Regiochemical Control in the Substitution Reactions of

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Cite This: Inorg. Chem. XXXX, XXX, XXX−XXX

Regiochemical Control in the Substitution Reactions of Cyclotriphosphazene Derivatives with Secondary Amines Serap Beşli,*,† Ceylan Mutlu Balcı,† Semih Doğan,† and Christopher W. Allen‡ †

Department of Chemistry, Gebze Technical University, 41400 Gebze Kocaeli, Turkey Department of Chemistry, University of Vermont, Burlington, Vermont 05405-0125, United States

‡

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S Supporting Information *

ABSTRACT: The substitution reactions of the monospiro and geminally disubstituted cyclotriphosphazene derivatives N 3 P 3 Cl 4 R 2 (R 2 = OCH 2 (CF 2 ) 2 CH 2 O (1a), SPh (1b), OCH2CH2CH2O (1c), NHPh (1d), OCH2CH2CH2NH (1e), NHBut (1f)) with two secondary amines (pyrrolidine and dimethylamine) were carried out to investigate geminal or nongeminal directing effects in mixed substituent cyclophosphazenes. The relative amounts of isomeric products, geminal and nongeminal trans or cis, was established quantitatively from the 31P NMR spectra of the reaction mixtures. Although secondary amines generally follow a non-geminal pathway in the reactions with hexachlorocyclotriphosphazene, in this work, the reactions of two different secondary amines with some N3P3Cl4R2 (R2 = OCH2CH2CH2NH, NHPh, NHBut) derivatives lead to the formation of geminal products. We have shown that this observation depends on the electron-donating properties of the PR2 groups. Isolated compounds were analyzed by standard techniques such as elemental analysis, mass spectrometry, and 1H and 31 P NMR spectroscopy. The structures of compounds for which suitable crystals could be obtained were characterized by X-ray crystallography.

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INTRODUCTION Nucleophilic substitution reactions leading to significant structure and property variations are central to cyclophosphazene chemistry.1−26 In most of the degrees of substitution of the cyclophosphazene, the question of geminal versus non-geminal replacement patterns arises.3,19,25−34 This in turn has led to a search for models to predict these regioand stereochemical outcomes.7,32 The reaction patterns observed when the nucleophile is an amine have been the most intensively investigated systems.31−41 The reactions of N3P3Cl6 with primary amines lead to both geminal and nongeminal products depending on the steric and electronic effects of the amine as well as the nature of the incoming group.32,42,43 In these systems, there are two competing mechanistic pathways with the bimolecular path providing the non-geminal product and a dissociative process giving the geminal product. However, most secondary amines, with the exception of aziridine, follow a predominantly non-geminal path, and these reactions are generally stereo- and regioselective with the trans non-geminal isomer as the major product. Detailed kinetic analyses have shown that the trans preference arises from the entropy of activation.32,42 Increased solvent polarity can also favor dissociative processes and hence geminal substitution in aminolysis reactions.42−45 The nature of the substituents on the ring plays a dominant role in directing the course of the reaction.32,42,46 We have previously shown that the reactions of the 3-amino1-propanoxy spiro derivative (1e) of hexachlorocyclotriphos© XXXX American Chemical Society

phazene with pyrrolidine proceed with an overwhelming preference for the bis geminal product at the disubstitution stage.47 While the predominant formation of non-geminal cis and trans isomers are the expected result from the reaction with a secondary amine, the exclusive formation of the bis geminal derivative at this relatively early stage of substitution indicated that additional factors become important as more of the chlorine atoms are replaced on the phosphazene ring. A geminal preference is uncommon and has only been previously observed at late stages of substitution.48 In order to uncover the origin of this behavior, we have undertaken an investigation of the nucleophilic substitution reactions of the mono spiro and gem-disubstituted cyclotriphosphazene derivatives N3P3Cl4R2 (R2 = OCH2(CF2)2CH2O (1a), SPh (1b), OCH2CH2CH2O (1c), NHPh (1d), OCH2CH2CH2NH (1e), and NHBut (1f)) with two different secondary amines. A summary of the reactants and products is given in Scheme 1. NMR and crystallographic methods were used to characterize the products, and 31P NMR measurements of the reaction mixtures were used to quantify the distribution of geminal and non-geminal (cis and trans) isomers. These studies provide a direct understanding of the role of the nature of the substituents already on the cyclophosphazene ring on the reaction pathway. Received: June 11, 2018

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DOI: 10.1021/acs.inorgchem.8b01620 Inorg. Chem. XXXX, XXX, XXX−XXX

Article

Inorganic Chemistry

Scheme 1. Products of the Reaction of Compounds 1a−f with the Secondary Amines Dimethylamine and Pyrrolidinea

a

An asterisk indicates that this product has been observed only in the 31P NMR spectrum of reaction mixture and has not been isolated. The compounds shown in blue have been observed as major product(s) in the 31P NMR spectrum of the reaction mixture.

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were determined using the direct methods procedure in SHELXS-97 and refined by full-matrix least squares on F2 using SHELXL-97.51 All non-hydrogen atoms were refined with anisotropic displacement factors, and C−H hydrogen atoms were placed in calculated positions and allowed to ride on the parent atom. The final geometrical calculations were carried out with PLATON52 and MERCURY53 programs, and the molecular drawings were done with the DIAMOND54 program. Structure determinations have been deposited with the Cambridge Crystallographic Data Centre with reference numbers CCDC 1841382−1841390 for nine structures, compounds (4a)ngtdma, (5a)ngcdma, (5b)ngcdma, (5b)ngcpyr, (3c)gdma, (5c)ngcpyr, (3d)gdma, (3e)gdma, and (3f)gpyr. Synthesis. Compounds 1a,55 1b,56 1c,57 1d,58 1e,59 and 1f60 were prepared by previously reported procedures. General Procedure Used for Reaction of Starting Compounds (1a−f) with Dimethylamine and Pyrrolidine in a 1:4.5 Ratio. Mono spiro-[N3P3Cl4(OCH2(CF2)2CH2O)] (1a; 0.87 g, 2.0 mmol) was dissolved in 6 mL of dry THF in a 50 mL three-necked roundbottomed flask. The dimethylamine (40% aqueous solution, 0.41 g, 9.0 mmol) was dropped into the stirred solution of 1a under an argon atmosphere. The reaction mixture was stirred for a further 24 h at room temperature followed by TLC on silica gel plates. The reaction mixture was filtered to remove the dimethylamine hydrochloride and any other insoluble material. The solvent was removed under reduced pressure, and the crude product was subjected to column chromatography. A summary for the preparation of all isolated compounds is given in Table 1. General Procedure Used for Workup of the Products of the Reaction of Each Starting Compound with Dimethylamine and Pyrrolidine. The products were isolated from the combined crude reaction mixture by column chromatography. Crystals of pure bisgeminal dimethylamine substituted compounds (3c)gdma, (3d)gdma, and (3e)gdma, bis-non-geminal trans-dimethylamine (4a)ngtdma, bisnon-geminal cis-dimethylamines (5a)ngcdma and (5b)ngcdma, the bisgeminal pyrrolidine-substituted compound (3f)gpyr, and the bis-non-

EXPERIMENTAL SECTION

Materials. Hexachlorocyclotriphosphazene (Aldrich) was purified by fractional crystallization from hexane. Dichloromethane (DCM; Merck), n-hexane (Merck), ethyl acetate (Merck), 2,2,3,3-tetrafluoro1,5-butanediol (Alfa Aesar), 3-amino-1-propanol (Merck), thiophenol (Merck), aniline (Merck), tert-butylamine (Merck), dimethylamine (Merck), and pyrrolidine (Merck) were used as received. 1,3Propanediol (Merck) was dried over 4 Å molecular sieves. Tetrahydrofuran (THF; Merck) was distilled over a sodium/ potassium alloy under an atmosphere of dry argon. All reactions were performed under a dry argon atmosphere. CDCl3 for NMR spectroscopy was obtained from Merck. Analytical thin layer chromatography (TLC) was performed on Merck silica gel plates (Merck, Kieselgel 60, 0.25 mm thickness) with F254 indicator. Column chromatography was performed on silica gel (Merck, Kieselgel 60, 70−230 mesh; for a 3 g crude mixture, 100 g of silica gel was used). Methods. Elemental analyses were obtained using a Thermo Finnigan Flash 1112 instrument. Molecular masses were measured using a Bruker MALDI-TOF (matrix-assisted laser desorption/ ionization time of flight) spectrometer using 2,5-dihydroxybenzoic acid as a matrix for compounds (4a)ngtdma, (5a)ngcdma, (5a)ngcpyr, (5b)ngcdma, (2b)mpyr, (5b)ngcpyr, (3c)gdma, (5c)ngcpyr, (2d)mdma, (3d)g dma, 2e(I)mdma, 2e(II)mdma, (3e)g dma, (3e)gpyr , (2f)mdma, (3f)gdma, (2f)mpyr, and (3f)gpyr and 1,8,9-trihydroxyanthracene as a matrix for compounds (2a)mpyr, (2b)mdma, (4b)ngtdma, (2d)mpyr, and (3d)gpyr. 1H and 31P NMR spectra were recorded for all compounds in CDCl3 on a Varian INOVA 500 MHz spectrometer using TMS as an internal reference for 1H and 85% H3PO4 as an external reference for 31P NMR measurements. X-ray Crystallography. Intensity data were recorded on a Bruker APEX II QUAZAR diffractometer using monochromated Mo Kα Xradiation (λ = 0.71073 Å). Absorption correction was performed by the multiscan method implemented in SADABS,49 and space groups were determined using XPREP implemented in APEX2.50 Structures B


Article

Inorganic Chemistry Table 1. Preparation of Isolated Productsa Dimethylamine Reactions dimethylamine

starting compound

amt, g

amt, mmol

amt, g

amt, mmol

chromatography mobile phase

product

isolated yield, %

mp, °C

0.41

9.00

1a

0.87

2.00

n-hexane/THF (8/1)

0.30

6.80

1b

0.74

1.50

n-hexane/DCM (1/1)

0.51 0.41

11.30 9.00

1c 1d

0.88 0.92

2.50 2.00

n-hexane/THF (3/1) n-hexane/DCM (1/1)

0.51

11.30

1e

0.88

2.50

n-hexane/THF (2/1)

0.24

5.30

1f

0.50

1.20

n-hexane/THF (5/1)

(4a)ngtdma (5a)ngcdma (2b)mdma (4b)ngtdma (5b)ngcdma (3c)gdma (2d)mdma (3d)gdma 2e(I)mdma 2e(II)mdma (3e)gdma (2f)mdma (3f)gdma

51 26 6 47 25 9 38 30 4 10 55 34 36

142 153 oily 73 88 139 140 143 oily 124 94 oily 69

Pyrrolidine Reactions pyrrolidine

starting compound

amt, g

amt, mmol

amt, g

amt, mmol

chromatography mobile phase

product

isolated yield, %

mp, °C

0.35

4.84

1a

0.47

1.10

n-hexane/THF (10/1)

0.48

6.70

1b

0.74

1.50

n-hexane/THF (10/1)

0.80 0.49

11.30 6.90

1c 1d

0.88 0.70

2.50 1.50

n-hexane/THF (2/1) n-hexane/ethyl acetate (3/1)

0.32 0.38

4.50 5.30

1e 1f

0.35 0.50

1.00 1.20

n-hexane/THF (2/1) n-hexane/THF (7/1)

(2a)mpyr (5a)ngcpyr (2b)mpyr (5b)ngcpyr (5c)ngcpyr (2d)mpyr (3d)gpyr (3e)gpyr (2f)mpyr (3f)gpyr

13 41 21 30 37 36 34 57 41 44

oily 144 95 133 123 170 oily 172 100 112

a

All reactions were carried out for 1 day.

geminal cis-pyrrolidines (5b)ngcpyr and (5c)ngcpyr were obtained from dichloromethane/n-hexane (1/3). Crystals suitable for X-ray crystallography were obtained for the dimethylamine-substituted compounds (4a) ngt dma , (5a) ngc dma , (5b)ngcdma, (3c)gdma, (3d)gdma, and (3e)gdma and pyrrolidinesubstituted compounds (5b)ngcpyr, (5c)ngcpyr, and (3f)gpyr. Although the molecular structures of compounds (5a)ngcpyr and 2e(II)mdma have been confirmed by X-ray crystallography, their structures are not reported due to the poor crystal quality. The mass, elemental analysis, and 1H NMR results are provided in the Supporting Information for each new isolated compound. The proton-decoupled 31P NMR spectra of isolated compounds are given in Figures S1−S23. The 31P NMR chemical shifts and phosphorus− phosphorus coupling constants of all compounds (isolated compounds together with compounds which were determined from the 31 P NMR spectra of the reaction mixtures) are summarized in Table S1.

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secondary amine (1:4.5), solvent (tetrahydrofuran), temperature (24 °C), and reaction time (24 h)). The 31P NMR investigations of the reaction mixtures allowed for the determination of the relative amounts of each isomer. The proton-decoupled 31P NMR spectra of the reaction mixtures of compound 1a with dimethylamine (Figure 1a) and pyrrolidine (Figure 1b) are quite simple. Both reaction mixtures are observed as a pair of A2X spin systems, having similar coupling constants and only small chemical shift differences between them, resulting from non-geminal trans ((4a)ngtdma, ca. 59% and (4a)ngtpyr, ca. 46%) and cis isomers ((5a)ngcdma, ca. 35% and (5a)ngtpyr, ca. 41%). Only the reaction mixture with pyrrolidine includes a small amount of the monosubstitution product (2a)mpyr (Figure 1b). The protondecoupled 31P NMR spectra of the reaction mixtures of compound 1c with the corresponding secondary amines are very similar to those of 1a. However, the reaction of 1c with dimethylamine gave some of the bis geminal product ((3c)gdma, ca. 12%), which has an ABX spin system due to the different environments for the three phosphorus nuclei of the cyclotriphosphazene ring. The geminal product may result from the increased stabilization of the dissociative intermediates by the more polar THF/water solvent. The major products are the bis non-geminal trans and cis isomers ((4c)ngtdma, ca. 47%; (5c)ngcdma, ca. 31%). When compound 1b is allowed to react with dimethylamine and pyrrolidine, the proton-decoupled 31P NMR spectra of the reaction mixtures in Figure 2 show formation of few monosubstituted products ((2b)mdma and (2b)mpyr) and an over-

RESULTS AND DISCUSSION

Synthesis and Characterization of Reaction Products by NMR Spectroscopy. Compounds 1a−f, N3P3Cl4R2 (R2 = OCH2(CF2)2CH2O (1a), SPh (1b), OCH2CH2CH2O (1c), NHPh (1d), OCH2CH2CH2NH (1e), and NHBut (1f)) were allowed to react with two different secondary amines, pyrrolidine and dimethylamine, to understand the roles of the group already present on the cyclophosphazene ring on distribution of the regioisomers (geminal and non-geminal cis/ trans). For comparison purposes, a standard set of conditions was used for each reaction (mole ratio of starting compound to C


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Inorganic Chemistry

Figure 1. Proton-decoupled 31P NMR spectra of the product of reaction of compound 1a with secondary amines in a 1:4.5 ratio in THF solution: (a) dimethylamine; (b) pyrrolidine. The reaction mixture was filtered and the solvent removed prior to dissolving in CDCl3 solution.

whelming number of bis non-geminal trans ((4b)ngtdma, ca. 56%; (4b)ngtpyr, ca. 48%) and cis ((5b)ngcdma, ca. 34%; (5b)ngcpyr, ca. 30%) products. Bis non-geminal trans and cis products display AX2 type spin systems. However, coupling constant values are very small, as expected.31There was no geminal product similar to the reactions of dimethylamine and pyrrolidine with compound 1a. The reactions of compound 1e with the corresponding secondary amines lead to the formation of mono ((2e)mdma and (2e)mpyr)- and bis-substituted products ((3e−5e)dma and (3e−5e)pyr) in each reaction (Figure 3). In principle, both mono- and bis-substituted non-geminal cis derivatives of compound 1e may exist as two configurational isomers, one in which the incoming substituent is in the cis position to the NH moiety of the spiro ring and another in which the substituent is trans to the NH moiety. However, only the geminal and nongeminal product distributions in the disubstituted stage were examined here, since cis and trans directions to the NH or O moieties is outside the scope of this paper. The bis geminal products (3e)gdma (ca. 65%) and (3e)gpyr (ca. 57%) exhibit an ABX spin system and AMX spin system, respectively, and they formed as major products in both reactions. The yields of bis non-geminal products, which exhibit an A 2 X spectra ((4e)ngtdma or (5e)ngcdma, ca. 3% for dimethylamine; (4e)ngtpyr and (5e)ngcpyr, ca. 14% for pyrrolidine) are low (Figure 3). The reactions of compounds 1d,f with both secondary amines result in a strong preference for the bis geminal product ((3d)gdma, ca. 38%; (3f)gdma, ca. 45%; (3d)gpyr, ca. 35%; (3f)gpyr, ca. 43%). The proton-decoupled 31P NMR spectra of the reaction mixtures of compound 1f are given in Figure 4 as example. Again, while the bis geminal products have ABX or AMX spin systems, the bis non-geminal trans and cis products exhibit A2X type spin systems.

The tetrachlorocyclophosphazene derivatives (1a−f) used in this work contain two PCl2 groups, thus providing the possibility for both regioisomers (geminal and non-geminal) and stereoisomers (racemate and meso). Although the main purpose of this study is to investigate the distribution of regioisomers, it is appropriate to mention the stereogenic properties of the new compounds. Mono-substituted compounds (2e)mdma and (2e)mpyr have two different chiral centers, and so there are two different racemic forms (diastereoisomers) for derivatives in which the incoming nucleophile is substituted cis (RS′ or SR′ configuration) or trans (RR′ or SS′ configuration) to the NH moiety. Other mono secondary amino derivatives ((2a)mpyr, (2b)mdma, (2b)mpyr, (2d)mdma, (2d)mpyr, (2f)mdma, and (2f)mpyr) contain one chiral center and exist as a racemate (R or S). Bis geminal products ((3c)gdma, (3d−f)gdma and pyr) except for (3e)gdma and (3e)gpyr have no stereogenic center. Compounds (3e)gdma and (3e)gpyr have one chiral center, and they are racemates, as shown by the crystal structure of compound (3e)gdma. Bis nongeminal substitution can produce two isomers which are cis and trans. The bis non-geminal trans compounds ((4a)ngtdma and (4b)ngtdma) contain two equivalent chiral centers and are chiral, existing as two enantiomers (RR/SS). The bis nongeminal cis compounds ((5a)ngcdma, (5a)ngcpyr, (5b)ngcdma, (5b)ngcpyr, and (5c)ngcpyr) also contain two equal chiral centers, but they are meso (RS/SR) because of they have a plane of symmetry.61,62 Characterization of Compounds by X-ray Crystallography. The crystal structures of nine cyclotriphosphazene derivatives, (4a)ngtdma, (5a)ngc dma, (5b)ngc dma, (5b) ngcpyr, (3c)gdma, (3d)gdma, (3e)gdma, (3f)gpyr, and (5c)ngcpyr, are presented in Figures 5−10, and the data collection and refinement parameters are reported in Tables S2 (dimethylD


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Inorganic Chemistry

Figure 2. Proton-decoupled 31P NMR spectra of the product of reaction of compound 1b with secondary amines in a 1:4.5 ratio in THF solution: (a) dimethylamine; (b) pyrrolidine. The reaction mixture was filtered and the solvent removed prior to dissolving in CDCl3 solution.

geminal cis dimethylamine groups ((5b)ngcdma)/pyrrolidine groups ((5b)ngcpyr) (Figure 6). The compound (5b)ngcdma contains two crystallographically independent molecules, denoted as molecules A and B; (5b)ngcdma(A) is presented in Figure 6. The P2 and P3 phosphorus atoms of (5b)ngcdma and (5b)ngcpyr molecules are equivalent stereogenic centers with opposite configurations, SR, so that the structures are meso and are shown in Figure 6. In the compound (5b)ngcdma, the six-membered cyclophosphazene ring is slightly twisted; the maximum deviation from the mean plane is 0.0724(15) Å (for atom P3) while in compound (5b)ngcpyr the ring has a twisted conformation; the maximum deviation from the mean plane is 0.1544(12) Å (for atom P1). Compounds (3c)gdma and (5c)ngcpyr are composed of the cyclotriphosphazene core substituted with the six-membered spiro ring of the OCH2CH2CH2O group and two dimethylamine groups for (3c)gdma and pyrrolidine groups for (5c)ngcpyr (Figure 7). Both Cl atoms of the PCl2 group are substituted with dimethylamino moieties to form the geminal compound (3c)gdma (Figure 7). In the compound (3c)gdma, the cyclotriphosphazene ring is planar; the maximum deviation from the mean plane is 0.0542(15) Å (for atom P3). X-ray crystallographic structures of the non-geminal bis-pyrrolidine substituted isomer compound (5c)ngcpyr are shown in Figure 6. The two pyrrolidine groups are in a cis configuration in the compound (5c)ngcpyr. Its geometric isomer in which the pyrrolidine groups are trans has been reported previously.63 The P2 and P3 phosphorus atoms of the (5c)ngcpyr molecule

amine series) and S3 (pyrrolidine series). The molecular structures of compound 2e(II)mdma (in which the incoming substituent is in the position cis to the NH moiety of the spiro ring) and (5a)ngcpyr (bis-non-geminal cis-pyrrolidine) were also confirmed by X-ray analysis, but the crystal structures could not be fully elucidated due to crystallographic problems which were probably caused by poor crystal quality. X-ray crystallographic structures of the non-geminal bisdimethylamino-substituted isomers, compounds (4a)ngtdma and (5a)ngcdma, are shown in Figure 5. The two dimethylamino groups are in a trans configuration in compound (4a)ngtdma and in a cis configuration in compound (5a)ngcdma; hence, compounds (4a)ngtdma and (5a)ngcdma are configurational isomers (Figure 5) The phosphorus atoms P2 and P3 are both stereogenic and, as they are equivalent centers of chirality, compound (4a)ngtdma is racemic and is the SS enantiomer shown in Figure 5. The P2 and P3 phosphorus atoms of the (5a)ngcdma molecule are equivalent stereogenic centers with opposite configurations, SR, so that the structure is meso and is shown in Figure 5. In compound (4a)ngtdma, the six-membered cyclophosphazene ring is in nearly planar; the maximum deviation from the mean plane is 0.0714(19) Å (for atom N2) while in compound (5a)ngcdma the ring has a slightly twisted conformation; the maximum deviation from the mean plane is 0.142(5) Å (for atom N2). Compounds (5b)ngcdma and (5b)ngcpyr are composed of the cyclotriphosphazene core six-membered ring (P3N3) substituted with the two geminal thiophenoxy groups and bis nonE


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Inorganic Chemistry

Figure 3. Proton-decoupled 31P NMR spectra of the product of reaction of compound 1e with secondary amines in a 1:4.5 ratio in THF solution: (a) dimethylamine; (b) pyrrolidine. The reaction mixture was filtered and the solvent removed prior to dissolving in CDCl3 solution.

(5b)ngcpyr, (3f)gpyr, and (5c)ngcpyr (pyrrolidine substituted) are summarized in Table S4, and each structure is composed of a cyclotriphosphazene core, which exhibits no unusual deviations in bond lengths and angles from either those of the corresponding starting compounds 1a,55 1b,56 1c,57 1d,58 1e,59 and 1f60 and from those observed in similar structures in the Cambridge Structural Database.64 The average values of endocyclic P−N bond distance of the cyclotriphosphazene ring are between 1.574 and 1.595 Å (1.578 Å for (4a)ngtdma, 1.581 Å for (5a)ngcdma, 1.586 Å for (5b)ngcdma, 1.589 Å for (5b)ngcpyr, 1.584 Å for (3c)gdma, 1.574 Å for (5c)ngcpyr, 1.584 Å for (3d)gdma, 1.588 Å for (3e)gdma, and 1.595 Å for (3f)gpyr). Additionally, the comparison of geminal substituted dimethylamine and pyrrolidine compound average exocyclic P−N (P2− N4 and P2−N5) bond lengths of compounds (3c)gdma, (3d)gpyr, (3e)gdma, and (3f)gpyr showed that the exocyclic P− N bond lengths of 1.640 Å were slightly longer than those of the non-geminal cis or trans dimethylamine-/pyrrolidinesubstituted compound exocyclic P−N bond lengths (1.621 Å) (Table S4). The average values of endocyclic N−P−N (117.31°) bond angles in germinal substituted (3c)gdma, (3d)gpyr, (3e)gdma, and (3f)gpyr which have dimethylamine or pyrrolidine were slightly smaller than those of non-geminal cis or trans substituted N−P−N (118.45°) angles in compounds (4a)ngtdma, (5a)ngcdma, (5b)ngcdma, (5b)ngcpyr, and (5c)ngcpyr (Table S4). When the average values of endocyclic P−N−P bond angles are examined, this time germinal substituted (3c)gdma, (3d)gpyr, (3e)gdma and (3f)gpyr (122.17°) have slightly larger values than non-geminal cis or trans substituted P−N−P

are equivalent stereogenic centers with opposite configurations, SR, so that the structure is meso as shown in Figure 7. The N3P3 ring has a slightly twisted conformation; the maximum deviation from the mean plane is 0.127(3) Å (for atom P3). In the compound (3e)gdma, the six-membered cyclotriphosphazene ring is spiro-substituted with an asymmetric difunctional 3-amino-1-propanoxy group and two dimethylamino groups (Figure 8). Both Cl atoms of the PCl2 group are substituted with dimethylamino moieties to form the geminal compound (3e)gdma (Figure 8). The P1 phosphorus atom of compound (3e)gdma is a stereogenic center because of the asymmetric unit. It is racemic, and the R enantiomer is shown in Figure 8. In compound (3e)gdma, the six-membered cyclophosphazene ring is planar; the maximum deviation from the mean plane is 0.0528(14) Å (for atom P1). In compounds (3d)gdma and (3f)gpyr, the six-membered cyclophosphazene ring has geminal bis aniline (3d)gdma and geminal bis tert-butylamine (3f)gpyr substituents and both Cl atoms of the PCl2 group are substituted with dimethylamino ((3d)gdma) and pyrrolidine ((3f)gpyr) moieties to form the geminal compounds (Figures 9 and Figure 10). Neither (3d)gdma nor (3f)gpyr has a stereogenic center. In compound (3d)gdma, the six-membered cyclophosphazene ring is nearly planar; the maximum deviation from the mean plane is 0.062(2) Å (for atom P1), while in compound (3f)gpyr the ring is in a slightly twisted conformation; the maximum deviation from the mean plane is 0.1307(9) Å (for atom P2). The selected bond lengths, bond angles, and torsion angles of compounds (4a)ngtdma, (5a)ngcdma, (5b)ngcdma (3c)gdma, (3d)gdma, and (3e)gdma (dimethylamine substituted) and F


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Inorganic Chemistry

Figure 4. Proton-decoupled 31P NMR spectra of the product of reaction of compound 1f with secondary amines in a 1:4.5 ratio in THF solution: (a) dimethylamine; (b) pyrrolidine. The reaction mixture was filtered and the solvent removed prior to dissolving in CDCl3 solution.

Figure 5. View of the molecular structures for (4a)ngtdma and (5a)ngcdma with the atom-numbering schemes. Displacement ellipsoids are drawn at the 50% probability level, and the hydrogen atoms have been omitted for clarity.

(120.19°) angles in compounds (4a)ngtdma, (5a)ngcdma, (5b)ngcdma, (5b)ngcpyr, and (5c)ngcpyr (Table S4). The investigation of crystal structures of compounds (4a) ngt dma , (5a) ngc dma , (5b) ngc dma, (5b) ngc pyr, (3c) g dma , (3d)gdma, (3e)gdma, (3f)gpyr and (5c)ngcpyr showed that, while there are no classic hydrogen bonds, there are many intermolecular short contacts where the separation between donor and acceptor atoms is less than 3.5 Å, which probably causes stabilization of the structures. Effects of Interaction between the Incoming Secondary Amine and the Substituents in the Cyclo-

phosphazene Ring on the Formation of Geminal/NonGeminal Isomers. Although the reactions of cyclotriphosphazene with amines and the mechanisms and stereochemical pathways of these reactions have been extensively investigated,32,42 there are fewer studies about the directing effect of the substituent already present on the cyclotriphosphazene ring on the incoming amine group.47 It is known that the nature of the substituent on a cyclophosphazene ring is one controlling factor in the formation of regio- and stereoisomers. Regiocontrol exercised by the substituent often depends on its electron-releasing capability.65−68 In order to determine the G


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Inorganic Chemistry

Figure 6. View of the molecular structures for (5b)ngcdma and (5b)ngcpyr with the atom-numbering schemes. Displacement ellipsoids are drawn at the 50% probability level, and the hydrogen atoms have been omitted for clarity.

Figure 7. View of the molecular structures for (3c)gdma and (5c)ngcpyr with the atom-numbering schemes. Displacement ellipsoids are drawn at the 50% probability level, and the hydrogen atoms have been omitted for clarity.

Figure 8. View of the molecular structure for (3e)gdma with the atomnumbering scheme. Displacement ellipsoids are drawn at the 50% probability level, and the hydrogen atoms have been omitted for clarity.

Figure 9. View of the molecular structure for (3d)gdma with the atomnumbering scheme. Displacement ellipsoids are drawn at the 50% probability level, and the hydrogen atoms have been omitted for clarity.

role of the substituent group on the formation of regioisomers, geminal and/or non-geminal for reactions with secondary amines, the tetrachlorocyclophosphazene derivatives N3P3Cl4R2 (R2 = OCH2(CF2)2CH2O (1a), SPh (1b),

OCH2CH2CH2O (1c), NHPh (1d), OCH2CH2CH2NH (1e), NHBut (1f)) were used as starting materials. Each of H


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Inorganic Chemistry

(4b)ngtdma 56% for dimethylamine; (4a)ngtpyr 46% and (4b)ngtpyr 48% for pyrrolidine) and cis ((5a)ngcdma 35% and (5b)ngcdma 34% for dimethylamine; (5a)ngcpyr 41% and (5b)ngcpyr 30% for pyrrolidine) products (Table 2). In the reactions of compound 1c with the amines, pyrrolidine gave again only non-geminal trans ((4c)ngtpyr, 63%) and cis ((5c)ngcpyr, 37%) derivatives whereas a small amount of geminal isomer ((3c)gdma 12%) in addition to the non-geminal trans ((4c)ngtdma 47%) and cis ((5c)ngcdma, 31%) isomers are formed for reaction with dimethylamine (Table 2). In the reaction of dimethylamine with compound 1e the geminal isomer ((3e)gdma 65%) is preferred in an approximate 22:1 ratio in comparison to the non-geminal isomers ((4e)ngtdma or (5e)ngcdma 3%), whereas in reactions with pyrrolidine both geminal ((3e)gpyr 57%) and non-geminal ((4e)ngtpyr or (5e)ngcpyr 14%) isomers are formed, albeit in aq ratio of about 4:1 (Table 2). On the other hand, the reactions of compounds 1d,f with the corresponding amines result in the formation of overwhelming amounts of the geminal products (geminal/nongeminal ratios for dimethylamine 3:1 and 6:1, respectively, and geminal/non-geminal ratios for pyrrolidine 2.5:1 and 4:1, respectively) (Table 2). It is likely that a dissociative mechanism, SN1, becomes preferred to the bimolecular mechanism, SN2, in the case of substituents such as aniline and tert-butylamine, which supply electrons to the cyclophosphazene ring and, as a result, geminal product yield increases. The direct correlation of the change of yield of geminal product with the basicity of the starting compound is shown in Figure 11. The decrease in formal positive charge on the cyclophosphazene starting material decreases its electrophilic character, thus rendering the bimolecular pathway less energetically favorable. Additionally, the increased negative charge will lower the activation energy of the dissociative process by stabilizing the positively charged phosphorus center in the intermediate. Furthermore, the electron-supplying properties of the PR2 groups (R = NHPh (1d), OCH2CH2CH2NH (1e), NHBut (1f)) make the gem-disubstituted starting materials less reactive toward nucleophilic substitution in comparison to the other PR2 groups (R = OCH2(CF2)2CH2O (1a), SPh (1b), OCH2CH2CH2O (1c)). Hence, the yield of mono substitution products ((2d)mdma 47% and (2f)mdma 43% for

Figure 10. View of the molecular structure for (3f)gpyr with the atomnumbering scheme. Displacement ellipsoids are drawn at the 50% probability level, and the hydrogen atoms have been omitted for clarity.

these derivatives contains two PCl2 groups, thus providing the possibility for both geminal and non-geminal substitution (Scheme 2). These starting compounds were selected in the order of the electron-supplying capacity (basicity) of the R groups on the cyclophosphazene ring. The basicity of the PR2 groups was calculated to be about 3.9 for spiro-(OCH2CF2CF2CH2O) (1a), 6.0 for (SPh)2 (1b), 7.5 for spiro-(OCH2CH2CH2O) (1c), 8.8 for (NHPh)2 (1d), 9.7 for spiro(OCH2CH2CH2NH) (1e), and 11.8 for (NHBut)2 (1f).65−68 Earlier studies reported that the replacement pattern of chlorine atoms in hexachlorocyclotriphosphazene with dimethylamine and pyrrolidine follows largely a non-geminal pattern and the geminal bis products occur only in trace amounts.48,69−71 In the current investigation, the aminolysis reactions of these two amines resulted in the formation of the geminal and/or non-geminal isomer in different ratios, depending on the basicity of the starting compound. The yields of the isolated isomers and the relative amounts of each isomer determined from the proton-decoupled 31P NMR spectra of the reaction mixtures are given in Table 2. The reactions of compounds 1a,b with both secondary amines gave only non-geminal trans ((4a)ngtdma 59% and

Scheme 2. Illustration of the Geminal- and Non-Geminal Pathways at the Second Stage of the Reaction of Compounds 1a−f with a Secondary Amine

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14 6 2

0/100 0/100 0/100 70/30 80/20 81/19 1

(4a)ngtpyr; 46 (5a)ngcpyr; 41 ngt (4b) pyr; 48 (5b)ngcpyr; 30 (4c)ngtpyr; 63 (5c)ngcpyr; 37 (4d)ngtpyr; 9 (5d)ngcpyr; 6 ngc [(4e) and (5e)ngt ]pyr; 14 (4f)ngtpyr; 7 (5f)ngcpyr; 3

10 2 9 5

0/100 0/100 13/87 75/25 96/4 87/13 6

(4a)ngtdma; 59 (5a)ngcdma; 35 ngt (4b) dma; 56 (5b)ngcdma; 34 (4c)ngtdma; 47 (5c)ngcdma; 31 (4d)ngtdma; 7 (5d)ngcdma; 6 ngc ngt [(4e) or (5e) ]dma; 3 (4f)ngtdma; 4 (5f)ngcdma; 3

Figure 11. Change of yield of geminal product with the basicity of the starting compound.

dimethylamine; (2d)mpyr 36% and (2f)mpyr 45% for pyrrolidine) is quite high. In the non-geminal pathways, stereoselectivity is also observed, and it is expected that steric requirements will favor a trans disposition of bulky groups.32 Detailed kinetic analyses have shown that the trans preference arises from the entropy of activation. Additionally the formation of regio- and stereoisomers depends on the solvent (polarity, aromaticity).32,35

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CONCLUSION In this study, a series of experiments in which we could focus on the properties of substituents on the ring were designed. This was accomplished by systematically investigating the aminolysis reactions of gem-N3P3Cl4R2 type cyclophosphazene derivatives with secondary amines. The R groups were chosen to examine their capacity for donating electrons to the cyclophosphazene ring. On the basis of the literature, secondary amines are, for the most part, expected to follow a non-geminal pathway in the reactions with hexachlorocyclotriphosphazene. However, in this work, we have demonstrated that the ratio of geminal to non-geminal isomers in reactions of two different secondary amines with the geminal N3P3Cl4R2 (R2 = OCH2CH2CH2NH, NHPh, NHBut) series leading to the formation of geminal products is controlled by the electron-donating properties of the R groups. This allows for a previously unavailable level of predictability in the question of regiochemical outcomes.

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ASSOCIATED CONTENT

* Supporting Information S

Other products not characterized.

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.inorgchem.8b01620. Characterization and structural data for the compounds in this paper (PDF) Accession Codes

CCDC 1841382−1841390 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

a

(2f)mpyr; 34

(3d)gpyr; 25 (3e)gpyr; 48 (3f)gpyr; 36 (2d)mpyr; 30

(2a)mpyr; 7 (2b)mpyr; 16

1a (3.9) 1b (6.0) 1c (7.5) 1d (8.8) 1e (9.7) 1f (11.8)

(2d)mdma; m

6 dma;

1a (3.9) 1b (6.0) 1c (7.5) 1d (8.8) 1e (9.7) 1f (11.8)

(2b)

m

38 2e(I+II) dma; 14 (2f)mdma; 34

(3c)gdma; 9 (3d)gdma; 30 (3e)gdma; 55 (3f)gdma; 36

Reactions of Nucleophile with Dimethylamine 1:4.5 Molar Ratio (4a)ngtdma; 51 (5a)ngcdma; 26 ngt (4b) dma; 47 (5b)ngcdma; 25 (2b)mdma; 10 (3c)gdma; 12 m (2d) dma; 47 (3d)gdma; 38 m 2e(I+II) dma; 23 (3e)gdma; 65 (2f)mdma; 43 (3f)gdma; 45 Reactions of Nucleophile with Pyrrolidine 1:4.5 Molar Ratio (5a)ngcpyr; 36 (2a)mpyr; 13 ngc (5b) pyr; 22 (2b)mpyr; 21 (5c)ngcpyr; 32 (2d)mpyr; 36 (3d)gpyr; 35 m 2e(I+II) pyr; 23 (3e)gpyr ; 57 m (2f) pyr; 45 (3f)gpyr; 43

other productsa non-geminal cis non-geminal trans geminal mono substition non-geminal cis non-geminal trans geminal mono substition starting compd (basicity of R2 group)

isolated product yield (compd; yield, %)

Table 2. Quantification of Products of Reactions of Nucleophiles with Dimethylamine and Pyrrolidine

31

P NMR of reaction mixture (compd; yield, %)

geminal/ non-geminal, %

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AUTHOR INFORMATION

Corresponding Author

*S.B.: tel, +902626053013; fax, +902626053005; e-mail, [email protected]. Notes

The authors declare no competing financial interest.

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ABBREVIATIONS mp, melting point; h, hour; SPh, thiophenol; NHPh, aniline; NHBut, tert-butylamine; THF, tetrahydrofuran; DCM, dichloromethane; TLC, thin-layer chromatography

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