Synthesis and properties of highly lipophilic phosphazene bases

Accepted Manuscript Synthesis and properties of highly lipophilic phosphazene bases Sigrid Selberg, Toomas Rodima, Märt Lõkov, Sofja Tshepelevitsh, Tõiv Haljasorg, Sahil Chhabra, Sandip A. Kadam, Lauri Toom, Signe Vahur, Ivo Leito PII: DOI: Reference:

S0040-4039(17)30479-3 http://dx.doi.org/10.1016/j.tetlet.2017.04.039 TETL 48831

To appear in:

Tetrahedron Letters

Received Date: Revised Date: Accepted Date:

16 February 2017 3 April 2017 11 April 2017

Please cite this article as: Selberg, S., Rodima, T., Lõkov, M., Tshepelevitsh, S., Haljasorg, T., Chhabra, S., Kadam, S.A., Toom, L., Vahur, S., Leito, I., Synthesis and properties of highly lipophilic phosphazene bases, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.04.039

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Graphical abstract

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Synthesis and properties of highly lipophilic phosphazene bases Sigrid Selberg, Toomas Rodima, Märt Lõkov, Sofja Tshepelevitsh, Tõiv Haljasorg, Sahil Chhabra, Sandip A. Kadam, Lauri Toom, Signe Vahur, Ivo Leito* Institute of Chemistry, University of Tartu, 14a Ravila Str, 50411 Tartu, Estonia

Abstract Twelve novel phosphazene bases (X-C6H4-N=N-C6H4-N=PR3) with an unusual combination of properties – high lipophilicity of both neutral and charged forms, lack of localized charges in the cations, and strong spectral changes upon protonation/deprotonation – were synthesized using the Staudinger reaction and characterized by UV-Vis spectra, pKa values and lipophilicities (logP values). The bases could potentially be useful as working agents in optical sensors and acid-base indicators for lipophilic membranes.

Keywords: phenylphosphazenes, lipophilicity, logP, pKa, Staudinger reaction.

*

Corresponding autor: e-mail: [email protected], phone: +372 5184 176.

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Introduction Recent efforts in the design of chemical sensors1,2 for applications in geology,3 oceanography,4 and molecular biology5–9 have led to a resurgence of interest in acid-base indicators with different combinations of properties (pKa value(s), spectral properties, lipophilicity). In specific applications polarity/hydrophilicity may be essential, as well as the ability of the indicator molecule to participate in specific interactions, primarily hydrogen bonding, with other molecules. On the other hand, in a number of applications it is desirable that the indicator molecule (in both forms) be non-polar and able to act as a “silent spectator”, not influencing the processes occurring in the system. For the latter property the indicator should have limited capability of specific interactions.2,10

Although a large number of acid-base indicators have been reported, the majority of available indicators have well-defined charged groups in at least one of their charge states. Furthermore, almost all indicators with a transition range in the basic (as opposed to acidic) region are polar molecules and in the deprotonated state have anionic groups with strong intermolecular interaction capabilities.

The aim of the current work was to create a family of indicators with a transition range in the basic region, which depending on substituents should have a wide range of possible pKa values (including high pKa values), low polarity (high lipophilicity) and, importantly, low capability to engage in specific intermolecular interactions. To ensure low polarity it was important that the compounds have (1) as lipophilic a structure as possible, (2) ionized forms that are singly charged (preferable charge patterns 0/+1 or -1/0) and (3) structures that allow for extensive charge delocalization (i.e. no well-defined charged centers are present in the ionized forms). Phosphazene11,12 structures allow the synthesis of 0/+1 charge type indicators which satisfy the above requirements. Phosphazenes are wellknown as strong bases but to the best of our knowledge have not been used in the design of indicators for basic media. Alkylated/arylated phosphazenes possess highly lipophilic charged forms because the charge is effectively delocalized in the phosphazene moiety and the many polar surface segments are sterically hindered by lipophilic alkyl/aryl groups.

Herein, we propose a family of phosphazene indicators 1a-3d with the core structure X-C6H4N=N-C6H4-N=PR3 (Scheme 1). The arylphosphazene structure is extended with the azo-group 3

in order to enhance its absorbance and shift the absorbance maximum to longer wavelengths. In each of the three series the number of phenyl and pyrrolidino groups attached to the phosphorus atom were varied. The relationships between the indicator structures and their basicities, spectral properties and lipophilicities have been investigated.

Results Synthesis of starting compounds 4-6 Compound 4, 4-azidoazobenzene, was synthesized according to the reaction (1) described by Kutonova and coworkers13–15 who showed that a variety of aromatic amines could be directly converted into the corresponding aromatic azides in high yields using a one-pot reaction.14

(1) The preparation of azides 5 and 6 according to reaction (1) were not successful; therefore they were synthesized using reaction (2).16 Ar NH2

NaNO2/HCl H2O, 0 °C

Ar N N Cl

NaN3 0 °C

Ar N3

Yield (%) 5 X = -NO2 64 6 X = -N(CH3)2 62

N2

NaCl

(2)

Synthesis of iminophosphoranes 1a-3d

Scheme 1. Synthesis of iminophosphoranes using the Staudinger reaction

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Iminophosphoranes 1a-3d, of which 11 have been synthesized for the first time, were synthesized using the Staudinger reaction (Scheme 1, see the ESI for detailed information). Compound 2a was previously reported by Katti and co-workers.16 The Kirsanov reaction, which is known to work with simpler phosphazenes,17 did not give the desired compounds. In most cases reaction of the azide with the trisubstituted phosphine in Et2O or CH2Cl2 proceeded at 0 °C, resulting in the visible elimination of nitrogen and direct formation of the corresponding iminophosphorane. In the case of tripyrrolidinophosphine, a higher temperature (50–60 °C) was required. The Staudinger reaction proceeds by nucleophilic attack of the phosphine at the terminal (γ) nitrogen of the azide to afford a phosphazide. The latter is usually not detectable and rapidly dissociates via a four-center transition state.17 We found that when an electron-withdrawing substituent (NO2) was on the azide and at least one electron-donating group (pyrrolidino) was on the phosphine (2b-d), then the phosphazide was stabilized by these substituents, the phosphazene did not form (or partially formed) and the phosphazide could be isolated. This was in line with earlier observations.13 The effect of electron-donating groups on the phosphine seems to be higher than the effect of the nitro group on the azide. The nitro group decreases the electron density on the α-nitrogen of the phosphazide and the pyrrolidino groups increases the electron density on the γ-nitrogen. As a result these effects jointly contribute to leveling of the formal bond order across the azido group, thereby contributing to the stability of the phosphazide. The phosphazide corresponding to 2d was obtained as the sole compound; it was stable enough to register UVVis spectra, but too labile to measure pKa and logP values. The phosphazide displayed absorbance in the visible spectral range and a shift of the absorbance band upon protonation of the neutral compound; absorption maxima of cationic/neutral form was 366/455 nm. The phosphazide corresponding to 1d was obtained as a mixture with compound 1d in a 3:2 ratio. In order to obtain the required iminophosphoranes 1d, 2d and 3d, the reaction conditions were optimized by increasing the temperature; higher temperature favors decomposition of the phosphazide forming the iminophosphorane. Table 1. Properties of the synthesized iminophosphoranes. Comp

mp (°C)

ound

1a

167.6–168.4

λmax (nm)

pKa

pKa

logP

cation/neutral/difference

(MeCN)a

(H2O)b

oct/w

tol/w

336/410/74

15.6

7.7

7.2

8.4

logP c

c

5

1b

135.9–136.8

340/411/71

16.8

8.4

7.1

8.0

1c

115.6–117.2

342/415/73

18.4

9.2

7.7

7.1

1d

145.4–146

347/428/81

20.2

10.2

8.5

5.4

2a

202.3–203.4

362/480/118

14.9

7.3

7.8

9.2

2b

128–129.9

365/483/118

16.2

8.0

7.2

9.1

2c

138.1–139.2

365/492/127

17.7

8.9

7.3

7.9

2d

146.1–146.8

371/512/141

19.5

9.8

7.9

6.1

3a

227.5–228.5

539/423/116

16.2

8.0

7.5

8.0

3b

179.5–180.9

543/423/120

17.4

8.7

7.8

7.3

3c

134.6–135.8

548/423/125

18.9

9.5

8.6

6.3

d

5.3

3d a

120.9–123.1

539/419/120

20.8 b

10.6

9.5

Experimental pKa values in MeCN from this work. Estimated aqueous pKa values (see ESI).

c

LogP values

d

estimated from directly measured logD values as described in the ESI. Value with high uncertainty (see ESI.

Properties UV-Vis spectra All compounds displayed absorbances in the visible spectral range and a shift of the absorbance band upon protonation of the neutral compound (Table 1, see also page 67 of the ESI for a photo of 1c, 2d and 3b in acidic and basic solutions). In the case of unsubstituted or 4-nitro-substituted compounds, remarkable shifts of the absorption maxima to shorter wavelengths were observed upon protonation. In the case of 4-dimethylamino-substituted compounds the absorption maxima shifted to longer wavelengths (red shift) upon protonation. Nitro- and dimethylamino-substituted compounds on average possess absorbance maxima at longer wavelengths than the unsubstituted compounds. A red shift was also observed when the phenyl groups attached to the phosphorus atom were replaced by pyrrolidino groups. Previously, we found that the nature of the phosphorus–nitrogen double bond in iminophosphoranes was important for understanding the basicity and spectral data of these compounds.19 In this respect iminophosphoranes behave analogously to phosphorus ylides, where the phosphorus–carbon bond can be regarded either as a formal double bond (ylenic) or a formal single bond between two oppositely charged centres (ylidic), i.e. a zwitterionic structure.11,19 The ylidic structure is generally considered to have higher contribution, as evidenced by computational and experimental results. We previously showed that in

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iminophosphoranes there is a strong contribution of the zwitterionic (ylidic) structure19 and there is every reason to expect the same with the phosphazenes in this work. This means that the nitrogen atom in the P=N fragment is isoelectronic with the oxygen atom in the phenolate and therefore significant delocalization of the electrons of the imino nitrogen into the aromatic ring is to be expected. This has been confirmed by basicity measurements of both phosphazenes19 and phosphorus ylides.20 Thus, the imino nitrogen is largely anionic and releases electrons by delocalization (behaves as a +R group). It is known that adding +R and –R (substituents that withdraw electrons by delocalization) substituents to conjugated positions in the aromatic system leads to the formation of intense long-wavelength absorption peaks due to intramolecular charge transfer.21 Adding an azogroup, which is a strong chromophore with –R characteristics, we can assume further shifts in the peak maxima to longer wavelengths. To increase the described effect we supplemented two chromophores: an azo-group and NO2- or (CH3)2N-substituents conjugated with the aromatic system. Table 1 reveals that upon addition of the (-R) NO2 -group (2a-d) to the conjugated position of the aromatic system containing a ylidic nitrogen (+R) on the other side, the intramolecular charge transfer absorption becomes strong and shifts to a longer wavelength. We can also deduce that adding pyrrolidino-groups to the phosphorous atom increases the electron density and the ylidic character of the imino nitrogen and thereby promotes a red shift in the neutral phosphazene. The effect of pyrrolidino-groups is smaller than the effect of +R/-R substituents in the conjugated position of the aromatic ring. This red shift increases the difference between the peak maxima of cationic and neutral forms, which is an anticipated and desired characteristic. Adding the (+R) (CH3)2N- group (3a-d) to the conjugated position also supports intramolecular charge transfer, but primarily in the cationic form. In the neutral form there are two +R substituents in conjugated positions, so the intramolecular charge transfer is weak. When protonated, the imino nitrogen shows strong –R character and naturally the strong intramolecular charge transfer now occurs in the protonated form. This is the reason why the cationic forms of compounds 3a-d absorb at longer wavelengths than the neutral forms (Table 1). All bases studied in this work and their conjugate acids have a significant spectral difference in the visible region, and thus they may be used as indicators. 7

Basicity The pKa values in MeCN range from 14.9 to 20.8 pKa units (Table 1). The pKa estimates in water were calculated from the pKa values in MeCN, as described in the ESI, and range from 7.3 to 10.6 pKa units. The basicity of the synthesized compounds is dependent on the number of pyrrolidino groups attached to phosphorus atom and on the 4-substituents on the phenyl ring. Replacing one phenyl ring with a pyrrolidino group leads to a basicity increase of 1.2– 1.9 pKa units. As expected, introducing the (–R) nitro group decreases the basicity of the compound by 0.6–0.7 pKa units. Introducing the (+R) dimethylamino group increases the basicity by 0.5–0.6 pKa units. The rather uniform nature of these structural effects enables their description using the following equation that takes into account the number of pyrrolidino-groups (Npyrr), resonance (δR) and inductive (δF) constants of the substituents (values in parenthesis are standard deviations): pKa(cal) = 15.43(±0.11) + 1.55(±0.04)·Npyrr – 1.22(±0.18)·δR – 0.73(±0.21)·δF

(3)

n = 12, R2 = 0.993, S = 0.17. The number of pyrrolidino groups in the molecule has the strongest effect on basicity, followed by the resonance and thereafter the field-inductive effect of the substituents in the phenyl ring. There is no question about the protonation center in the case of unsubstituted or nitrosubstituted compounds, however, in the case of dimethylamino-substituted compounds the dimethylamino group could be an alternative protonation center. The fact that the dimethylamino compounds are adequately described by the above correlation is one piece of evidence in favor of protonation on the imino nitrogen. The other one is the emergence of the long-wavelength absorption band in the spectra upon protonation. This is consistent with the formation of a strong –R group upon protonation of the imino group. Together these pieces of evidence permit the conclusion that the imine nitrogen is the protonation center in all of these phosphazenes. Solubility, lipophilicity All synthesized compounds were practically insoluble in water, but were soluble in chloroform (and other chlorinated solvents trichloroethane, carbon tetrachloride, methylene

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chloride), toluene, acetonitrile, acetone, methanol, ethanol and octanol. Compounds 3a-d demonstrated slightly lower solubility in these solvents than the other studied bases. The logP values (estimated as described in the ESI) presented in Table 1 clearly demonstrate the high lipophilicity of the synthesized compounds and also its dependence on the number of pyrrolidino groups attached to the phosphorus atom and the substituent in position 4 of the phenyl ring. Interestingly, the within-series (i.e. in compound subsets with the same parasubstituent but a different number of pyrrolidino groups) trends of logP values in the octanol/water and toluene/water systems are almost reversed. Replacing the phenyl rings with pyrrolidino groups consistently led to decreased lipophilicity in the toluene/water system. The trends in the octanol/water system are more complex. In series 3 the lipophilicity steadily increases with the number of pyrrolidino groups in the molecule, whereas in series 1 and 2 the addition of the first pyrrolidino group causes a decreased lipophilicity; the lowest lipophilicity belongs to the Ph2(pyrr) derivatives. In all series the (pyrr)3 derivatives are the most lipophilic in the octanol/water system. The main trends of lipophilicity changes may be explained by the fact that in terms of interaction with water molecules, the phenyl ring is somewhat more polar than the alkyl moiety of the pyrrolidino group. In the compound structures the nitrogen atoms in the pyrrolidino groups have a slight negative partial charge and could potentially interact with water molecules and are essentially buried between the substituents and therefore interactions with water molecules are prevented. Due to this effect the phenyl groups in this type of phosphazenes are slightly more polar and in the case of the octanol/water system favor partition into water. On the other hand, in the case of toluene as the organic phase, the π-π interaction between toluene and the phenyl rings in the phosphazenes outweighs the phenylwater interaction. Substitution of the phenyl groups by pyrrolidino groups leads to a lower intensity of the π-π interactions that support solubility of the compounds in toluene and thus a decrease in the number of phenyl groups and leads to a lipophilicity decrease in the toluene/water system. The within-series trends are more noticeable in the toluene/water system. The minor details of lipophilicity-structure trends are probably related to the effect of the pyrrolidino groups on the basicity center. Introduction of pyrrolidino groups increases electron density on the imino nitrogen and its +R character, which in the case of unsubstituted and especially nitro-substituted phosphazenes notably enhances polarizability of the molecule. 9

Similar to the effect of π-π interactions described above, an increase in polarizability is likely to increase lipophilicity in the toluene/water system and decrease it in the octanol/water system. In the latter system, the increase of polarizability could explain the lipophilicity decrease upon addition of the first pyrrolidino group in series 1 and 2. The effect is absent in series 3, where due to the presence of the (+R) dimethylamino substituent the growing +R character of the basicity center does not have a strong effect on the polarizability, so the lipophilicity trends are determined mainly by the relative polarities of phenyl and pyrrolidino groups. Also, the increase in electron density on the imino nitrogen enhances its hydrogenbond accepting capability, which favors partition into water as a medium with stronger hydrogen-bond donating properties than either of the organic phases. Naturally, this effect would be more pronounced in toluene as an aprotic solvent. In the toluene/water system, replacing one phenyl ring by a pyrrolidino group leads to a lipophilicity decrease of 0.1–1.7 logP units. In series 1 and 2 the difference of logP values between the P(Ph)3 and P(pyrr)3 are slightly bigger than in series 3: 3.0–3.1 and 2.7 logP units, respectively. In the octanol/water system replacing one phenyl ring by a pyrrolidino group leads to the lipophilicity increase of 0.3–0.9 logP units in series 3. In series 1 and 2 replacing the first phenyl ring by a pyrrolidino group leads to a lipophilicity decrease of 0.2–0.6 logP units, but upon replacing the next phenyl ring the logP value starts to increase. In the case of toluene as the solvent, introduction of the (–R) nitro group slightly increases (by 0.8–1.1 log units) the lipophilicity of the bases with respect to their unsubstituted analogues, while the (+R) dimethylamino group decreases it by 0.1–0.8 log units. This is probably connected to the effect of the substituents on the polarizability of the molecules. The effect is practically reversed in octanol, where introducing the dimethylamino group increases the lipophilicity by 0.3–0.9 logP units. The effect of nitro-group, however, is smaller and more complex.

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Conclusion A series of novel phosphazene bases have been synthesized and characterized. They have a useful and unusual combination of properties: 0/+1 charge states, pKa in the basic range, high lipophilicity of both neutral and protonated forms, lack of any localized charges in the respective cations, and significant spectral changes in the visible region upon protonation. Almost all well-known indicators with transition ranges in the basic region are polar molecules, have 0/-1 charge states and in the deprotonated state possess anionic groups with strong intermolecular interaction capability, most often the phenolate group. The indicators developed in this work stand out by the lack of any such groups and are therefore well suited for acting as "silent spectators" in monitoring the acidity/basicity of different low-polarity systems.

Acknowledgement This work was supported by the EU through the European Regional Development Fund (TK141 “Advanced materials and high-technology devices for energy recuperation systems”) and by the Institutional funding projects IUT20-14 and IUT20-15 from the Estonian Ministry of Education and Research.

Supporting Information Details regarding the synthesis of compounds 1a-3d and characterization data are available in the Supporting Information.

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Highlights of the article "Synthesis and properties of highly lipophilic phosphazene bases"

1) Synthesis of twelve novel phosphazene-based compounds. 2) Unusual combination of properties: basicity, high lipophilicity, significant spectral differences in the visible region. 3) Modified logP and pKa measurement protocol for highly lipophilic compounds.

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