.1. Variable-

temperature 162

O R HN

R1 O O C N R2 P O

HN

R

B' (Z)

O O C N

HN P O HN

R2

O R1 P O C N

HN

R2

O

B

O

H

O

O H

R

O

HN

R

O H

R1

O

H

H

R

A

R

O O HN

R2

O

C N P O

HN

R

O

R2

O O HN

R1

HN

H

R

C N P O

O C

TE D

O

R

R O

H

O

O

H

H

M AN U

MHz 31P NMR spectra of 3e measured in DMSO-d6

AC C

EP

Scheme 3. The transformation between the two conformational isomers

Fig.2. Variable-temperature 400 MHz 1H NMR spectra of 3e measured in DMSO-d6

H O

C' (E )

R1

4

Tetrahedron

SC

RI PT

ACCEPTED MANUSCRIPT

EP

TE D

M AN U

Fig.3. Variable-temperature 400 MHz 1H NMR spectra of 3a measured in DMSO-d6

AC C

Fig.4. Variable-temperature 400 MHz 1H NMR spectra of 3a measured in CDCl3

H1

H3

H2/H4 O H H1 O

H2

O

HN P O C

N

HN O

H2/H4

H O

H3 H4

H3 H1

5

AC C

EP

TE D

M AN U

SC

RI PT

1 Fig.5. 1H-ACCEPTED H COSY of N-methylene of 3a in CDCl3 at 213K MANUSCRIPT level of the delocalization between the nitrogen lone pair and the resolved into one broadened signal at 1.08 ppm at 323K, indicating that raising temperature also accelerated the rotation of carbonyl group is high enough or the speed of the C-N bond rotation is slow enough, there might be an equilibrium between C-N bond of symmetrical spirophosphorane carbamates. When conformational isomers B’ and C’. For symmetrical temperature increased further, the signal showed a triplet which spirophosphorane carbamates 3a-3c with same N-substituted was only influenced by the adjacent methylene. Thus, the same alkyl, conformational isomers B’ and C’ are the same conformers alkyls attached to the nitrogen atom were non-equivalent at room and have the same 31P NMR signal. However, the dynamic 1H temperature due to conformational isomerization. All compounds were studied in DMSO-d6, while CDCl3 with a lower melting NMR of the N-substituted alkyl for the symmetrical point was applied for symmetrical spirophosphorane carbamates spirophosphorane carbamates can also exhibit the progress of Cat low temperature. The 1H NMR spectra of the symmetrical N bond rotation. If the speed of the C-N bond rotation is slow spirophosphorane carbamates 3a were recorded in CDCl3 from enough, N-substituents R sometimes presents different signals 293K to 213K as shown in Fig. 4. The proton at nitrogen atom in that come from conformational isomerism. On the other hand, for the five-membered ring gave a doublet at 3.59-3.63 ppm. With asymmetrical spirophosphorane carbamates 3d-3h with different temperature decreasing, the signals at 3.17-3.37 ppm substituents to the nitrogen atom, the dynamic processes can be corresponding to the N-methylene protons gradually broadened. recorded not only by dynamic 1H NMR spectra but also by When the temperature decreased further, the signals began to dynamic 31P NMR spectra. The distance between the different Nseparate and turn into three broadened peaks at 3.14, 3.28 and substituents and phosphorus is near enough to influence the 3.41 ppm. Broadness and splitting of the signals suggested the signal of phosphorus, so two signals of conformational isomers presence of conformational isomers arising from slow rotation B’ and C’ can be observed in 31P NMR spectra at room 3 around the N–(C=O) bond. It could be concluded that lowering temperature. The results of NMR experiments found that the the temperature slowed down the rotation of C-N bond, thus the different substituent group to the nitrogen atom has a crucial same alkyl exhibited non-equivalent and more split signals. effect on the signals of 31P NMR and 1H NMR for asymmetrical 1 Comparing the H NMR signals of the N-methylene protons at spirophosphorane carbamates. With temperature increasing, the 3.20 ppm in DMSO-d6 (Fig. 3) to those at 3.30 ppm in CDCl3 molecule possesses sufficient energy to overcome the barriers to rotate, which accelerates the rotational rate of C-N bond. Thus, (Fig. 4), it was obvious that the signals were more split in CDCl3 than that in DMSO-d6 at 293K. It indicated that the rotational the rapid rotation leads to a similar chemical environment for the barrier proved to be apparently sensitive to solvent polarity.13 substituent groups to nitrogen atom, and thus the N-alkyl Moreover, for the compounds 3b and 3c, cooling to low substituents become equivalent for E/Z conformers. Hence, just temperature allowed the similar observation from the dynamic 1H as shown in Scheme 3, the rapid rotation leads that both NMR spectra in CDCl3. conformational isomers B’ and C’ transform into conformer A As shown in Fig. 4, the signals at 3.17-3.37 ppm of 3a when temperature increases. So the relevant signals of corresponding to the N-methylene proton split into three broaden asymmetrical spirophosphorane carbamates in 1H NMR or 31P signals at 213K with the decrease of temperature. The integral NMR coalesce into one signal at high temperature. Therefore, both the dynamic 31P NMR spectra and 1H NMR spectra can be ratio of the three peaks from downfield to upfield signals was 1:1:2, which corresponded to the protons of two N-methylenes. used as a probe for investigations on such phenomena for In order to investigate further the interaction among the three asymmetrical spirophosphorane carbamates. signals of 3a, the 1H-1H COSY technique was applied in CDCl3 At high temperature, 31P NMR signals for the different 1 1 at 213K and the result was shown in Fig. 5. From the H- H conformers B’ and C’ can be observed for asymmetrical COSY spectrum, it was obvious that the signals of H2 and H4 spirophosphorane carbamates, and the rotation barriers can be gave a broaden peak at 3.10 ppm and the signals of H1 and H3 easily measured at signals coalescence.14 The calculation results exhibited an almost similar peak at 3.30 and 3.40 ppm, of the dynamic 31P NMR study of all the asymmetrical 1 1 respectively. The H- H COSY spectrum showed that both H1 and spirophosphorane carbamates 3d-3h in DMSO-d6 are shown in H3 had correlations with H2 and H4. It testified that at low Table 1. The rate constants, kc, for the present dynamic process temperature, the molecule was unable to gain sufficient energy to of the compounds 3d-3h were calculated at the coalescence overcome the barriers of C-N rotation, and the restricted rotation temperature (Tc) employing the Gutowsky-Holm equation kc of C-N bond led to the nonequivalent environment around the N=π∆ν/21/2.15-17 The peak separation (∆ν) was all obtained from methylene protons. Thus the two N-methylenes exhibited spectra acquired at room temperature (293K) well below different signals as shown in Fig. 4 and Fig. 5. coalescence. Assuming the transmission coefficient, κ, to be It is well known that the conjugation between the nitrogen unity, the free energies of activation (∆G≠) were calculated from the Eyring equation (∆G≠= RTc[lnTc -lnkc + 23.76]).4, 17-21 lone pair and the carbonyl group of an amide group lead the Thus, the barriers to rotate obtained for 3d-3h were given in double-bond character of the C-N bond as shown in Scheme 3. Table 1 and proved to be similar. The calculation results showed Sometimes, the C-N bond rotation is restricted at room temperature, and there are high barriers for rotation. Therefore, if that the barriers of the C-N bond rotation of asymmetrical spirophosphorane carbamates were about 16-18 kcal/mol. Due to the spirophosphorane carbamates investigated have different Nthe high rotation barriers, the rotational rate of C-N bond was substituents, R1≠R2, both conformational isomers B’ and C’ might coexist at room temperature as shown in Scheme 3. If the sufficiently slow and the E and Z conformers of the asymmetrical Table 1. Dynamic 31P NMR data in DMSO-d6 and calculation results for spirophosphorane carbamates 3d-3h

Compound

31

P Chemical shifts (ppm)

Tc (K)

∆ν (Hz)

kc (s-1)

∆G≠ (kcal/mol)

3d

-54.70, -55.05

338

56.5

125.52

16.62

3e

-54.54, -55.03

358

79.5

176.70

17.40

3f

-54.91, -55.02

338

18.7

41.60

17.36

3g

-55.17, -55.51

348

54.0

119.91

17.17

Tetrahedron

-55.34, -55.50

348 25.8 57.22 ACCEPTED MANUSCRIPT

3c and 3f revealed that they had different configuration from hydrospirophosphoranes 1 with the inversion of configuration at phosphorus as shown in Scheme 2. The conjugation between the carbonyl and the nitrogen lone pair led the sp2 character of the nitrogen atom. As shown in Table 2, the total of bond angles around the N atom of N-C(=O) bond was 359.8° for 3c with two butyl groups, while it was 357.4° for 3f with benzyl and i-Pr group to the nitrogen atom. The results showed that the geometry of the nitrogen atom was not totally planar according to the degree of pyramidalization, defined as 360°-∑(R-N-R).17 The deviation were 0.2° and 2.6° for 3c and 3f, respectively, and the results meant a delocalization of the nitrogen lone pair with the carbonyl group. Furthermore, it could be observed that the E conformation for 3f was preferred in the crystalline state from X-ray diffraction analysis as shown in Fig. 6.

Table 2. Selected angles in compounds 3c and 3f 3c C11-N3-C12 122.0 C11-N3-C16 117.9 C12-N3-C16 119.9 Total: 359.8 C11-N3-C12-C16 174.5

Bond angles (°)

Dihedral angles (°)

3f C11-N1-C9 116.4 C11-N1-C7 120.5 C9-N1-C7 120.5 Total: 357.4 C11-N1-C9-C7 162.0

M AN U

spirophosphorane carbamates can be observed at room temperature obviously by 31P NMR. It can be concluded that the rotation barriers of 3e, 3f and 3h with a benzyl attached to the nitrogen atom are higher than that of 3d and 3g with alkyl groups from Table 1. It was deduced that there might be an interaction between the benzyl group and the N-C(=O) bond. Inspired by the structure of the single crystals of 3f (Fig. 6), we found that the π system of benzyl group might have a coverage with the p orbit of nitrogen atom. Therefore, the electron density of N-C(=O) bond might increased and the double-bond character of the C-N bond was enhanced. Because of the interaction of benzyl group with the N-C(=O) bond, the rotational energy for C-N bond was increased. It was proposed that the benzyl group increased the rotation barriers through the spacial interaction. Comparing the free energies of activation of 3e with 3f in Table 1, the isopropyl group attached to amide nitrogen of 3f caused lower rotation barrier than that of 3e with the methyl group. It was presumed that the bulkier alkyl group attached to amide nitrogen decreased the rotation barriers for C-N bond rotation which was in agreement with previous study.22 From the free energies of 3d and 3g, 3f and 3h with different R group at the ring and the same substituent to amide nitrogen, 3g and 3h also had higher rotation barriers than those of 3d and 3f. This result showed that s-Bu substituent attached to five-membered ring led higher rotation barriers than i-Pr substituent.

17.68

RI PT

3h

SC

6

2.3. X-ray crystallography

In order to investigate the correlation established between the preferred conformation determined by the experiments and the relative stabilities for the asymmetrical spirophosphorane carbamates at room temperature, the energy characteristics for the E and Z conformers shown in Scheme 3 were calculated by density functional theory (DFT). Their theoretical and relative energies were estimated from molecular theory calculations, and the results were shown in Table 3.

AC C

EP

TE D

Fortunately, compounds 3c and 3f gave single crystals suitable for X-ray diffraction analysis. The corresponding structures were collected in Fig. 4, and the lattice constants and relevant crystal data were determined. The crystal structures of

2.4. Theoretical barriers

Fig.6. X-ray diffraction structures of 3c and 3f.

Table 3. Theoretical energies (∆Hf) and relative energies (Erel) for E and Z conformers of 3d-3h Compound

Isomers Ratio

Conformer

∆Hf (kcal/mol)

Erel (kcal/mol)

3d

1:1

E

-969868.65

0.03

Z

-969868.68

0

3e

1.3:1

E

-1065471.48

0

Z

-1065470.26

1.22

E

-1114857.35

0

3f

1.1:1

7

Z -1114857.14 ACCEPTED MANUSCRIPT

3h

1:1

E

-1019208.35

0.15

Z

-1019208.50

0

E

-1164197.12

0

Z

-1164196.91

0.21

Fig.7. Conformational profiles for 3d-3h obtained at the molecular theory calculations. The dihedral angle is defined by C(7)-N(1)-C(11)-O(2). The minima correspond to the E and Z conformers.

TE D

M AN U

The isomers ratio observed was determined by the integration of 31P NMR spectra and they varied from 1:1 to 1.3:1 at room temperature. The data in Table 3 reveal that the theoretical energies of E and Z conformers are similar and most E rotamers have a relative lower energy. Therefore, the E rotamers are the preferred conformation for compound 3e, 3f and 3h, which is in agreement with X-ray diffraction conformation as shown in Fig. 6. In addition, the theoretical barriers for conformers E and Z of asymmetrical spirophosphorane carbamates 3d-3h were also calculated by DFT method, and the results were shown in Fig. 7. It could be obtained that the conformers E and Z of 3d-3h could interconvert into each other by overcoming energy barriers of 19.9, 17.7, 19.4, 17.7 and 17.8 kcal/mol, respectively. The energy was essentially determined by the degree of dihedral angle, which was defined by C(7)-N(1)-C(11)-O(2) of 3f as shown in Fig. 6. The change of the degree led the change of conjugation formed between the nitrogen lone pair and the carbonyl group. When the degree of the dihedral angle was 0° (or 180°), the nitrogen lone pair was almost parallel with the carbonyl π system, and the delocalization was perfect. At this very moment, the energy of the molecule was the lowest and the molecule was the most stable. With the degree of the dihedral angle increased, the lone pair moved away from the π system. Hence, the conjugation was gradually destroyed, and the delocalization was attenuated. The energy became the highest when the nitrogen lone pair separated from the π system entirely. As shown in Fig. 7, the rotamer with the dihedral angle 110° (or 300°) represented a higher energy conformation. Therefore, the E rotamers and Z rotamers of the spirophosphorane carbamates had lower energies, due to the perfect delocalization between the nitrogen lone pair and the carbonyl group.

RI PT

1:1

SC

3g

0.21

3. Conclusions

AC C

EP

To summary, the rotational restriction of the N-C(=O) bond of spirophosphorane carbamates led to conformational isomers of E/Z type. The dynamic 1H NMR and 31P NMR were applied to investigate the C-N rotation on the NMR time scale. The ∆G≠ figured out by Eyring equation showed that the spirophosphorane carbamates had higher rotational free energies (16-18 kcal/mol). Moreover, it was proposed that the benzyl group attached to the nitrogen atom increased the C-N bond rotation barriers of spirophosphorane carbamates. The density functional theory (DFT) was also used to presume the preferred conformation, which was supported by X-ray diffraction analysis. 4. Experimental

4.1. Synthesis All compounds were prepared according to literature procedures.6 To a stirred solution of compound 1 (131 mg, 0.5 mmol) in CH3CN (3 mL) were added CCl4 (1.0 mmol), Cs2CO3 (488 mg, 1.5 mmol) and Compounds 2 (1 mmol) at room temperature in a CO2 atmosphere. The reaction mixture was stirred at room temperature in a CO2 atmosphere until the 31P NMR signal of reactant 1 disappeared. Then the mixture was

filtered, and the filtrate was concentrated in vacuum. The residue was purified by silica gel (200−300 mesh) column chromatography to give 3 as a white solid. 1 H and 13C NMR spectra were recorded in CDCl3 with tetramethylsilane (TMS) as the internal standard, and 31P NMR spectra were obtained in CDCl3 with H3PO4 as the internal standard using the Bruker Avance Ⅲ-400 instrument. ESI-HRMS was performed on Agilent 1290-6540 UPLC Q-TOF mass spectrometer. Melting points were determined on a XTS4A micro melting apparatus. The IR spectra were acquired from the NEXUS-470 instrument. The spectra data of 3a-3f were in agreement with the data reported.6 3g: petroleum ether/AcOEt, 2:1. Mp 135-136 °C; 31P NMR (162 MHz, CDCl3): δ -57.05/-57.2 (1:1) ppm; 1H NMR (400 MHz, CDCl3): δ 0.87-0.95 (m, 15H, 5×CH3), 1.34 (q, 4H, J= 5.6 Hz, J= 13.2 Hz, 2×CH2), 1.45-1.59 (m, 4H, 2×CH2), 1.88 (s, 2H, CH2), 2.89 (s, 3H, CH3), 3.16-3.28 (m, 2H, CH2), 3.75 (d, 2H, 2JHNP = 15.6Hz, 2×NH), 3.99 (s, 2H, 2×CH) ppm; 13C NMR (100 MHz, CDCl3): δ 10.96, 11.3/11.8, 15.6, 20.3, 20.2, 34.7/34.9, 37.7 (d, 3 JCCNP = 7.0 Hz), 50.9/51.4, 59.7 (d,2JCNP = 4.0 Hz), 150.5, 169.5 (d,2JC(O)OP = 12.0 Hz) ppm; FTIR (KBr): νmax 3296 (N-H), 2964 (C-H), 2936 (C-H), 2877 (C-H), 1750 (C=O), 1713 (O=C-N), 1464, 1437, 1401, 1267 (P-O-CO), 1162, 1072, 927, 838 cm-1; HRMS (ESI): m/z [M+Na]+, calcd for C17H32NaN3O6P 428.1921, found 428.1925. 3h: CH2Cl2/CH3COCH3, 30:1. Mp 172-173 °C; 31P NMR (162 MHz, CDCl3): δ -58.20/-57.40 (2.3:1) ppm; 1H NMR (400 MHz, CDCl3): δ 0.86-0.96/1.10-1.19 (m, 15H,5×CH3), 1.01-1.03/1.241.26 (d, 4H, 2×CH2), 1.34-1.39/1.40-1.50 (m, 2H, 2×CH), 1.79/1.90 (s, 2H, 2×CH), 3.28/3.70 (d, 2H, 2JHNP = 15.2 Hz, 2×NH), 3.65-3.67/3.99-4.03 (m, 2H, 2×CH), 4.36-4.46/4.26-4.30 (m, 2H, CH2), 7.25-7.31/7.31-7.36 (m, 5H, 5×Ar-H) ppm; 13C NMR (100 MHz, CDCl3 ): δ 11.7/11.8, 15.7, 20.2, 21.2, 24.3/24.5, 37.5/37.7 (d, 3JCCNP = 7.0 Hz), 46.8/47.8, 48.8/49.9, 59.5/59.8 (d,2JCNP = 4.0 Hz), 126.3, 127.0/127.2, 128.6, 139.0/138.0, 150.4/151.2 (d,2JNC(O)OP = 5.0 Hz), 169.3/169.4 (d, 2 JC(O)OP = 12.0 Hz) ppm; FTIR (KBr): νmax 3308 (N-H), 2963 (C-

8

Tetrahedron

H), 2926 (C-H), 2878 (C-H), 1756 (C=O), 1712 (O=C-N), 1496 MANUSCRIPT The variable temperature measurements were estimated to be ACCEPTED (Ar), 1454 (Ar), 1399, 1258 (P-O-CO), 1120, 1027, 891, 840, accurate to ±3K. The chemical shifts difference ∆ν (in Hz) was 731 cm-1 ; HRMS (ESI): m/z [M+Na]+, calcd for C23H36NaN3O6P determined by extrapolation from the lower temperature available 504.2234, found 504.2235. to Tc used to calculate kc and the ∆G≠ by the Eyring equation at Tc. 4.2. NMR measurements

4.3. X-ray structural analysis

31

The H and P NMR spectra were registered for 10-20% solutions on a Bruker Avance 400 instrument at 400 and 162 MHz in DMSO-d6, respectively, using TMS and H3PO4 as internal standard. When the temperature was changed every 10Ⅲ, the NMR spectra were acquired as the temperature stabilized.

X-ray structural analysis shown in Table 4 was performed at the Bruker SMART APEX II. The crystals of 3c grew from a 3:1 petroleum ether / CH3COOCH2CH3 mixture. The crystals of 3f grew from a 1:1 CH3CN / n-hexane mixture.

RI PT

1

Table 4. X-ray data collection and processing parameters for 3c and 3f compound formula size/mm3 Crystal system Space group a/Å b/Å c/Å α/° β/° γ/° Volume/Å3 Z ρcalcmg/mm3 m/mm-1 T/K 2Θ range /° Reflections collected Independent reflections Data/restraints/parameters Goodness-of-fit on F2 Final R indexes [I>=2σ (I)] Final R indexes [all data] Largest diff. peak/hole / e Å-3

TE D

M AN U

SC

3c C19H36N3O6P 0.2 × 0.14 × 0.13 monoclinic P21 10.02685(16) 10.35683(16) 23.9983(5) 90.00 97.9548(18) 90.00 2468.16(8) 4 1.167 1.289 291.15 7.44 to 134.14° 20047 8522[R(int) = 0.0274] 8522/36/547 1.033 R1 = 0.0529, wR2 = 0.1452 R1 = 0.0585, wR2 = 0.1520 0.54/-0.25

CCDC no.

937366

EP

4.4. Theoretical calculations

AC C

All calculations were performed using the Gaussian 0923 suite of programs. The structures were optimized at the B3LYP/6-31G (d, p) level in DMSO solvent, using the polarizable continuum model (PCM). Among the calculation in Fig. 7, a relaxed potential energy surface (PES) scan is performed, which is along with the Opt keyword (with geometry optimization at each point by fixing the dihedral angles at the same level).

Acknowledgments

This work was funded by the National Natural Science Foundation of China (Grants No: 21172201).

References and notes 1.

2.

(a) Dugave, C.; Demange, L. Chem. Rev. 2003, 103, 2475–2532; (b) Eliel, E. L.; Wilen, S. H. Wiley: NewYork, 1994; (c) Olsen, R. A.; Liu, L.; Ghaderi, N.; Johns, A.; Hatcher, M. E.; Mueller, L. J. J. Am. Chem. Soc. 2003, 125, 10125–10132. Suárez-Castillo, O. R.; Contreras-Martínez, Y. M. A.; BeizaGranados, L.; Meléndez-Rodríguez, M.; Villagómez-Ibarra, J. R.;

3f C21H32N3O6P 0.20 × 0.20× 0.17 monoclinic P21 20.014(4) 6.1055(12) 20.653(4) 90.00 101.36(3) 90.00 2474.4(8) 4 1.217 0.150 293(2) 2.01 to 25.50° 8190 4530 [R(int) = 0.0306] 4530/1/286 1.133 R1 = 0.0821, wR2 = 0.1732 R1 = 0.1079, wR2 = 0.1898 0.460/-0.155

951765 Torres-Valencia, J. M.; Morales-Ríos, M. S.; Joseph-Nathan, P. Tetrahedron 2005, 61, 8809–8820. 3. Morales-Ríos, M. S.; Joseph-Nathan, P. Magn. Reson. Chem. 1987, 25, 911–918. 4. Modarresi-Alam, A. R.; Najafi, P.; Rostamizadeh, M.; KeyKha, H.; Bijanzadeh, H.-R.; Kleinpeter, E. J. Org. Chem. 2007, 72, 2208-2211. 5. Stewart, W. E.; Siddall, T. H. III. Chem. Rev. 1970, 70, 517–551. 6. Cao, S. X.; Gao, P.; Guo, Y. C.; Zhao, H. M.; Wang, J.; Liu, Y. F.; Zhao, Y. F. J. Org. Chem. 2013, 78, 11283–11293. 7. Hounjet, L. J.; Caputo, C. B.; Stephan, D. W. Angew. Chem. Int. Ed. 2012, 51, 4714–4717. 8. (a) Lunazzi, L.; Mancinelli, M.; Mazzanti, A.; Lepri, S.; Ruzziconi, R.; Schlosser, M. Org. Biomol. Chem. 2012, 10, 1847−1855; (b) Mazzanti, A.; Chiarucci, M.; Bentley, K. W.; Wolf, C. J. Org. Chem. 2014, 79, 3725−3730. 9. (a) Szatmári, I.; Heydenreich, M.; Koch, A.; Fülöp, F.; Kleinpeter, E. Tetrahedron 2013, 69, 7455−7465; (b) Lazareva, N. F.; Albanov, A. I.; Shainyan, B. A.; Kleinpeter, E. Tetrahedron 2012, 68, 1097−1104; (c) Lunazzi, L.; Mancinelli, M.; Mazzanti, A. J. Org. Chem. 2012, 77, 3373−3380; (d) Xia, J. L.; Liu, S. H.; Cozzi, F.; Mancinelli, M.; Mazzanti, A. Chem. Eur. J. 2012, 18, 3611−3620; (e) Lazareva, N. F.; Shainyan, B. A.; Schilde, U.; Chipanina, N. N.; Oznobikhina, L. P.; Albanov, A. I.; Kleinpeter, E. J. Org. Chem. 2012, 77, 2382−2388; (f) Ambrogi, M.; Ciogli, A.; Mancinelli, M.; Ranieri, S.; Mazzanti, A. J. Org. Chem. 2013, 78, 3709−3719; (g) Alfonso, I.; Burguete, M. I.; Luis, S. V. J. Org. Chem. 2006, 71, 2242−2250. 10. (a) Alfonso, I.; Burguete, M. I.; Galindo, F.; Luis, S. V.; Vigara, L.

9

17. 18.

19. 20. 21. 22. 23.

SC

15. 16.

M AN U

14.

TE D

13.

EP

12.

AC C

11.

RI PT

ACCEPTED MANUSCRIPT

J. Org. Chem. 2007, 72, 7947-7956; (b) Dial, B. E.; Rasberry, R. D.; Bullock, B. N.; Smith, M. D.; Pellechia, P. J.; Profeta, S.; Jr.; Shimizu, K. D. Org. Lett. 2011, 13, 244−247; (c) Dial, B. E.; Pellechia, P. J.; Smith, M. D.; Shimizu, K. D. J. Am. Chem. Soc. 2012, 134, 3675−3678. Mamula, O.; Von Zelewsky, A.; Bark, T.; Stoekli-Evans, H.; Neels, A.; Bernardinelli, G. Chem. Eur. J. 2000, 6, 3575-3585. Cao, S. X.; Zhou, Z. F.; Dai, W.; Zhao, P.; Guo, Y. C.; Zhao, Y. F. Phosphorus, Sulfur, and Silicon and the Related Elements 2015, doi:10.1080/10426507.2014.991824. (a) Cox, C.; Lectka, T. J. Org. Chem. 1998, 63, 2426-2427; (b) Rablen, P. R. J. Org. Chem. 2000, 65, 7930−7937. Arteḿev, A. V.; Shagun, V. A.; Gusarova, N. K.; Liu, C. W.; Liao, J. H.; Gatilov, Y. V.; Trofimov, B. A. J. Organomet. Chem. 2014, 768, 151−156. Oki, M. VCH Publishers: New York, 1985. Pinto, B. M.; Grindley, T. B.; Szarek, W. A. Magn. Reson. Chem. 1986, 24, 323–331. Garratt, P. J.; Thom, S. N.; Wrigglesworth, R. Tetrahedron 1994, 50, 12211–12218. Modarresi-Alam, A. R.; Khamooshi, F.; Rostamizadeh, M.; Keykha, H.; Nasrollahzadeh, M.; Bijanzadeh, H.-R.; Kleinpeter, E. J. Mol. Struct. 2007, 841, 61–66. Modarresi-Alam, A. R.; Keykha, H.; Khamooshi, F.; Dabbagh, H. A. Tetrahedron 2004, 60, 1525–1530. Dabbagh, H. A.; Modarresi-Alam, A. R.; Tadjarodi, A.; Taeb, A. Tetrahedron 2002, 58, 2621–2625. Basso, E. A.; Oliveira, P. R.; Wiectzycoski, F.; Pontes, R. M.; Fiorin, B. C. J. Mol. Struct. 2005, 753, 139–146. Skorupsk, E. A.; Nazarskib, R. B.; Ciechańska, M.; Jóźwiak, A.; Kłys, A. Tetrahedron 2013, 69, 8147-8154. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. 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, J. A.; Jr; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Keith, T.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. 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, Revision C. 01, 2010.