Phosphorus-nitrogen compounds. Part 24. Syntheses, crystal structures, spectroscopic and stereogenic properties, biological activities, and DNA interactions of novel spiro-ansa-spiro- and ansa-spiro-ansa- cyclotetraphosphazenes

Article

pubs.acs.org/IC

Phosphorus−Nitrogen Compounds. Part 24. Syntheses, Crystal

Structures, Spectroscopic and Stereogenic Properties, Biological

Activities, and DNA Interactions of Novel Spiro-ansa-spiro- and Ansa-

spiro-ansa-cyclotetraphosphazenes

Gamze Elmas (nee Egemen),^†Aytug Okumus,^†

̧

Zeynel Kılıc,

̧

*^,†Tuncer Hokelek,^‡Leyla Acı

̧

k,^§

̆

̈

Hakan Dal,^⊥Nagehan Ramazanoglu,^§and L.Yasemin Koc^#

̧

̆

^†Department of Chemistry, Ankara University, 06100 Ankara, Turkey

^‡Department of Physics, Hacettepe University, 06800 Ankara, Turkey

^§Department of Biology, Gazi University, 06500 Ankara, Turkey

^⊥Department of Chemistry, Anadolu University, 26470 Eskise

̧ hir, Turkey

^#Department of Biology, Ankara University, 06100 Ankara, Turkey

S

* Supporting Information

ABSTRACT: The reactions of octachlorocyclotetraphosphazene, N₄P₄Cl₈, with N₂O₂

donor-type aminopodands (1a, 1b, 1g, and 1h) aﬀorded two kinds of derivatives, namely,

spiro-ansa-spiro (sas) (2a, 2b, 2g, and 2h) and ansa-spiro-ansa (asa) (3a and 3b)

phosphazenes. The partly substituted sas phosphazenes (2a and 2b) reacted with excess

pyrrolidine and morpholine in tetrahydrofuran to produce the tetrapyrrolidino (2c and 2d)

and morpholino (2e and 2f) derivatives. The reactions of the asa phosphazenes (3a and 3b)

with excess pyrrolidine and morpholine produced gem-2-trans-6-dichloropyrrolidinophos-

phazenes (3c and 3d) and -morpholinophosphazenes (3e and 3f). However, the fully

substituted products were not obtained in these solvents. In addition, the expected fully

substituted compound was not obtained from the reaction of 3a with excess pyrrolidine by

standard or microwave-assisted methods. The reaction of the long-chain starting compound

(1g) with N₄P₄Cl₈gave sas (2g) and the interesting 2,6-ansa-spiro-bicyclo product (bicyclo-

2,6-as; 4g), while the reaction of 1h with N₄P₄Cl₈yielded only sas (2h). The structural

investigations of the compounds were veriﬁed by elemental analyses, mass spectrometry, Fourier transform infrared, and DEPT,

1

HSQC, HMBC, H, ¹³C, and ³¹P NMR techniques. The crystal structures of 2b, 3a, 3b, 3e, and 4g were determined by X-ray

crystallography. Compounds 2a−2h, 3a−3f, and 4g had two stereogenic P atoms. Compound 3b had one enantiomer according

to the Flack parameter, and 3f was a racemic mixture, as shown by chiral high-performance liquid chromatography and chiral-

solvating-agent, (R)-(+)-2,2,2-triﬂuoro-1-(9′-anthryl)ethanol, experiments. Furthermore, compounds 2a, 2c, and 2d exhibited

weak antibacterial activity against (G+) bacterium, and 3c and 3d displayed moderate antifungal activity against Candida

tropicalis. Gel electrophoresis data demonstrated that 2e, 3c, and 3e promoted the formation of DNA cleavage. The prevention of

BamHI digestion by 2a−2f and 3a−3f, except 2b and 2e, disclosed binding with GG nucleotides in DNA.

dispiro (2,4- and 2,6-), trispiro, tetraspiro, ansa, spiro-ansa (2,4-

and 2,6-), spiro-ansa-spiro (sas), bino, spiro-bino, and di(spiro-

bino) products depending on the reaction conditions.⁶Our

group has focused on the reactions of N₂O₂donor-type

tetradentate ligands with N₃P₃Cl₆and isolated sas and spiro-

bino-spiro (sbs) but not ansa-spiro-ansa (asa) products.⁷A

review of the literature shows that there are no reports of the

reactions of N₄P₄Cl₈with N₂O₂donor-type tetradentate

ligands. This paper is focused primarily on the chloride

replacement reactions of N₄P₄Cl₈with N₂O₂tetradentate

ligands with the aim of obtaining novel polyheterocyclote-

traphosphazenes for comparison with cyclotriphosphazene

INTRODUCTION

■

Cyclophosphazenes are an important class of inorganic ring

systems and exhibit very diﬀerent physical and chemical

properties depending on the types and properties of the

substituents bonded to the P atoms.¹The replacement reaction

patterns of Cl atoms in N₃P₃Cl₆with mono-, di-, tri-, and

tetrafunctional amines, such as diaminoalkanes, diaminopo-

lyethers, spermidine, and spermine, have been extensively

studied²and reported as chemotherapeutic agents and selective

carriers for delivering anticancer drugs to malignant target

cells.³Although a large number of N₄P₄Cl₈derivatives have also

been prepared with mono- and difunctional ligands,⁴

discussions of the substitution reaction patterns with polyfunc-

tional ligands are relatively limited in the literature.⁵N₄P₄Cl₈

with bidentate and/or polydentate amines may produce spiro,

Received: August 7, 2012

Published: November 19, 2012

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Scheme 1. Phosphazene Derivatives Obtained from the Reactions of N₄P₄Cl₈with Aminopodands, Pyrrolidine, and Morpholine

derivatives and also exploring their biological activity. The

stereogenic properties of cyclotriphosphazene derivatives are a

new subject of interest.⁸The stereogenic properties of some of

the cyclotriphosphazene derivatives have been investigated

using ³¹P NMR spectroscopy in the presence of chiral-

solvating-agent (CSA) and high-performance liquid chroma-

tography (HPLC) techniques.⁹Cyclotriphosphazenes have

been extensively used as building blocks for the synthesis of

phosphazenes, polymers, and dendrimers, and cyclophospha-

zenes may be useful as strong bases in the syntheses of

coordination complexes. Chiral cyclophosphazenes are im-

portant compounds for the preparation of chiral complexes and

polymers.¹⁰Organophosphazenes have various applications of

technological and medicinal importance, such as the production

of inﬂammable textile ﬁbers,¹¹hydraulic ﬂuids,¹²lubricants,¹³

ionic liquids,¹⁴liquid-crystalline materials,¹⁵advanced elasto-

mers,¹⁶rechargeable lithium batteries,¹⁷anticancer and

antimicrobial agents,¹⁸membranes,¹⁹and synthetic bones and

biomedical materials.^20,21Octapyrrolidinocyclotetraphospha-

zene has signiﬁcant anticancer activity.²²The copper(II)

complex of a fully phenoxy-substituted star-branched cyclo-

tetraphosphazene derivative is active in the oxidative cleavage of

DNA.²³

The choice of tetradentate symmetric ligands is very

important for this study because stereochemically controlled

reactions can be achieved with these ligands, leading to the

arrangement of conﬁgurations of tetracoordinated P and

tricoordinated N atoms, which form stereogenic centers. If

the N atoms have three diﬀerent substituents and restricted

single-bond rotations about N atoms, atropisomerism may arise

in cyclotetraphosphazene derivatives. This phenomenon is well-

known for some organic compounds.²⁴

We report herein (i) the synthesis of novel sas (2a−2h), asa

(3a−3f), and 2,6-ansa-spiro-bicyclo (bicyclo-2,6-as; 4g) cyclo-

tetraphosphazenes with conventional methods and microwave-

assisted preparations of 3c (Scheme 1), (ii) the structural

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Article

products, 2a and 3a, were puriﬁed by column chromatography with

toluene.

determination of compounds by mass spectrometry (MS),

Fourier transform infrared (FTIR), one-dimensional (1D) H,

1

¹³C, and ³¹P NMR, distortionless enhancement by polarization

transfer (DEPT), and two-dimensional (2D) heteronuclear

single quantum coherence (HSQC), and heteronuclear multi-

ple-bond correlation (HMBC) techniques, (iii) the solid-state

and molecular structures of 2b, 3a, 3b, 3e, and 4g, (iv) the

stereogenic properties of 3f investigated by ³¹P NMR

measurements in the presence of CSA and chiral HPLC, (v)

the investigations of antibacterial and antifungal activities of

2a−2f and 3a−3f, and (vi) interactions between the

compounds 2a−2f, 3a−3f, and pBR322 DNA.

Compound 2a was crystallized from acetonitrile. Yield: 0.36 g

(22%). Mp: 249 °C. Anal. Calcd for C₁₆H₁₆O₂N₆P₄Cl₄: C, 32.57; H,

2.73; N, 14.24. Found: C, 32.76; H, 2.77; N, 14.28. APIES-MS

(fragments are based on ³⁵Cl; Ir % designates the fragment abundance

percentage): m/z 589 ([MH]⁺, 87). FTIR (KBr, cm⁻¹): ν 3067

(asymm), 3027 (symm, C−H arom), 2920, 2851 (C−H aliph), 1579

(CC), 1313 (asymm), 1180 (symm, PN), 544 (asymm), 483

(symm, PCl). ¹H NMR (500 MHz, CDCl₃, ppm): δ 7.26 (m, 2H, H₄),

2

3

7.07 (m, 6H, H₂, H₃, H₅), 4.62 (dd, 2H, J_HH= 11.5 Hz, J_PH= 15.5

2

3

Hz, ArCH₂N), 4.02 (dd, 2H, J_HH= 11.5 Hz, J_PH= 15.3 Hz,

ArCH₂N), 3.42, 3.31 (m, 4H, NCH₂). ¹³C NMR (500 MHz, CDCl₃,

ppm): δ 150.61 (d, ²J_PC= 5.0 Hz, C₆), 128.96 (s, C₄), 126.90 (s, C₂),

123.63 (s, C₃), 121.85 (t, ³J_PC= 10.4 Hz, C₁), 119.11 (t, ³J_PC= 9.5 Hz,

C₅), 53.27 (s, ArCH₂N), 52.52 (s, NCH₂).

EXPERIMENTAL SECTION

■

Compound 3a was crystallized from acetonitrile. Yield: 1.12 g

(69%). Mp: 302 °C. Anal. Calcd for C₁₆H₁₆O₂N₆P₄Cl₄: C, 32.57; H,

2.73; N, 14.24. Found: C, 32.61; H, 2.80; N, 14.16. APIES-MS

(fragments are based on ³⁵Cl, Ir %): m/z 589 ([MH]⁺, 68). FTIR

(KBr, cm⁻¹): ν 3077 (asymm), 3019 (symm, C−H arom), 2932, 2863

(C−H aliph), 1582 (CC), 1283 (asymm), 1167 (symm, PN),

539 (asymm), 492 (symm, PCl). ¹H NMR (500 MHz, CDCl₃, ppm):

δ 7.40 (m, 2H, H₄), 7.35 (d, 2H, H₅), 7.29 (m, 2H, H₃), 7.26 (d, 2H,

General Methods. Commercial-grade reagents were used without

further puriﬁcation. Solvents were dried and distilled by standard

methods. All reactions were monitored using thin-layer chromatog-

raphy (TLC) on Merck DC Alufolien Kiesegel 60 B₂₅₄sheets. Column

chromatography was performed on Merck Kiesegel 60 (230−400

mesh ATSM) silica gel. All reactions were carried out under an argon

atmosphere. Melting points were measured on a Gallenkamp

apparatus using a capillary tube. ¹H, ¹³C, and ³¹P NMR, HSQC,

DEPT, and HMBC spectra were recorded on a Bruker DPX FT-NMR

(500 MHz) spectrometer (SiMe₄as internal and 85% H₃PO₄as

external standards). The spectrometer was equipped with a 5 mm

PABBO BB inverse-gradient probe. Standard Bruker pulse programs²⁵

were used. The numbering of the protons and carbons of all of the

phosphazene derivatives is given in Scheme 1. IR spectra were

recorded on a Mattson 1000 FTIR spectrometer in KBr disks and were

reported in cm⁻¹units. Microanalyses were carried out by the

microanalytical service of TUBITAK Turkey. APIES-MS spectra were

recorded on an Agilent 1100 MSD spectrometer. Microwave-assisted

experiments have been performed with a Milestone Start S system by

using a weﬂon magnet for tetrahydrofuran (THF), toluene, and o-

xylene. Experiments involving the CSA were carried out by the

addition of small aliquots of a concentrated solution of CSA in the

solvent used for NMR spectroscopy and the proton-decoupled ³¹P

NMR spectrum recorded at each addition. HPLC experiments were

performed with an Agilent 1100 series HPLC system (Chemstation

software) equipped with a G 1311A pump and a G 1315B diode-array

detector monitoring the range of 220−360 nm. The detection

wavelength was set at 254 nm for 3f. A reversible chiral column (R,R)-

whelk-01 (250 × 4.6 mm) from Regis Tech. Inc. was used for HPLC.

Antibacterial susceptibility testing was performed by the BACTEC

MGIT 960 (Becton Dickinson, Sparks, MD) system using the agar-

well diﬀusion method²⁶(section S1 in the Supporting Information,

SI). The DNA binding abilities were examined using agarose gel

electrophoresis (section S2 in the SI).^27,28

2

3

H₂), 4.69 (dd, 2H, J_HH= 10.3 Hz, J_PH= 14.9 Hz, ArCH₂N), 3.68

(dd, 2H, ²J_HH= 10.4 Hz, ³J_PH= 15.4 Hz, ArCH₂N), 3.31, 3.04 (m, 4H,

NCH₂). ¹³C NMR (500 MHz, CDCl₃, ppm): δ 148.42 (d, J_PC= 4.7

2

3

Hz, C₆), 132.58 (s, C₂), 130.19 (s, C₄), 127.52 (t, J_PC= 7.3 Hz, C₁),

126.13 (s, C₃), 123.50 (t, ³J_PC= 6.7 Hz, C₅), 44.32 (d, ²J_PC= 12.0 Hz,

NCH₂), 43.72 (s, ArCH₂N).

sas 2b and asa 3b. The workup procedure was similar to that of

compounds 2a and 3a, using 1b (1.50 g, 5.00 mmol), K₂CO₃(2.90 g,

21.00 mmol), N₄P₄Cl₈(2.43 g, 5.00 mmol), and triethylamine (5.90

mL). The products, 2b and 3b, were puriﬁed by column

chromatography with toluene.

Data for 2b. Yield: 0.44 g (29%). Mp: 218 °C. Anal. Calcd for

C₁₇H₁₈N₆O₂P₄Cl₄: C, 33.80; H, 3.00; N, 13.91. Found: C, 33.91; H,

3.12; N, 13.94. APIES-MS (fragments are based on ³⁵Cl, Ir %): m/z

603 ([MH]⁺, 71). FTIR (KBr, cm⁻¹): ν 3082 (asymm), 3021 (symm,

C−H arom), 2947, 2850 (C−H aliph), 1588 (CC), 1276 (asymm),

1186 (symm, PN), 546 (asymm), 484 (symm, PCl). ¹H NMR (500

MHz, CDCl₃, ppm): δ 7.25 (m, 2H, H₄), 7.05 (m, 6H, H₂, H₃, H₅),

4.46 (dd, 2H, ²J_HH= 9.0 Hz, ⁰J_PH= 15.3 Hz, ArCH₂N), 4.14 (dd, 2H,

3

²J_HH= 8.9 Hz, J_PH= 15.2 Hz, ArCH₂N), 3.41 (m, 4H, NCH₂), 1.81,

1.71 (m, 2H, NCH₂CH₂). ¹³C NMR (500 MHz, CDCl₃, ppm): δ

151.05 (t, ²J_PC= 5.1 Hz, C₆), 129.17 (s, C₄), 126.81 (s, C₂), 123.61 (s,

C₃), 123.27 (t, ³J_PC= 9.4 Hz, C₁), 119.23 (t, ³J_PC= 8.7 Hz, C₅), 50.54

(s, ArCH₂N), 45.90 (s, NCH₂), 27.11 (s, NCH₂CH₂).

Data for 3b. Yield: 0.95 g (63%). Mp: 267 °C. Anal. Calcd for

C₁₇H₁₈N₆O₂P₄Cl₄: C, 33.80; H, 3.00; N, 13.91. Found: C, 33.77; H,

2.91; N, 13.97. APIES-MS (fragments are based on ³⁵Cl, Ir %): m/z

603 ([MH]⁺, 85). FTIR (KBr, cm⁻¹): ν 3092 (asymm), 3025 (symm,

C−H arom), 2955, 2856 (C−H aliph), 1584 (CC), 1291 (asymm),

1170 (symm, PN), 576 (asymm), 480 (symm, PCl). ¹H NMR (500

MHz, CDCl₃, ppm): δ 7.49 (m, 2H, H₄), 7.32 (m, 2H, H₅), 7.30 (d,

The starting compounds N₄P₄Cl₈(a gift from Otsuka Chemical Co.

Ltd.), aliphatic amines (Fluka), pyrrolidine (Fluka), morpholine

(Fluka), and salicylaldehyde (Fluka) were purchased. The CSA was

obtained from Aldrich Chemical Co.

Preparation of Compounds. 2,2′-[1,2-Ethanediylbis-

(iminomethanediyl)]diphenol (1a), 2,2′-[1,3-propanediylbis-

(iminomethanediyl)]diphenol (1b), 2,2′-[1,4-butanediylbis-

(iminomethanediyl)]diphenol (1g), and 2,2′-[1,6-hexanediylbis-

(iminomethanediyl)]diphenol (1h) have been synthesized according

to the methods reported in the literature.²⁹

sas 2a and asa 3a. K₂CO₃(3.00 g, 22.00 mmol) was added to a

stirred solution of 1a (1.50 g, 5.50 mmol) in dry THF (200 mL). The

mixture was reﬂuxed for 4 h and cooled to ambient temperature.

Afterward, a mixture of triethylamine (6.10 mL) and N₄P₄Cl₈(2.55 g,

5.50 mmol) in dry THF (100 mL) is added dropwise to the stirred

solution of 1a at −10 °C for over 5 h. After the mixture had been

allowed to warm to ambient temperature, it was stirred for 16 h under

an argon atmosphere. The precipitated amine hydrochloride and

excess K₂CO₃were ﬁltered oﬀ, and the solvent was evaporated. The

2

3

2H, H₂), 7.28 (d, 2H, H₃), 4.62 (dd, 2H, J_HH= 11.5 Hz, J_PH= 15.3

2

3

Hz, ArCH₂N), 3.71 (dd, 2H, J_HH= 13.4 Hz, J_PH= 15.4 Hz,

ArCH₂N), 3.12 (m, 4H, NCH₂), 1.75 (m, 2H, NCH₂CH₂). ¹³C NMR

2

(500 MHz, CDCl₃, ppm): δ 148.09 (d, J_PC= 4.8 Hz, C₆), 132.12 (s,

3

C₂), 130.31 (t, J_PC= 7.0 Hz, C₁), 130.01 (s, C₄), 126.52 (s, C₃),

122.58 (t, ³J_PC= 6.9 Hz, C₅), 48.60 (s, NCH₂), 46.21 (d, ²J_PC= 3.3 Hz,

3

ArCH₂N), 26.13 (d, J_PC= 7.2 Hz, NCH₂CH₂).

sas 2g and bicyclo-2,6-as 4g. The workup procedure was similar

to that of compounds 2a and 3a, using 1g (1.50 g, 5.00 mmol), K₂CO₃

(2.46 g, 25.00 mmol), N₄P₄Cl₈(2.32 g, 5.00 mmol), and triethylamine

(5.60 mL). The products, 2g and 4g, were puriﬁed by column

chromatography with toluene.

Data for 2g. Yield: 0.10 g (6%). Mp: 158 °C. Anal. Calcd for

C₁₈H₂₀N₆O₂P₄Cl₄: C, 34.98; H, 3.26; N, 13.59. Found: C, 35.28; H,

3.26; N, 13.26. APIES-MS (fragments are based on ³⁵Cl, Ir %): m/z

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617 ([MH]⁺, 79). FTIR (KBr, cm⁻¹): ν 3080 (asymm), 3022 (symm,

C−H arom), 2952, 2853 (C−H aliph), 1587 (CC), 1272 (asymm),

1185 (symm, PN), 566 (asymm), 484 (symm, PCl). ¹H NMR (500

MHz, CDCl₃, ppm): δ 7.20 (m, 2H, H₄), 7.06 (m, 6H, H₂, H₃, H₅),

chromatography with benzene−THF (1:1) and crystallized from

acetonitrile−THF (3:1). Yield: 0.43 g (70%). Mp: 180 °C. Anal. Calcd

for C₃₃H₅₀O₂N₁₀P₄: C, 53.37; H, 6.79; N, 18.86. Found: C, 53.49; H,

6.70; N, 18.79. APIES-MS (fragments are based on ³⁵Cl, Ir %): m/z

743 ([MH]⁺, 100). FTIR (KBr, cm⁻¹): ν 3077 (asymm), 3043 (symm,

C−H arom), 2958, 2848 (C−H aliph), 1587 (CC), 1281 (asymm),

1166 (symm, PN), 566 (asymm), 489 (symm, PCl). ¹H NMR (500

MHz, CDCl₃, ppm): δ 7.13 (m, 2H, H₄), 7.01 (m, 2H, H₂), 6.92 (m,

4H, H₃, H₅), 4.32 (dd, 2H, ²J_HH= 10.2 Hz, ³J_PH= 15.6 Hz, ArCH₂N),

4.18 (dd, 2H, ²J_HH= 8.2 Hz, ³J_PH= 15.9 Hz, ArCH₂N), 3.50, 3.31 [m,

4H, NCH₂(ansa)], 3.11 [m, 16H, NCH₂(pyrr)], 1.79 [m, 2H,

NCH₂CH₂(ansa)], 1.62 [m, 16H, NCH₂CH₂(pyrr)]. ¹³C NMR (500

4.46 (d, 4H, ³J_PH= 14.4 Hz, ArCH₂N), 3.13 (m, 4H, NCH₂), 1.62 (m,

2

4H, NCH₂CH₂). ¹³C NMR (500 MHz, CDCl₃): δ 150.08 (t, J_PC

=

5.4 Hz, C₆), 131.06 (s, C₄), 129.98 (s, C₂), 125.53 (s, C₃), 123.60 (t,

3

³J_PC= 9.5 Hz, C₁), 123.91 (t, J_PC= 8.8 Hz, C₅), 51.13 (s, ArCH₂N),

47.94 (s, NCH₂), 26.86 (s, NCH₂CH₂).

Data for 4g. Yield: 0.26 g (17%). Mp: 262 °C. Anal. Calcd for

C₁₈H₂₁N₆O₂P₄Cl₅: C, 33.03; H, 3.23; N, 12.84. Found: C, 33.13; H,

3.24; N, 12.93. APIES-MS (fragments are based on ³⁵Cl, Ir %): m/z

653 ([MH]⁺, 35). FTIR (KBr, cm⁻¹): ν 3327 (O−H), 3079 (asymm),

3026 (symm, C−H arom), 2947, 2848 (C−H aliph), 1585 (CC),

1262 (asymm), 1173 (symm, PN), 568 (asymm), 489 (symm, PCl).

¹H NMR (500 MHz, CDCl₃, ppm): δ 7.91 (b, H, ArOH), 7.36 (m, H,

H₅), 7.30 (dd, H, H₂), 7.18 (d, H, H′₅), 7.15 (dd, H, H₄), 7.09 (d, H,

H′₂), 7.03 (dd, H, H′₄), 6.83 (dd, H, H₃), 6.75 (dd, H, H′₃), 4.32 (d,

2

MHz, CDCl₃, ppm): δ 151.80 (d, J_PC= 4.9 Hz, C₆), 127.81 (s, C₄),

126.55 (s, C₂), 122.93 (t, ³J_PC= 7.9 Hz, C₁), 121.79 (s, C₃), 118.83 (t,

³J_PC= 7.2 Hz, C₅), 50.51 (s, ArCH₂N), 46.37 [s, NCH₂(ansa)], 46.29,

3

46.47 [s, NCH₂(pyrr)], 27.61 [s, NCH₂CH₂(ansa)], 26.46 [t, J_PC

9.5 Hz, NCH₂CH₂(pyrr)].

=

sas 2e. A solution of morpholine (0.60 mL, 6.80 mmol) in dry

THF (50 mL) was slowly added to a stirred solution of triethylamine

(0.40 mL) and 2a (0.40 g, 0.70 mmol) in dry THF (100 mL) at room

temperature. The solution was heated to reﬂux for 10 h with argon

being passed over the mixture. The precipitated amine hydrochloride

was ﬁltered oﬀ, and the solvent was evaporated at reduced pressure.

The oily residue was puriﬁed by column chromatography with

toluene−THF (1:1) and crystallized from acetonitrile−THF (3:1).

Yield: 0.36 g (67%). Mp: 197 °C. Anal. Calcd for C₃₂H₄₈O₆N₁₀P₄C₇H₈

(toluene): C, 52.94; H, 6.33; N, 15.84. Found: C, 52.19; H, 6.29; N,

16.39. APIES-MS (fragments are based on ³⁵Cl, Ir %): m/z 793

([MH]⁺, 100). FTIR (KBr, cm⁻¹): ν 3063 (asymm), 3029 (symm, C−

H arom), 2957, 2849 (C−H aliph), 1585 (CC), 1294 (asymm),

1180 (symm, PN), 538 (asymm), 486 (symm, PCl). ¹H NMR (500

MHz, CDCl₃, ppm): δ 7.20 (m, 2H, H₄), 7.03 (m, 2H, H₂), 6.96 (m,

2H, H₃), 6.94 (m, 2H, H₅), 4.51 (dd, 2H, ²J_HH= 10.6 Hz, ³J_PH= 15.3

3

2H, ³J_PH= 12.5 Hz, ArCH₂N), 4.24 (d, 2H, J_PH= 8.6 Hz, ArCH₂N),

3.12 (m, 4H, NCH₂), 1.59, 1.27 (m, 4H, NCH₂CH₂). ¹³C NMR (500

2

MHz, CDCl₃): δ 155.81 (s, C′₆), 150.22 (d, J_PC= 12.1 Hz, C₆),

132.72 (s, C′₄), 130.12 (s, C₄), 129.91 (d, ⁴J_PC= 2.2 Hz, C′₂), 125.62

(d, ⁴J_PC= 2.1 Hz, C₂), 129.35 (d, ³J_PC= 6.9 Hz, C′₁), 123.10 (d, ³J_PC

=

3

6.1 Hz, C₁), 129.94 (s, C′₅), 120.42 (t, J_PC= 3.6 Hz, C₅), 119.55 (s,

C′₃), 116.09 (s, C₃), 48.31 (d, ²J_PC= 4.7 Hz, ArC′H₂N), 45.82 (d, ²J_PC

= 6.7 Hz, NC′H₂), 44.36 (d, ²J_PC= 6.0 Hz, ArCH₂N), 42.72 (d, ²J_PC

7.9 Hz, NCH₂), 27.63 (s, NCH₂C′H₂), 24.01 (s, NCH₂CH₂).

=

sas 2h. The workup procedure was similar to that of compounds

2a and 3a, using 1h (1.50 g, 4.50 mmol), K₂CO₃(2.53 g, 19.00

mmol), N₄P₄Cl₈(2.10 g, 4.50 mmol), and triethylamine (3.70 mL).

The product 2h was puriﬁed by column chromatography with toluene.

Yield: 0.12 g (4%). Mp: 203 °C. Anal. Calcd for C₂₀H₂₄N₆O₂P₄Cl₄: C,

37.18; H, 3.74; N, 13.01. Found: C, 37.47; H, 3.75; N, 13.08. APIES-

MS (fragments are based on ³⁵Cl, Ir %): m/z 645 ([MH]⁺, 37). FTIR

(KBr, cm⁻¹): ν 3078 (asymm), 3042 (symm, C−H arom), 2957, 2846

(C−H aliph), 1584 (CC), 1280 (asymm), 1183 (symm, PN),

570 (asymm), 489 (symm, PCl). ¹H NMR (500 MHz, CDCl₃, ppm):

δ 7.24 (m, 2H, H₄), 7.05 (m, 6H, H₂, H₃, H₅), 4.34 (d, 4H, ³J_PH= 14.8

Hz, ArCH₂N), 3.18 (m, 4H, NCH₂), 1.61 (m, 8H, NCH₂CH₂and

NCH₂CH₂CH₂). ¹³C NMR (500 MHz, CDCl₃, ppm): δ 151.64 (t,

²J_PC= 6.9 Hz, C₆), 128.79 (s, C₄), 127.27 (s, C₂), 123.20 (s, C₃),

122.52 (t, ³J_PC= 11.2 Hz, C₁), 119.15 (t, ³J_PC= 9.3 Hz, C₅), 46.80 (s,

2

3

Hz, ArCH₂N), 4.01 (dd, 2H, J_HH= 10.6 Hz, J_PH= 15.2 Hz,

ArCH₂N), 3.62 [m, 16H, NCH₂CH₂(mor)], 3.32, 3.11 [m, 4H,

NCH₂(ansa)], 3.11 [m, 16H, NCH₂(mor)]. ¹³C NMR (500 MHz,

CDCl₃, ppm): δ 150.21 (d, ²J_PC= 4.8 Hz, C₆), 128.32 (s, C₄), 126.83

(s, C₂), 122.45 (s, C₃), 118.82 (t, ³J_PC= 6.7 Hz, C₅), 112.94 (t, ³J_PC

=

3

7.3 Hz, C₁), 67.31 [t, J_PC= 9.6 Hz, NCH₂CH₂(mor)], 53.24 (s,

ArCH₂N), 52.22 [s, NCH₂(ansa)], 45.16, 44.92 [s, NCH₂(mor)].

sas 2f. The workup procedure was similar to that of compound 2e,

using 2b (0.50 g, 0.80 mmol), morpholine (0.70 mL, 8.30 mmol), and

triethylamine (0.45 mL). Yield: 0.41 g (62%). Mp: 147 °C. Anal. Calcd

for C₃₃H₅₀O₆N₁₀P₄: C, 49.14; H, 6.25; N, 17.37. Found: C, 50.01; H,

6.48; N, 17.96. APIES-MS (fragments are based on ³⁵Cl, Ir %): m/z

808 ([M + 2H]⁺, 100). FTIR (KBr, cm⁻¹): ν 3066 (asymm), 3043

(symm, C−H arom), 2956, 2848 (C−H aliph), 1589 (CC), 1288

3

ArCH₂N), 46.43 (s, NCH₂), 27.43 (d, J_PC= 6.1 Hz, NCH₂CH₂),

23.44 (s, NCH₂CH₂CH₂).

sas 2c. A solution of pyrrolidine (0.60 mL, 6.80 mmol) in dry THF

(50 mL) was slowly added to a stirred solution of triethylamine (0.40

mL) and 2a (0.40 g, 0.70 mmol) in dry THF (100 mL) at room

temperature. The solution was heated to reﬂux for 12 h under an

argon atmosphere. The precipitated triethylamine hydrochloride was

ﬁltered oﬀ, and the solvent was evaporated. The product was puriﬁed

by column chromatography with toluene−THF (1:1), and a white

powder was crystallized from acetonitrile−THF (3:1). Yield: 0.36 g

(73%). Mp: 203 °C. Anal. Calcd for C₃₂H₄₈O₂N₁₀P_{4 .}H₂O: C, 51.43;

H, 6.70; N, 18.75. Found: C, 51.81; H, 6.39; N, 18.11. APIES-MS

(fragments are based on ³⁵Cl, Ir %): m/z 729 ([MH]⁺, 100). FTIR

(KBr, cm⁻¹): ν 3415 (O−H), 3064 (asymm), 3039 (symm, C−H

arom), 2958, 2864 (C−H aliph), 1581 (CC), 1295 (asymm), 1180

(symm, PN), 571 (asymm), 503 (symm, PCl). ¹H NMR (500 MHz,

toluene, ppm): δ 6.93 (m, 4H, H₄, H₅), 6.77 (m, 4H, H₂, H₃), 3.54

1

(asymm), 1184 (symm, PN), 538 (asymm), 489 (symm, PCl). H

NMR (500 MHz, CDCl₃, ppm): δ 7.26 (m, 2H, H₄), 7.06 (m, 2H,

H₂), 6.98 (m, 2H, H₃), 6.95 (m, 2H, H₅), 4.43 (dd, 2H, ²J_HH= 9.4 Hz,

³J_PH= 15.2 Hz, ArCH₂N), 4.25 (dd, 2H, ²J_HH= 9.3 Hz, ³J_PH= 15.1 Hz,

ArCH₂N), 3.72 [t, 16H, NCH₂CH₂(mor)], 3.40, 3.25 [m, 4H, NCH₂

(ansa)], 3.12 [m, 16H, NCH₂(mor)], 1.82, 1.63 [m, 2H, NCH₂CH₂

2

(ansa)]. ¹³C NMR (500 MHz, CDCl₃, ppm): δ 151.43 (d, J_PC= 4.7

3

Hz, C₆), 128.25 (s, C₄), 126.69 (s, C₂), 123.56 (t, J_PC= 8.4 Hz, C₁),

3

122.34 (s, C₃), 119.03 (d, J_PC= 8.6 Hz, C₅), 67.42 [t, J_PC= 9.8 Hz,

NCH₂CH₂(mor)], 50.39 (s, ArCH₂N), 45.91 [s, NCH₂(ansa)],

45.23, 45.12 [s, NCH₂(mor)], 30.37 [s, NCH₂CH₂(ansa)].

asa 3c. The workup procedure was similar to that of compound 2c,

using 3a (0.80 g, 1.35 mmol), pyrrolidine (1.10 mL, 13.50 mmol), and

triethylamine (0.80 mL). The oily residue was puriﬁed by column

chromatography with benzene−THF (1:1) and crystallized from

acetonitrile−THF (3:1). Yield: 0.76 g (85%). Mp: 308 °C. Anal. Calcd

for C₂₄H₃₂O₂N₈P₄Cl₂: C, 43.72; H, 4.89; N, 16.99. Found: C, 44.39;

H, 5.00; N, 16.48. APIES-MS (fragments are based on ³⁵Cl, Ir %): m/z

659 ([MH]⁺, 100). FTIR (KBr, cm⁻¹): ν 3072 (asymm), 3029 (symm,

C−H arom), 2955, 2857 (C−H aliph), 1582 (CC), 1272 (asymm),

1177 (symm, PN), 549 (PCl). ¹H NMR (500 MHz, CDCl₃, ppm):

δ 7.36 (m, 4H, H₄and H₅), 7.19 (m, 4H, H₂and H₃), 4.68 (dd, 2H,

(dd, 2H, ²J_HH= 10.7 Hz, ³J_PH= 14.7 Hz, ArCH₂N), 4.56 (d, 2H, ³J_PH

=

14.8 Hz, ArCH₂N), 3.08, 2.80 [m, 4H, NCH₂(ansa)], 3.22 [m, 16H,

NCH₂(pyrr)], 1.65 [m, 16H, NCH₂CH₂(pyrr)]. ¹³C NMR (500

2

MHz, CDCl₃, ppm): δ 151.59 (d, J_PC= 4.8 Hz, C₆), 127.86 (s, C₄),

126.58 (s, C₂), 122.96 (t, ³J_PC= 8.2 Hz, C₁), 121.86 (s, C₃), 118.78 (t,

³J_PC= 9.2 Hz, C₅), 53.43 (s, ArCH₂N), 52.27 [s, NCH₂(ansa)], 46.76,

3

46.65 [s, NCH₂(pyrr)], 26.59 [s, J_PC= 9.7 Hz, NCH₂CH₂(pyrr)].

sas 2d. The workup procedure was similar to that of compound 2c,

using 2b (0.50 g, 0.80 mmol), pyrrolidine (0.70 mL, 8.30 mmol), and

triethylamine (0.45 mL). The oily residue was puriﬁed by column

3

2

²J_HH= 14.8 Hz, J_PH= 15.1 Hz, ArCH₂N), 3.63 (dd, 2H, J_HH= 14.8

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Table 1. Crystallographic Details

2b

3a

3b

3e

4g

empirical formula

fw

C₁₇H₁₈Cl₄N₆O₂P₄

C₁₆H₁₆Cl₄N₆O₂P₄

590.03

C₁₇H₁₈Cl₄N₆O₂P₄

604.05

C₂₄H₃₂Cl₂N₈O₄P₄

691.36

C₁₈H₂₁Cl₅N₆O₂P₄

654.54

604.05

orthorhombic

Pbnm

cryst syst

space group

a (Å)

monoclinic

C2/c

orthorhombic

P2₁2₁2₁

9.9387(3)

11.7933(3)

20.7778(6)

90.00

monoclinic

P2₁/c

monoclinic

C2/c

9.4186(3)

12.1307(4)

21.1905(7)

90.00

23.3455(4)

8.4787(2)

24.5024(5)

90.00

14.6946(2)

8.7960(1)

23.8967(3)

90.00

18.241(3)

8.516(2)

35.359(5)

90.00

b (Å)

c (Å)

α (deg)

β (deg)

90.00

106.38(5)

90.00

98.723(1)

90.00

102.90(2)

90.00

γ (deg)

V (Å³)

90.00

2421.10(14)

4

4653.1(12)

8

2435.37(12)

4

3053.01(7)

4

5354.0(18)

8

Z

μ(Mo Kα) (cm⁻¹

ρ(calcd) (g/cm³)

no. of total reﬂns

)

7.83

8.13

7.79

4.69

8.12

1.657

1.684

1.647

1.504

1.624

3079

5803

5984

7594

6616

no. of unique reﬂns

R_int

2443

5133

5850

5683

5085

0.0353

56.74

0.0259

0.0191

0.0743

0.1097

2θ_max(deg)

56.68

56.66

57.58

T

_min/T_max

0.7990/0.8591

154

0.7264/0.8164

289

0.7407/0.8000

298

0.8346/0.9416

379

0.7643/0.8416

320

no. of param

R1 [F²>2σ(F²)]

wR2

0.0277

0.0706

0.0244

0.0210

0.0350

0.0483

0.0684

0.0555

0.0805

0.0914

Hz, ³J_PH= 15.3 Hz, ArCH₂N), 3.78, 2.96 [m, 4H, NCH₂(spiro)], 3.41,

3.26 [m, 8H, NCH₂(pyrr)], 1.91 [m, 8H, NCH₂CH₂(pyrr)]. ¹³C

and triethylamine (0.75 mL). The oily residue was puriﬁed by column

chromatography with benzene−THF (1:1) and crystallized from

acetonitrile. Yield: 0.70 g (74%). Mp: >320 °C. Anal. Calcd for

C₂₄H₃₂O₄N₈P₄Cl₂: C, 41.70; H, 4.67; N, 16.21. Found: C, 41.92; H,

4.61; N, 16.12. APIES-MS (fragments are based on ³⁵Cl, Ir %): m/z

691 ([MH]⁺, 100). FTIR (KBr, cm⁻¹): ν 3073 (asymm), 3029 (symm,

C−H arom), 2959, 2846 (C−H aliph), 1583 (CC), 1286 (asymm),

1179 (symm, PN), 538 (PCl). ¹H NMR (500 MHz, CDCl₃, ppm):

δ 7.37 (m, 4H, H₄and H₅), 7.21 (m, 4H, H₂and H₃), 4.64 (dd, 2H,

2

NMR (500 MHz, CDCl₃, ppm): δ 149.66 (d, J_PC= 5.7 Hz, C₆),

132.27 (s, C₂), 129.64 (s, C₄), 127.97 (t, ³J_PC= 7.2 Hz, C₁), 125.12 (s,

3

2

C₃), 123.56 (t, J_PC= 6.6 Hz, C₅), 46.40 [d, J_PC= 5.0 Hz, NCH₂

(pyrr)], 44.33 [d, ²J_PC= 11.6 Hz, NCH₂(spiro)], 43.51 (s, ArCH₂N),

26.52 [d, J_PC= 9.7 Hz, NCH₂CH₂(pyrr)].

3

Microwave-Assisted Synthesis of 3c. Pyrrolidine (1.10 mL,

13.50 mmol) in dry THF (50 mL) was slowly added to a stirred

solution of triethylamine (0.80 mL) and 3a (0.80 g, 1.35 mmol) in dry

THF (100 mL). The mixture was reﬂuxed for 0.50 h, and

triethylamine hydrochloride was ﬁltered oﬀ. THF was evaporated,

and the crude product was puriﬁed by column chromatography with

benzene−THF (1:1) and crystallized from acetonitrile−THF (3:1).

Yield: 0.85 g (95%).

Compound 3c was also synthesized in toluene and o-xylene. The

workup procedure was similar to that of the THF solvent, whereas the

mixture was reﬂuxed for 0.75 h in toluene [yield: 0.80 g (90%)] and in

o-xylene for 1 h [yield: 0.70 g (78%)].

asa 3d. The workup procedure was similar to that of compound 2c,

using 3b (0.80 g, 1.30 mmol), pyrrolidine (1.10 mL, 13.00 mmol), and

triethylamine (0.75 mL). The oily residue was puriﬁed by column

chromatography with THF and crystallized from acetonitrile−THF

(3:1). Yield: 0.74 g (83%). Mp: 302 °C. Anal. Calcd for

C₂₅H₃₄O₂N₈P₄Cl₂: C, 44.59; H, 5.09; N, 16.64. Found: C, 45.26; H,

5.13; N, 16.40. APIES-MS (fragments are based on ³⁵Cl, Ir %): m/z

673 ([MH]⁺, 100). FTIR (KBr, cm⁻¹): ν 3057 (asymm), 3030 (symm,

C−H arom), 2922, 2852 (C−H aliph), 1581 (CC), 1268 (asymm),

1176 (symm, PN), 544 (PCl). ¹H NMR (500 MHz, CDCl₃, ppm):

δ 7.35 (dd, 2H, H₄), 7.28 (d, 4H, H₂, H₅), 7.18 (dd, 2H, H₃), 4.81 (dd,

3

²J_HH= 8.9 Hz, J_PH= 15.3 Hz, ArCH₂N), 3.78, 3.72 [m, 8H,

2

3

NCH₂CH₂(mor)], 3.63 (dd, 2H, J_HH= 13.7 Hz, J_PH= 15.3 Hz,

ArCH₂N), 3.41, 3.28 [m, 8H, NCH₂(mor)], 3.24, 2.97 [m, 4H, NCH₂

2

(spiro)]. ¹³C NMR (500 MHz, CDCl₃, ppm): δ 149.40 (d, J_PC= 4.9

Hz, C₆), 132.18 (s, C₂), 129.93 (s, C4), 128.03 (t, ³J_PC= 7.4 Hz, C₁),

3

125.22 (s, C₃), 123.22 (t, J_PC= 6.9 Hz, C₅), 67.12 [t, J_PC= 9.2 Hz,

2

NCH₂CH₂(mor)], 44.77 (s, NCH₂(mor)], 44.37 [d, J_PC= 12.0 Hz,

NCH₂(spiro)], 43.41 (s, ArCH₂N).

asa 3f. The workup procedure was similar to that of compound 2e,

using 3b (0.70 g, 1.15 mmol), morpholine (1.00 mL, 11.50 mmol),

and triethylamine (0.65 mL). The oily residue was puriﬁed by column

chromatography with THF and crystallized from chloroform. Yield:

0.61 g (75%). Mp: 270 °C. Anal. Calcd for C₂₅H₃₄O₄N₈P₄Cl₂: C,

42.57; H, 4.86; N, 15.89. Found: C, 42.96; H, 4.88; N, 15.70. APIES-

MS (fragments are based on ³⁵Cl, Ir %): m/z 705 ([MH]⁺, 100). FTIR

(KBr, cm⁻¹): ν 3062 (asymm), 3037 (symm, C−H arom), 2954, 2846

(C−H aliph), 1583 (CC), 1288 (asymm), 1176 (symm, PN),

1

551 (PCl). H NMR (500 MHz, CDCl₃, ppm): δ 7.39 (t, 2H, H₄),

2

7.32 (t, 4H, H₂and H₅), 7.21 (t, 2H, H₃), 4.76 (dd, 2H, J_HH= 10.7

Hz, ³J_PH= 15.1 Hz, ArCH₂N), 3.78, 3.71 [m, 8H, NCH₂CH₂(mor)],

3.57 (dd, 2H, ²J_HH= 11.1 Hz, ³J_PH= 15.0 Hz, ArCH₂N), 3.36, 3.27 [m,

8H, NCH₂(mor)], 3.18, 3.08 [m, 4H, NCH₂(spiro)], 1.77 [m, 2H,

NCH₂CH₂(spiro)]. ¹³C NMR (500 MHz, CDCl₃₃, ppm): δ 149.16 (d,

²J_PC= 8.4 Hz, C₆), 131.34 (s, C₂), 130.31 (d, J_PC= 8.4 Hz, C₁),

129.12 (s, C₄), 125.25 (s, C₃), 122.81 (d, ³J_PC= 7.5 Hz, C₅), 66.92 [d,

2

3

2

2H, J_HH= 8.9 Hz, J_PH= 15.5 Hz, ArCH₂N), 3.56 (dd, 2H, J_HH

=

10.7 Hz, ³J_PH= 15.7 Hz, ArCH₂N), 3.33, 3.27 [m, 8H, NCH₂(pyrr)],

3.19, 3.10 [m, 4H, NCH₂(spiro)], 1.90 [m, 8H, NCH₂CH₂(pyrr)],

1.77 [m, 2H, NCH₂CH₂(spiro)]. ¹³C NMR (500 MHz, CDCl₃,

2

³J_PC= 9.6 Hz, NCH₂CH₂(mor)], 48.81 [d, J_PC= 4.7 Hz, NCH₂

ppm): δ 149.26 (d, ²J_PC= 8.4 Hz, C₆), 131.09 (s, C₂), 130.45 (t, ³J_PC

=

3

(spiro)], 47.32 (s, ArCH₂N), 44.83 [s, NCH₂(mor)], 26.45 [d, ³J_PC

9.4 Hz, NCH₂CH₂(spiro)].

=

8.2 Hz, C₁), 129.42 (s, C₄), 125.23 (s, C₃), 122.91 (t, J_PC= 6.8 Hz,

C₅), 48.92 [s, NCH₂(spiro)], 47.28 (d, ²J_PC= 3.9 Hz, ArCH₂N), 46.52

2

3

[d, J_PC= 5.0 Hz, NCH₂(pyrr)], 26.48 [d, J_PC= 9.4 Hz, NCH₂CH₂

(pyrr)], 26.35 [d, J_PC= 7.4 Hz, NCH₂CH₂(spiro)].

X-ray Crystal Structure Determinations. The colorless crystals

of compounds 2b, 3a, 3b, 3e, and 4g were crystallized from

acetonitrile at room temperature. The crystallographic data are given

in Table 1, and selected bond lengths and angles are listed in Table 2.

3

asa 3e. The workup procedure was similar to that of compound 2e,

using 3a (0.80 g, 1.35 mmol), morpholine (1.20 mL, 13.60 mmol),

12845

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Inorganic Chemistry

Article

Table 2. Selected Bond Lengths (Å) and Angles (deg) for 2b, 3a, 3b, 3e, and 4g

2b

3a

3b

3e

4g

P1−N1

P1−N4

1.576(1)

1.594(1)

P1−N1

P1−N4

P2−N1

P2−N2

P3−N3

P3−N2

P4−N3

P4−N4

P1−N5

P2−N5

P2−N6

P3−N5

P3−N6

P1−Cl1

P3−Cl2

P4−Cl3

P4−Cl4

P4−Cl5

P2−Cl2

P2−Cl3

1.554(1)

1.579(1)

1.603(1)

1.576(1)

1.561(1)

1.564(1)

1.567(1)

1.546(1)

1.581(1)

1.610(1)

1.598(1)

1.575(1)

1.550(1)

1.566(1)

1.561(1)

1.565(1)

1.549(1)

1.598(1)

1.605(1)

1.555(1)

1.561(1)

1.593(1)

1.584(1)

1.577(2)

1.573(2)

1.544(2)

1.608(2)

1.640(2)

1.562(2)

1.551(2)

P4−N3

P4−N4

P1−N5

P2−N5

1.563(1)

1.560(1)

1.626(1)

1.645(1)

1.650(1)

1.633(1)

1.639(1)

1.649(1)

P3−N5

P3−N6

P4−Cl1

P4−Cl2

1.637(2)

1.612(2)

1.963(7)

1.999(6)

2.024(6)

2.009(5)

2.011(5)

2.009(5)

1.999(5)

2.024(5)

2.032(6)

2.009(6)

2.005(6)

2.029(7)

2.033(7)

2.022(8)

2.025(9)

2.033(8)

2.016(9)

N1−P1−N4

N5−P2−N6

N5−P3−N6

114.00(9)

N1−P1−N4

N5−P2−N6

N5−P3−N6

N1−P2−N2

N7−P4−N8

N2−P3−N3

N3−P4−N4

N5−P1−N1

N5−P2−N1

N6−P2−N2

N6−P2−N1

N5−P3−N3

N2−P3−N6

P3−N3−P4

P1−N1−P2

P3−N2−P2

P1−N4−P4

122.21(6)

95.49(7)

123.49(7)

104.65(7)

125.16(8)

95.05(8)

121.29(11)

103.42(9)

112.89(6)

112.44(7)

113.09(8)

102.80(8)

125.27(8)

117.64(8)

123.00(11)

N7−P4−N8

123.31(6)

121.89(7)

123.71(7)

122.29(8)

113.94(9)

N3−P4−N4

N5−P1−N1

N5−P2−N1

N6− P2− N2

122.57(10)

118.06(9)

121.69(10)

108.54(6)

115.91(6)

108.54(6)

110.97(7)

110.73(7)

110.59(7)

114.93(8)

114.55(8)

109.12(8)

N5−P3−N3

N2−P3−N6

P3−N3−P4

P1−N1−P2

106.98(9)

103.10(10)

129.99(12)

130.06(13)

133.64(12)

127.01(11)

141.37(14)

128.77(13)

129.34(9)

129.35(7)

128.27(8)

128.67(9)

129.52(10)

132.35(9)

134.27(9)

132.65(10)

131.01(11)

128.81(10)

128.15(10)

137.42(10)

P1−N4−P4

126.91(10)

SN¹(P) are written in the scheme. The reactions of N₄P₄Cl₈

with an equimolar amount of dipotassium salts,

(KOPhCH₂NH)₂R, of aminopodands (1a and 1b) aﬀord the

novel sas (2a and 2b) and asa (3a and 3b) tetrachlorocyclote-

traphosphazenes in THF, respectively (Scheme 1). On the

other hand, the reaction of N₄P₄Cl₈with an equimolar amount

of potassium salts of the long-chain starting compound (1g)

gives sas (2g) and the interesting bicyclo-2,6-as product (4g).

Hence, the formation of 4g indicates that the monopotassium

salt of 1g is present in the reaction mixture of 1g, K₂CO₃, and

N₄P₄Cl₈. However, the equimolar amount of the dipotassium

salt of the long-chain starting compound 1h produces only sas

(2h). The expected asa products of N₄P₄Cl₈with 1g and 1h

were not obtained in THF. If the alkyl chain lengths increase,

the sas compounds are the major products, whereas as the alkyl

chain lengths decrease, the asa derivatives are dominant. The

sas and asa products may occur competitively via SN²(P) or

SN¹(P) mechanisms. These compounds are the ﬁrst examples

of cyclotetraphosphazene derivatives with the bulky N₂O₂

donor-type aminopodands, while in the literature,^5athere is

only one bicyclo-2,6-as compound and one bicyclo-2,6-sas

Crystallographic data were recorded on a Bruker Kappa APEXII CCD

area-detector diﬀractometer using Mo Kα radiation (λ = 0.71073 Å) at

T = 100(2) K. Absorption corrections by multiscan³⁰were applied.

Structures were solved by direct methods and reﬁned by full-matrix

least squares against F²using all data.³¹All non-H atoms were reﬁned

anisotropically. In compound 4g, only the H atom of the OH group

was located in a diﬀerence Fourier synthesis and reﬁned isotropically

[O−H = 0.83(4) Å; U_iso(H) = 0.17(2) Å²]. The remaining H-atom

positions were calculated geometrically at distances of 0.93 Å (CH)

and 0.97 Å (CH₂) (for compounds 2b, 3b, and 4g) and 0.95 Å (CH)

and 0.99 Å (CH₂) (for compounds 3a and 3e) from the parent C

atoms; a riding model was used during the reﬁnement process, and the

U_iso(H) values were constrained to be 1.2U_eq(carrier atom).

RESULTS AND DISCUSSION

■

Synthesis. All aminopodands [(HOPhCH₂NH)₂R, where R

= (CH₂)_n, with n = 2 (1a), n = 3 (1b), n = 4 (1g), and n = 6

(1h)] have been prepared by the reduction of bis-

(iminopodands) (Schiﬀ bases) with the NaBH₄−borax

system.²⁹The tentative reaction pathways suggested for the

reactions of N₄P₄Cl₈with tetradentate ligands are given in

Scheme 2. The possible reaction mechanisms SN²(P) and/or

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Scheme 2. Tentative Reaction Pathways of N₄P₄Cl₈with Aminopodands in THF

compound obtained with spermidine and spermine, respec-

tively. Generally, the yields of asa products (3a and 3b) are

higher than those of sas products (2a and 2b). In addition, the

yields of both sas (2a and 2b) and asa (3a and 3b)

phosphazenes also depend on the chain lengths [R =

(CH₂)_n] of aminopodands. For instance, the yields of both

sas (2a, yield 22%) and asa (3a, yield 69%) products, which

have the smallest alkyl chains, R = (CH₂)₂, are higher than

those of sas (2b, yield 29%) and asa (3b, yield 63%) products,

R = (CH₂)₃. Parts a and b of Figure 1 depict the reaction

products of N₃P₃Cl₆and N₄P₄Cl₈with the tetradentate ligands

(1a and 1b) and 1g.

If the alkyl chains are (CH₂)₂and (CH₂)₃, sbs compounds^7a

are formed with N₃P₃Cl₆, but sbs compounds with N₄P₄Cl₈are

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Figure 1. Expected and observed distributions of the reaction products of N₃P₃Cl₆and N₄P₄Cl₈with N₂O₂donor-type aminopodands.

not observed, whereas for asa compounds, the reverse is true. It

is noteworthy that the reactions of both N₃P₃Cl₆and N₄P₄Cl₈

with these aminopodands (1a and 1b) produce sas compounds.

Compound 1g, which has the long alkyl chain (CH₂)₄, gives sas

and sbs compounds with N₃P₃Cl₆, while it produces sas (2g)

and bicyclo-2,6-as (4g) products with N₄P₄Cl₈.

increase, which can be attributed to the presence of the negative

hyperconjugation (see crystallographic part). This situation

might be related to the electronic properties of the nonreactive

P−Cl bonds. Contemporaneously, the lack of reactivity at P1−

Cl1 and P3−Cl2 presumably depends upon the steric eﬀect of

the substituents.

The reactions of the partly substituted sas (2a and 2b) and

asa (3a and 3b) phosphazenes with excess pyrrolidine and

morpholine in THF produce fully substituted sas [(2c and 2d)

and (2e and 2f)] and partly substituted gem-2-trans-6-

dichlorophosphazene asa [(3c and 3d) and (3e and 3f)]

derivatives, respectively (Scheme 1). The complete chloride

replacement of 2-trans-6-dichlorophosphazene asa (3c−3f)

compounds with excess pyrrolidine, morpholine, and sodium 4-

nitrophenoxide in boiling THF for 6 days was not achieved,

indicating that both Cl atoms are signiﬁcantly inert. The

chloride replacement reactions of 3a were carried out separately

in THF, toluene, and o-xylene by microwave-assisted experi-

ments. The use of microwave irradation for the preparation of

3c from 3a reduces the reaction time and increases the yield in

comparison with the conventional method. Even then, no fully

substituted products were obtained; instead, compound 3c was

isolated. The microwave-assisted reaction of 3c with excess

pyrrolidine did not yield fully substituted products. Con-

sequently, these Cl atoms in asa derivatives are highly resistant

to replacement reactions by the nucleophile. This may result

from both endocyclic P−N bond strengthening and steric

hindrance of the bulky N₂O₂donor-type aminopodands

bonded to 2,6-P atoms. The structural data of the asa

compounds (3a, 3b, and 3e) may support these statements.

The values of the P1−N1 and P3−N2 bond lengths are

1.554(1) and 1.561(1) Å for 3a, 1.546(1) and 1.550(1) Å for

3b, and 1.565(1) and 1.561(1) Å for 3e (Table 1). It could be

seen that these endocyclic P−N bonds are systematically short,

indicating that the electron densities on the P1 and P3 atoms

The synthetic results mentioned above demonstrate that the

choice of the tetradentate symmetric ligands is very important

because stereochemically controlled reactions can be achieved.

In other words, it is possible to arrange the conﬁgurations of

tetrahedral P atoms to form controlled stereogenic centers as

changing alkyl chain lengths of tetradentate symmetric ligands.

All of the compounds have two stereogenic P centers, as

discussed later on together with the NMR data of the

phosphazene derivatives. The phosphazene derivatives contain-

ing N atoms on the spiro or ansa rings have restricted rotation

around the P−N and C−N single bonds, leading to

atropisomerism, a stereochemical phenomenon^24ain which

hindered single-bond rotation leads to isolable stereoisomers.

Some of the phosphazene derivatives obtained in this study

may also have atropisomers.

Data obtained from the microanalyses FTIR, APIES-MS, and

¹H, ¹³C, and ³¹P NMR, DEPT, HSQC, and HMBC are

consistent with the proposed structures of the compounds. The

MS spectra of all of the compounds except 2f show the

protonated molecular (MH)⁺ion peaks, while a protonated

molecular [M + 2H]⁺ion peak is observed at m/z 808 for 2f.

The crystal structures of 2b, 3a, 3b, 3e, and 4g are also

determined by X-ray crystallography. To the best of our

knowledge, there are no reports on the tetrameric sas, asa, and

bicyclo-2,6-as compounds that have been characterized

structurally by spectroscopic and/or X-ray diﬀraction techni-

ques. Spectral and crystallographic data of the compounds are

presented in the following.

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NMR and IR Spectroscopy. The spin systems of

tetrameric phosphazenes indicate that two kinds of novel

tetrameric phosphazene derivatives, namely, sas (2a−2h) and

asa (3a−3f), have been prepared, whereas the other expected

products such as sbs and di(spiro-bino-spiro) [di(sbs)] have

not been obtained (Figure 1).

three Cl atoms in N₄P₄Cl₈to give 4g (Figure 2). These results

indicate that monopotassium and dipotassium salts of 1g are

present in the reaction mixture.

The P atoms of some of the compounds obtained in this

study are stereogenic because they have four diﬀerent

substituents. The sas phosphazene derivatives (2a−2h) having

two equivalent stereogenic P atoms are considered to be only in

the meso form because the compounds have symmetric

structures. The asa phosphazene derivatives (3a−3f), which

have trans structures according to Cl atoms, also have two

stereogenic P atoms. They are expected to be in the racemic

form. However, compound 3b has one enantiomer, as shown

by the X-ray structural data, and 3f is a racemic mixture,

according to the chiral HPLC and CSA experiments.

Compound 4g, having two stereogenic P atoms, is expected

to exist as two enantiomers. Table 4 shows stereoisomeric

assignments for compounds 2b, 3a, 3b, 3e, 3f, and 4g studied

as examples.

As expected, the ¹H-decoupled ³¹P NMR spectra of sas (2a−

2h) derivatives exhibit A₂X₂(A₂B₂for 2d) type spectra because

of two diﬀerent phosphorus environments within the molecules

1

(Figure 2). The H-decoupled and -coupled ³¹P NMR spectra

Compounds 2a−2h could have racemic and meso forms.

However, the only meso forms can form because the

compounds have symmetric structures. On the other hand,

4g having two stereogenic P atoms is expected to exist as two

enantiomers. According to Table 4, compounds 3a−3f may

have racemate (trans) and meso (cis) forms. However, the

structure of 3b is crystallized in the noncentrosymmetric space

group P2₁2₁2₁, meaning that there is only one enantiomer in

the unit cell (Table 1). The Flack absolute structure

parameter³²of 3b is reﬁned; the expected values are 0.00 for

the correct and +1.00 for the inverted absolute structure. The

reﬁned value is 0.03(3). So, the absolute structure (SS) is

determined reliably. Because of the presence of the stereogenic

centers in all of the phosphazene derivatives, one would expect

the occurrence of diastereomers that should give rise to

distinguishable NMR signals. Table 3 lists only a single set of

signals. The stereogenic properties of the phosphazene

derivatives may be determined by ³¹P NMR spectroscopy in

the presence of CSA. The ³¹P NMR signals of the stereogenic

compounds may split into two lines, indicating that they exist as

racemates.^8bThe stereogenic property of 3f is determined by

³¹P NMR spectroscopy in the presence of CSA using the

literature procedure.^9a,33As an example, the ³¹P NMR spectrum

of 3f is depicted in Figure 3. In the presence of CSA, the ³¹P

NMR signals of 3f split into two lines (for δ PNN_mor),

indicating that it exists as a racemate. Upon titration with CSA,

the chemical shifts change as a result of the equilibrium

between the compound and its ligand-complexed form, and the

changes (in ppb) at a mole ratio of CSA−compound of 10:1

are listed in Table 5.

The HPLC method was used for characterization of the

racemic (trans) form of 3f. The sample is dissolved in hexane−

THF (1:2) at a concentration of 10 μg/mL. The separation is

made at room temperature. The peak of the solvent front is

considered to be equal to the dead time. It is about 2.02 min at

a ﬂow rate of 1.5 mL/min. There is resolution of 3f with a

separation factor of 1.04 in using a mobile phase containing

96% hexane−4% THF. As expected, there are two peaks for 3f.

The peaks for the compound separate into two peaks of the

ratio of 1:2 intensity corresponding to the two enantiomers.

The peak area of one isomer is 33.1%, and the other one is

66.9%, indicating that both isomers (RR and SS) do not form

equally. The HPLC chromatogram of 3f is presented in Figure

S4 in the SI. The racemate (3f) in two enantiomers is eluted at

25.993 and 26.925 min. The chromatographic conditions for

Figure 2. Spatial views of all of the compounds based on the ORTEP

diagrams of 2b, 3a, 3b, 3e, and 4g.

of 2a are depicted in Figure S1a,b in the SI, respectively, as

1

examples. One of the multiplets (δ 2.59 ppm) at the H-

coupled ³¹P NMR spectrum is broadened, which indicates the

existence of the δ OPN (P_A) P atoms. The δ P and coupling

constant (²J_PP) values of the other sas derivatives are assigned

as 2a (Table 3). The chemical shifts of spiro and PCl₂values of

2b and 2h are −0.95 and 0.01 and −2.62 and −3.59 ppm,

respectively, and the P spiro values are more downﬁeld in

contrast to that of 2a, but PCl₂values are opposite. It is

2

noteworthy that the J_PPvalues for 2a and 2b are considerably

lower than the corresponding values in the other sas

compounds (2c−2f).

The asa isomers (3a−3f) having three diﬀerent phosphorus

environments (Figure 2) display the A₂BC (for 3b), ABX₂(for

3e and 3f), and AB₂X (for 3a, 3c, 3d, and 4g) spin systems

1

consisting of three multiplets at the H-decoupled ³¹P NMR

spectra. As examples, the ¹H-decoupled and -coupled ³¹P NMR

spectra of 3f are depicted in parts a and b of Figure S2 in the SI,

respectively. All of the P atoms are unambiguously

1

distinguished from the H-coupled ³¹P NMR spectrum of 3f,

showing three sets of multiplets corresponding to the P spiro

(P_A), POCl (P_X), and P(mor)₂(P_B) groups. The δ P and

coupling constant (²J_PP) values of the other asa derivatives are

also assigned as 3f (Table 3).

Parts a and b of Figure S3 in the SI indicate that the reactions

of 1g, K₂CO₃, and N₄P₄Cl₈produce two kinds of products, sas

(2g) and bicyclo-2,6-as (4g). Both compounds are separated

using column chromatography (Figure S3c,d in the SI).

Compound 2g has a A₂X₂spin system, but the ³¹P NMR

spectrum (AB₂X spin system) of 4g possessing three sets of

triplets corresponding to the P spiro (P_A), POCl (P_X), and PCl₂

(P_B) groups is depicted in Figure S3d in the SI. One of the

1

triplets (δ 8.11 ppm) at the H-coupled ³¹P NMR spectrum is

broadened, which indicates the existence of the δ PNN P atom

and that the signals of the POCl (δ 5.61 ppm) and PCl₂groups

(δ 4.81 ppm) remain unchanged. The ¹H-decoupled ³¹P NMR

spectrum of 4g shows that the potassium salts of 1g replace

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a

Table 3. ³¹P NMR (Decoupled) Spectral Data of the Compounds

δ (ppm)

PCl₂

compound

spin system

OPN

NPN

POCl

²J_PP(Hz)

2a

2b

2c

2d

2e

2f

A₂X₂

A₂B₂

A₂X₂

AB₂X

2.59

−0.95

7.08

−4.42

−2.62

²J_AX= 16.5

²J_AX= 19.5

²J_AX= 33.4

²J_AB= 37.5

²J_AX= 37.2

²J_AX= 39.7

²J_AX= 37.0

²J_AX= 44.3

²J_AB= 49.6

²J_BX= 44.2

²J_AB= 56.8

²J_BC= 38.4

²J_AB= 65.0

²J_BX= 51.8

²J_AB= 58.0

²J_BX= 48.1

²J_AX= 42.3

²J_BX= 29.1

²J_AB= 59.9

²J_BX= 55.0

²J_AX= 29.1

²J_BX= 28.0

12.02

4.18

4.46

7.70

6.12

4.95

4.37

2g

2h

3a

6.42

1.76

−3.59

3.44

0.01

12.11

4.32

−1.03

6.02

3b

3c

3d

3e

3f

A₂BC

AB₂X

ABX₂

AB₂X

−0.31

−1.44

12.41 (spiro)

4.24 (pyrr)

2.53 (spiro)

−0.72 (pyrr)

12.33 (spiro)

6.85 (mor)

4.57 (spiro)

−0.45 (mor)

8.11

1.14

12.12

1.33

4g

4.81

5.61

a

Chemical shifts (δ) are reported in ppm and J values in Hz. ³¹P NMR measurements for 3b in CD₃CN, for 2c in toluene, and for other compounds

in CDCl₃solutions at 293 K.

2

HPLC resolution of trans (3f) and the obtained results are

presented in Table S1 in the SI. Additionally, this compound is

the ﬁrst example of tetrameric phosphazene derivatives, with

chirality conﬁrmed by ³¹P NMR/CSA and chiral HPLC

methods.

The two bond-coupling constants, J_PNC, for the NCH₂

carbons of the ﬁve-membered spiro rings of asa (3a, 3c, and

3e) compounds are in the ranges of 11.6−12.0 Hz. However,

the corresponding values for the asa compounds with the six-

membered spiro rings (3b and 3d), except 3f (²J_PNC= 4.7 Hz),

1

2

The H and ¹³C NMR signals of both sas (2a−2h) and asa

are not observed. Furthermore, the J_PNCvalues for NCH₂

(3a−3f) derivatives are assigned on the basis of chemical shifts,

multiplicities, coupling constants, and DEPT spectra. The

signals of nonprotonated C atoms of 3d disappear in the DEPT

carbons of ansa rings of sas (2a−2f) derivatives are not also

observed. This situation may depend on the size of the rings.

The average values of ³J_PNCCfor the NCH₂CH₂carbons of asa

(3b, 3d, and 3f) derivatives are 8.4 Hz (for spiro rings), 9.6 Hz

(for pyrrolidine rings), and 9.4 Hz (for morpholine rings),

while the corresponding values of NCH₂CH₂carbons of ansa

rings for the sas compounds are not observed. The δ shifts of

aromatic C₁, C₂, C₃, C₄, and C₅carbons of all of the asa (3a−

3f) compounds are larger than those of the corresponding sas

(2a−2f) derivatives, while the δ shifts of aromatic C₆carbons

1

135 spectrum (Figure S5a in the SI) compared with the H-

decoupled ¹³C NMR spectrum (Figure S5b in the SI). The

assignments are made unambiguously by HSQC using values

corresponding to ¹J_CHand by HMBC using values correspond-

2

3

4

ing to J_CH, J_CH, and J_CHbetween the protons and carbons

(Table S2 in the SI). The HMBC and HSQC spectra of 3e are

illustrated in Figure S6a,b in the SI, as examples of asa (3a−3f)

phosphazene derivatives. In light of the ¹H and ¹³C NMR data,

sas (2a−2h) and asa (3a−3f) compounds seem to have

symmetric structures in solution. The X-ray crystallographic

data of 2b conﬁrm its symmetric structure, but 3a, 3b, and 3e

do not have symmetric structures in the solid state.

3

are in the opposite direction. In addition, the J_PNCCvalues of

aromatic C₁and C₅carbons of all of the sas derivatives are

larger than those of the corresponding asa derivatives. The

average values of C₁and C₅carbons are 8.5 and 8.4 Hz for sas

derivatives and 7.6 and 6.9 Hz for asa derivatives, respectively,

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Table 4. Theoretical Stereoisomer Distributions and Expected Geometrical Isomers of Compounds 2b, 3a, 3b, 3e, 3f, and 4g

a

steroisomers (2ⁿ)

b

compound

2b

stereogenic P atoms (n)

(expected)

chirality (expected)

chirality (found)

geometrical isomer

O1O1 (cis)

2

1

2

3

4

1

2

3

4

1

2

3

4

1

2

3

4

RR

racemic (lines 1/4)

meso (lines 2 = 3)

RS

SR

SS

3a, 3e, and 3f

RR

RS

SR

SS

racemic (lines 1/4)

meso (lines 2 = 3)

racemic (lines 1/4)

enantiomer (line 4)

Cl1Cl2 (trans)

3b

4g

RR

RS

SR

SS

racemic (lines 1/4)

meso (lines 2 = 3)

RR

RS

SR

SS

enantiomer 1 (lines 1/4)

enantiomer 2 (lines 2/3)

a

b

P(OArN) and P(ArOCl) as labeled R/S for 2b, 3a, 3b, 3e, and 3f, respectively, and P(ArOCl) and P(NRN) as labeled R/S for 4g. Cis/trans

isomerism is labeled explicitly according to Figures 4−8.

Figure 3. (a) ¹H-decoupled ³¹P NMR spectrum of 3f. (b) Addition of CSA at ca. 10:1 mol ratio showing the doubling of P_Bsignals, indicating the

characteristics of the racemate.

2

whereas the J_PNCvalues of aromatic C₆carbons are in the

reverse direction; e.g., the average values of C₆carbons are 4.9

Hz [for sas (2a−2f)] and 6.2 Hz [for asa (3a−3f)].

Additionally, the expected 18 carbon signals of 4g are

unambiguously assigned from the ¹³C NMR spectrum. The

²J_PNCvalues of benzylic OArCH₂N and C₆carbons are found to

be 6.0, 4.7, and 12.1 Hz, respectively. These values are much

larger than those of sas and asa derivatives. The ⁴J_PNCCCvalues

of aromatic C₂and C₂′ carbons are also found to be 2.1 and 2.2

Hz for 4g.

peak groups is in the ranges of δ 4.62−4.32 ppm for sas (2a−

2f) and 4.81−4.62 ppm for asa (3a−3f) compounds, whereas

the other is in the ranges of δ 4.25−4.01 ppm for sas (2a−2f)

and 3.71−3.56 ppm for asa (3a−3f) compounds. As expected,

the benzylic protons give rise to an ABX spin system because of

the geminal proton−proton coupling and vicinal coupling with

the ³¹P nucleus, except 2g, 2h, and 4g. The compounds 2g, 2h,

and 4g probably do not exhibit atropisomerism. The large ansa

rings (the long alkyl chains in the ansa rings) allow for rotations

and lead to enantioconversion at ambient temperatures. Thus,

the peaks of benzylic protons are observed as doublets only for

2g, 2h, and 4g. The average ²J_HHand ³J_PHcoupling constants of

the compounds sas (2a−2g) and asa (3a−3f) phosphazenes,

which have ABX spin systems, are 9.9 and 15.4 Hz and 11.6 and

15.3 Hz, respectively. The δ shift and ³J_PHcoupling constant of

benzylic ArCH₂of 2h are 4.34 ppm and 14.8 Hz. The benzylic

HOArCH₂N and OArCH₂N protons of 4g are observed at 4.32

1

The H NMR spectra of sas (2c−2f) compounds indicate

that four substituents (pyrrolidine or morpholine) are bonded

to P atoms, whereas only two substituents (pyrrolidine or

morpholine) are bonded to P atoms in asa (3c−3f) derivatives.

1

All of the phosphazene derivatives give very complex H NMR

spectra because all of the aliphatic protons are diastereotopic.

The diastereotopic benzylic ArCH₂protons are separated from

each other and can be distinguished undoubtedly. One of the

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Table 5. ³¹P NMR Parameters of Compound 3f and the

a

Eﬀect of CSA on the ³¹P NMR Chemical Shifts

δ (ppm)

compound

>P(NN)

>P(OCl)

J_PP(Hz)

(i) ³¹P NMR Chemical Shifts (ppm) and Geminal PNP Coupling Constants

(Hz)

3f

4.57 (spiro)

1.33

²J_PP= 59.9

²J_PP= 55.0

−0.45 (mor)

(ii) Eﬀect of CSA on the ³¹P NMR Chemical Shifts (ppb) at a 10:1 Mole Ratio

3f

75 (spiro)

45 (mor)

22

²J_PP= 60.3

²J_PP= 54.4

(iii) Separation of the Enantiomeric Signals (ppb) at a 10:1 Mole Ratio of

CSA−Molecule

3f

b (spiro)

b

Figure 5. ORTEP-3⁴²drawing of 3a with the atom-numbering

scheme. Displacement ellipsoids are drawn at the 30% probability

level.

57 (mor)

a

b

³¹P NMR measurements in CDCl₃solutions at 293 K. Magnitude of

the eﬀect too small to observe up to a 10:1 mole ratio.

ppm (³J_PH= 12.5 Hz) and 4.24 ppm (³J_PH= 8.6 Hz) as

doublets.

The characteristic ν_N−Hbands of aminopodands (1a, 1b, 1g,

and 1h) at 3276, 3289, 3291, and 3293 cm⁻¹, respectively, are

not present in the FTIR spectra of the cyclotetraphosphazenes.

The tetrachloro- and pentachlorocyclotetraphosphazenes ex-

hibit strong absorption frequencies in the ranges of 1313−1262

and 1186−1166 cm⁻¹ascribed to ν_PNbands of phosphazene

rings.³⁴The asymmetric and symmetric vibration bands of PCl₂

are observed in the ranges of 576−538 and 503−476 cm⁻¹,

respectively. The FTIR spectra of the sas (2a−2f) and asa

(3a−3f) phosphazenes exhibit two medium-intensity absorp-

tion signals between 3092 and 3057 cm⁻¹and between 3043

and 3019 cm⁻¹attributed to the asymmetric and symmetric

stretching vibrations of the Ar−H bonds. Additionally, the ν_O−H

broadening band of 4g observed at 3327 cm⁻¹indicates

hydrogen bonding.

X-ray Structures of 2b, 3a, 3b, 3e, and 4g. The X-ray

structural determinations of these compounds conﬁrm the

assignments of their structures from spectroscopic data. The

molecular and solid-state structures of 2b, 3a, 3b, 3e, and 4g

along with the atom-numbering schemes are depicted in

Figures 4−8, respectively. The asymmetric unit of compound

2b contains only half a molecule, while the asymmetric units of

the remaining compounds contain one crystallographically

Figure 6. ORTEP-3⁴²drawing of 3b with the atom-numbering

scheme. Displacement ellipsoids are drawn at the 30% probability

level.

Figure 7. ORTEP-3⁴²drawing of 3e with the atom-numbering

scheme. Displacement ellipsoids are drawn at the 30% probability

level.

Figure 4. ORTEP-3⁴²drawing of 2b with the atom-numbering

scheme. Displacement ellipsoids are drawn at the 30% probability

level.

independent molecule. The four P atoms of 2b, 3a, 3b, 3e, and

4g are noncoplanar, and the four N atoms are displaced above

(+) and below (−) their best least-squares planes through the P

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N5/C7/C1/C6/O1) rings is not planar, having total puckering

amplitudes, Q_T,³⁵of 1.187(1) Å (for the tetrameric N₄P₄ring)

and 1.509(1) Å (for the ansa ring) [Figure S12a,b in the SI].

The seven-membered ring (P3/N5/C8/C9/C10/C11/N6) has

a twisted conformation with a total puckering amplitude, Q_T, of

1.317(3) Å (Figure S12c in the SI).

In the phosphazene rings, the endocyclic P−N bond lengths

are in the ranges of 1.560(1)−1.594(1) Å (for 2b), 1.554(1)−

1.603(1) Å (for 3a), 1.546(1)−1.610(1) Å (for 3b), 1.549(2)−

1.605(2) Å (for 3e), and 1.544(2)−1.640(2) Å (for 4g) (Table

2). The average endocyclic P−N bond lengths in tetrameric

phosphazene rings are 1.573(1), 1.576(1), 1.573(1), 1.576(2),

and 1.575(1) Å, which are shorter than the average exocyclic

P−N bond lengths of 1.614(1), 1.645(1), 1.641(1), 1.644(2),

and 1.624(2) Å for 2b, 3a, 3b, 3e, and 4g, respectively. In

phosphazenes, the P−N single and double bonds are generally

in the ranges of 1.628−1.691 and 1.571−1.604 Å, respec-

tively,³⁶and they are among the most intriguing bonds in

phosphazene chemistry. Recently, natural bond orbital (NBO)

and topological electron density analyses are used to investigate

the electronic structures of phosphazenes.³⁷The most likely

phosphazene bonding alternatives, namely, negative hyper-

conjugation and ionic bonding, were evaluated using NBO.

Ionic bonding was found to be the dominant feature, and the

multiple-bond character could be attributed, in part, to the

presence of negative hyperconjugation.^4e,38

As can be seen from Table 2, the P−N−P bond angles of 2b,

3a, 3b, 3e, and 4g are in the ranges of 126.91(10)−

141.37(14)°, 128.27(8)−129.35(7)°, 129.52(10)−134.27(9)°,

128.15(10)−137.42(10)°, and 127.01(11)−133.64(12)° [the

average value is 131.0(1)°]. The P−N−P bond angles of 3a are

almost the same, but the others are spread. In the literature,^4b,39

similar spreads of P−N−P angles were found in some

phosphazene derivatives. The variations in the endocyclic N−

P−N bond angles are also very large, ranging from 114.00(9)°

to 122.57(10)° (for 2b), from 112.89(6)° to 123.31(6)° (for

3a), from 112.44(7)° to 123.71(7)° (for 3b), from 113.09(8)°

to 125.27(8)° (for 3e), and from 113.94(9)° to 123.00(11)°

(for 4g) with an average value of 119.82(8)°. The endocyclic

N−P−N bond angles (for P atoms containing spiro

substituents) are much aﬀected by the N₂O₂donor-type

tetradentate ligands (1a−1d) bonded to the P atoms [average

value is 113.27(8)°], while the exocyclic N−P−N bond angles

are less aﬀected compared to the corresponding angle in the

standard compound, N₄P₄Cl₈. In N₄P₄Cl₈, the endocyclic N−

P−N and P−N−P and exocyclic Cl−P−Cl bond angles are

121.2°, 131.3°, and 102.8°.⁴⁰The variations of the P−N−P and

N−P−N angles of 2b, 3a, 3b, 3e, and 4g may reﬂect the steric

hindrances of the bulky side groups and could be ascribed to

the substituent-dependent charges at the P centers and negative

hyperconjugation.^4e,37,38

Figure 8. ORTEP-3⁴²drawing of 4g with the atom-numbering

scheme. Displacement ellipsoids are drawn at the 30% probability

level. The hydrogen bond is shown as a dashed line.

atoms by the following distances: N1 + 0.0000(1), N3 +

0.0000(1), N4 − 2.0883(1), and N4′ + 2.0894(1) for 2b, N1 +

0.614(1), N2 − 0.667(1), N3 + 0.571(1), and N4 − 0.531(1)

for 3a, N1 − 0.553(1), N2 + 0.554(1), N3 − 0.532(1), and N4

+ 0.484(1) for 3b, N1 + 0.635(2), N2 − 0.639 (1), N3 +

0.543(2), N4 − 0.316(2) for 3e and N1 + 0.090(2), N2 −

0.546(2), N3 + 0.354(2), N4 − 0.375(2) for 4g. The

conformation of the macrocyclic phosphazene rings are

depicted by the torsion angles of the ring bonds (Figure S7

in the SI). Compound 2b consists of a centrosymmetric

nonplanar cyclic tetrameric phosphazene ring in a sofa (chair)

conformation (Figures S8a in the SI) with the tetradentate

ligand (1b) bonded to the P atoms in a spiro-ansa-spiro (2,4-

sas) fashion, while the crystal structures of 3a, 3b, and 3e

indicate that the tetradentate ligands (1a and 1b) are bonded to

the P atoms in an ansa-spiro-ansa (2,4,6-asa) fashion and the

Cl atoms bonded to the P1 and P3 atoms in a trans fashion. In

addition, compound 4g consists of a bicyclo-2,6-as structure.

In 2b, the bicyclic part (Figure S8a,b in the SI) is made up of

eight-membered tetrameric N₄P₄and ansa (N1/P1/N5/C8/

C9/C8′/N5′/P1′) rings fused by a common PNP fragment.

The tetrameric N₄P₄ring is in a sofa conformation, but the ansa

ring is in a crown conformation. The six-membered spiro [(P1/

O1/C6/C1/C7/N5) and (P1′/O1′/C6′/C1′/C7′/N5′)] rings

are in twisted-boat conformations [Figure S8c in the SI; Q_T=

2.424(2) Å, φ₂= 91.17(3)°, and θ₂= 90.69(8)°]. In 3a, 3b, and

3e, the tricyclic parts (Figures S9b, S10b, and S11b in the SI)

are made up of three eight-membered rings, which are not

planar, having total puckering amplitudes, Q_T,³⁵of 1.206(1) Å

(for the tetrameric N₄P₄ring of 3a), 1.379(4) Å [for the ansa

(P1/N1/P2/N5/C7/C1/C6/O1) ring of 3a], 3.607(2) Å [for

the ansa (P3/N2/P2/N6/C10/C11/C16/O2) ring of 3a],

1.088(1) Å [for the tetrameric N₄P₄ring of 3b], 1.073(2) Å

[for the ansa (P1/N1/P2/N5/C7/C1/C6/O1) ring of 3b],

3.644(2) Å (for the ansa (P3/N2/P2/N6/C11/C12/C17/O2)

ring of 3b], 1.089(1) Å (for the tetrameric N₄P₄ring of 3e),

1.352(2) Å [for the ansa (P1/N1/P2/N5/C7/C1/C6/O1)

ring of 3e], and 2.756(4) Å (for the ansa (P3/N2/P2/N6/

C10/C11/C16/O2) ring of 3e]. In 3a and 3e, the ﬁve-

membered spiro rings (P2/N5/C8/C9/N6) are in twisted

conformations (Figure S9c in the SI for 3a and Figure S11c in

the SI for 3e). In 3b, the six-membered spiro ring is in a chair

conformation [Figure S10c in the SI; Q_T= 0.749(5) Å, φ₂=

−21.1(1)°, and θ₂= 140.2(1)°]. In 4g, the bicyclic system

made up of phosphazene and the ansa (P1/N4/P4/N3/P3/

Moreover, compound 4g consists of a bicyclo-2,6-as

structure with an intramolecular O2−H2A···N2 hydrogen

bond (Figure 8).⁴¹The C−H···π contacts in compounds 3a,

3b, and 3e may further stabilize the structure (Table S3 in the

SI).

Antimicrobial Activities. The tetrapyrrolidinocyclotetra-

phosphazene derivatives (2c and 2d) exhibit weak antibacterial

activity against (G+) bacterium, and racemic gem-2-trans-6-

dichloropyrrolidinocyclotetraphosphazene derivatives (3c and

3d) show moderate antifungal activity against only Candida

tropicalis. The starting compound (N₄P₄Cl₈), pyrrolidine,

morpholine, 1a, 1b, 1g, and 1h are checked for the same

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bacteria and fungi. Morpholine and N₄P₄Cl₈exhibit weak

antibacterial activity against Pseudomonas aeroginosa (G−), 1b,

and N₄P₄Cl₈to Bacillus cereus (G+), 1b, to Escherichia coli

(G−), 1h, to Staphylococcus aureus (G+), 1g, to Bacillus subtilis

(G+). None of them shows antifungal activity. The results are

given in section S1 in the SI for comparison to the

cyclotetraphosphazene derivatives. The antifungal activity of

3c and 3d may have arisen from the whole structure of these

compounds.

Interaction with pBR322 Plasmid DNA and Restriction

Enzyme Digestion. Interactions of the starting compound

(N₄P₄Cl₈), pyrrolidine, morpholine, 1a, 1b, 1g, and 1h and

cyclotetraphosphazene derivatives 2a−2f and 3a−3f with

supercoiled pBR322 DNA were investigated using agarose gel

electrophoresis. Pyrrolidine, morpholine, 1a, 1b, 1g, and 1h

have no eﬀect on plasmid DNA except N₄P₄Cl₈. However, it

was observed that compounds 2e, 3c, and 3e are able to cleave

the DNA. The presence of the linear form III in the DNA−

compound mixtures indicates the conformational changes of

DNA. It is noteworthy that the covalent interactions may play

an important role in the changes. Moreover, restriction analyses

indicate that 2a−2f and 3a−3f compounds bind to GG of the

DNA except compound 2b and partly 2e (section S2 in the SI).

Further detailed studies of the long-chain aminopodands

with N₄P₄Cl₈are under investigation.

ASSOCIATED CONTENT

■

S

* Supporting Information

1

Additional ﬁgures giving H-decoupled and H-coupled ³¹P

NMR spectra of 2b, 3f, and 4g (Figures S1−S3), HPLC proﬁle

of compound 3f (Figure S4), the DEPT and ¹³C NMR spectra

of 3d (Figure S5), the HMBC and HSQC spectra of 3e (Figure

S6), the shape of the phosphazene rings in 2b, 4g, 3a, 3b, and

3e with torsion angles given (Figure S7), crystal ring

conformations (Figures S8−S12), X-ray crystallographic ﬁles

in CIF format for compounds 2b, 3a, 3b, 3e, and 4g,

chromatographic conditions for TLC and HPLC resolution of

racemic cyclotetraphosphazene derivative (3f) (Table S1), 2D

¹H−¹³C HSQC and HMBC correlations for compounds 2a, 2b,

2c, 3a, 3c, and 3e (Table S2), hydrogen-bond geometries

(Table S3), antimicrobial activities (section S1), and DNA and

compound interactions (section S2). This material is available

free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION

Corresponding Author

*E-mail: zkilic@science.ankara.edu.tr.

■

CONCLUSIONS

■

Notes

In summary, the reactions of N₄P₄Cl₈with the N₂O₂donor-

type tetradentate ligands (1a, 1b, 1g, and 1h) give two kinds of

novel sas (2a, 2b, 2g, and 2h) and asa (3a and 3b)

tetraphosphazene derivatives, which are the ﬁrst examples of

multihetereocyclic cyclotetraphosphazenes. The partly substi-

tuted sas (2a and 2b) compounds reacted with excess

pyrrolidine and morpholine in THF to produce tetrapyrrolidi-

nocyclotetraphosphazenes (2c and 2d) and tetramorpholino-

cyclotetraphosphazenes (2e and 2f). The reactions of partly

substituted asa (3a and 3b) derivatives with excess pyrrolidine

and morpholine in THF produce partly substituted gem-2-trans-

6-dicloropyrrolidinocyclotetraphosphazenes (3c and 3d) and

-morpholinocyclotetraphosphazenes (3e and 3f). The partly

substituted phosphazenes could be useful as precursors for

preparing unique mixed-substituent phosphazenes because the

chiral systems and biologically active materials exhibit chemo-

therapeutic or antibacterial activity behaviors. The fully

substituted phosphazenes (2c−2f) are possible ligating agents

for transition-metal cations. All of the compounds were fully

characterized by one- and two-dimensional NMR techniques,

where the compounds (2b, 3a, 3b, 3e, and 4g) have been

characterized crystallographically. From the NMR and X-ray

crystallographic results, it was shown that the stereogenic P and

N centers are likely to be generated using tetradentate

symmetric ligands. Moreover, atropisomerism may arise from

the restricted single-bond rotations about N atoms. The

investigations of the possible stable conformers of atropisomers

are an important topic for future research in our group. In 2a−

2h, which are symmetric structures, there are two stereogenic P

atoms and they are in meso form, while the interesting

compound 4g, which is accidentally obtained from the reaction

of N₄P₄Cl₈with 1g, has two stereogenic P atoms and is

expected to be in enantiomeric mixtures. On the other hand, in

3a−3f, there are also two stereogenic P atoms. X-ray

crystallographic data conﬁrm that 3b has one enantiomer

(SS). Additionally, the stereogenic property of 3f was

determined by ³¹P NMR spectroscopy in the presence of

CSA and chiral HPLC methods.

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

The authors thank the Scientiﬁc and Technical Research

Council of Turkey (Grant 211T019) and the Medicinal Plants

and Medicine Research Center of Anadolu University,

Eskisȩ hir, for use of their X-ray and NMR facilities. T.H. is

indebted to Hacettepe University, Scientiﬁc Research Unit

(Grant 0202602002), for their ﬁnancial support. L.A. grateful to

State Planning Organisation for ﬁnancial support for the

research (Grant No. 1998K121480). The authors acknowledge

Professor C. Allen for his helpful scientiﬁc discussions and

corrections.

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Phosphorus-nitrogen compounds. Part 24. Syntheses, crystal structures, spectroscopic and stereogenic properties, biological activities, and DNA interactions of novel spiro-ansa-spiro- and ansa-spiro-ansa- cyclotetraphosphazenes

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