Di(hydroperoxy)cycloalkanes Stabilized via Hydrogen Bonding by

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Di(hydroperoxy)cycloalkanes Stabilized via Hydrogen Bonding by Phosphine Oxides: Safe and Efficient Baeyer-Villiger Oxidants Shin Hye Ahn, Destiny Lindhardt, Nattamai Bhuvanesh, and Janet Bluemel ACS Sustainable Chem. Eng., Just Accepted Manuscript • DOI: 10.1021/ acssuschemeng.8b00652 • Publication Date (Web): 06 Apr 2018 Downloaded from http://pubs.acs.org on April 9, 2018

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ACS Sustainable Chemistry & Engineering

Di(hydroperoxy)cycloalkanes Stabilized via Hydrogen Bonding by Phosphine Oxides: Safe and Efficient Baeyer-Villiger Oxidants Shin Hye Ahn, Destiny Lindhardt, Nattamai Bhuvanesh, Janet Blümel* Department of Chemistry, Texas A&M University, College Station, TX, 77842-3012, USA

AUTHOR INFORMATION Dr. Shin Hye Ahn, Destiny Lindhardt, Dr. Nattamai Bhuvanesh, Prof. Dr. Janet Blümel, Texas A&M University, Department of Chemistry, 580 Ross Street (MS3255), College Station, TX 77842-3012, USA

Corresponding Author: *Janet Blümel, e-mail: [email protected]; tel: (979)845-7749.

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ABSTRACT: The synthesis of two new representatives of di(hydroperoxy)cycloalkane adducts of phosphine oxides, Cy3PO·(HOO)2C(CH2)4

and

Cy3PO·(HOO)2C(CH2)6,

and

the

new

hydroperoxy(hydroxy)alkane

adduct

Cy3PO·(HOO)(HO)C(CH2)5 are described. Different synthetic routes were explored. The formation of the adducts proceeds from hydrogen peroxide adducts of phosphine oxides in the presence of cyclic ketones. Additionally, the direct addition of Cy3PO to free di(hydroperoxy)cycloalkanes results in the desired adducts. A mechanism for the formation is proposed which is supported by generating and identifying the monoperoxy adduct Cy3PO·(HOO)(HO)C(CH2)5. All adducts are fully characterized with single crystal X-ray crystallography, NMR, and IR spectroscopy. All adducts are safe and solid and have shelf lifetimes of months. They are highly soluble in organic solvents which allows for homogeneous reactions in non-aqueous media. This was demonstrated

by

selectively

oxidizing

Ph2P-PPh2

to

the

moisture-sensitive

Ph2P(O)-P(O)Ph2.

All

adducts

Cy3PO·(HOO)2C(CH2)4-6 perform efficient Baeyer-Villiger oxidations under mild and anhydrous conditions requiring only catalytic amounts of acid.

Keywords Peroxides, di(hydroperoxy)alkanes, phosphine oxides, hydrogen bonding, diphosphine dioxides, adducts, oxidizing agents, hydrogen peroxide

INTRODUCTION Peroxides are ubiquitous in daily life.1-3 They are active ingredients for disinfecting and bleaching in (1) the production of goods and cosmetics, (2) the household, and (3) wastewater treatment. They also play important roles in medicine, such as (1) the treatment of skin infections, and (2) wound cleaning. Artemisinin and related organic peroxides play special roles as antiparasitic and anti-malarial agents, as underscored by the 2015 Nobel Prize in Medicine awarded to Youyou Tu.4 Peroxides are also employed industrially as radical initiators for polymerizations.2 For synthetic chemistry, oxidation reactions are crucial, and inorganic and organic peroxides, either solo or in the presence of catalysts, play central roles.1-3 Important applications would be the oxidation of amines to amides,5,6 alkane activation,7-10 epoxidation reactions,11-15 and selective transformations of sulfides to sulfoxides.16-21 Many groups also study practical and theoretical aspects of the catalyst-free oxidation of phosphines

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to their oxides.20-28 In academia as well as industry, Baeyer-Villiger oxidations are indispensable for synthesizing esters from ketones, or more specifically lactones from cyclic ketones.12,29-34 Recently, advances have also been made regarding mechanistic aspects of the Baeyer-Villiger oxidation. A stereoelectronic trap for the Criegee intermediate could successfully be implemented by interrupting the BaeyerVilliger rearrangement.35 The ideal peroxide in preparative chemistry would be inexpensive, easy to synthesize, reproducible in stoichiometry, and soluble in organic solvents. It would be thermally and mechanically stable at ambient temperatures over prolonged time periods, while retaining its oxidizing power. A solid oxidizing agent would be preferred due to the ease of purification by crystallization, handling, and storage. Although aqueous H2O2 is an enticing oxidizing agent in academic settings, it is still far from ideal. Under present safety regulations it is commercially available for laboratories in concentrations up to 30 wt%. The major drawback of aqueous H2O2 remains the abundance of water in the reaction mixture which can render some syntheses impossible or entail unwanted secondary reactions. Another ingredient of commercial aqueous H2O2 is nitric acid, which is added as a stabilizer to adjust the pH value to 1 to 2 to achieve the longest lifetime. Furthermore, aqueous H2O2 that is shared among many users degrades at unpredictable rates, and has to be titrated36,37 prior to each application when exact stoichiometry is required. Additionally, in case the reagents are not water soluble the oxidation reactions have to be performed in a biphasic system, slowing rates and requiring phase separations later. Water free formulations of H2O2 such as urea hydrogen peroxide (UHP)38-40 and peroxocarbonates are also used.41-43 However, the stoichiometry of these materials is not well defined, and they are insoluble in organic solvents. Both water and urea have to be removed after the oxidation reaction, with the high reactivity of urea posing yet another problem. In other formulations H2O2 has been encapsulated44 and immobilized.45,46 H2O2 adducts of metal complexes with demanding syntheses have been characterized.47-50 Peroxides like (Me3SiO)2 are in use, but their synthesis, purification and storage are problematic.50,51 For the last decade, di(hydroperoxy)cycloalkanes were intensively studied, and practically rediscovered as inexpensive starting reagents with multifaceted potential for applications in academia and industry. For example, they have been shown to play important roles in Baeyer-Villiger oxidations.32-34 Correspondingly, easy and straightforward syntheses for di(hydroperoxy)cycloalkanes have been described.52,53



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The research presented in this contribution aims to explore new adducts of peroxides, stabilized by hydrogen bonding to phosphine oxides, as oxidizing agents with highly desirable characteristics. The work is based on the recent discovery that H2O2 and di(hydroperoxy)alkanes, (HOO)2CRR',52,53 are stabilized by well-defined hydrogen bonding to phosphine oxides without compromising their oxidative efficiency.20-22 In earlier work, our research on immobilized catalysts with phosphine linkers54-67 necessitated the investigation of phosphine oxides adsorbed on silica surfaces and their dynamic properties.23 For these studies very clean phosphine oxides were essential, and were best obtained by oxidizing phosphines with aqueous H2O2 in a biphasic system.22 In the course of this work we discovered two classes of hitherto unknown adducts. The phosphine oxides are able to stabilize H2O2 via the formation of hydrogen bonds. Three hydrogen peroxide adducts (R3PO·H2O2)2 (R = Cy, tBu, Ph) have been isolated by combining phosphines or their oxides with aqueous H2O2.20,22 In the presence of ketones (R'COR") the new hydroperoxide adducts R3PO·(HOO)2CR'R" (R = Cy, Ph; R',R" = Me, Et, Bu, Ph) were generated.20,21 These adducts fulfill many of the points on the above wish list for the ideal oxidizing agent, and additionally, no acid has to be added to prolong the peroxide life time, since the phosphine oxides serve as stabilizers. The hydroperoxide adducts are safe and solid, and they can be obtained in high yields with reproducible stoichiometry. They selectively oxidize sulfides to sulfoxides and phosphines to phosphine oxides.

Scheme

1.

Di(hydroperoxy)cycloalkane

adducts

of

tricyclohexylphosphine

hydroperoxy(hydroxy)cyclohexane adduct 4.


oxide

1,

2,

and

3,

and

the

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The main focus of this contribution is to broaden the range of possible di(hydroperoxy)alkane adducts by adding cyclic alkane moieties to the known open chain alkane adducts (Scheme 1).20,21 The influence of the ring size is of special interest. By its systematic variation, it will be demonstrated that the adducts R3PO·(HOO)2CR'R" are of a general nature, and that a large variety of ketones, including cyclic ones can be used to form R3PO·(HOO)2C(CH2)n (n = 4-6) (Scheme 1). The adducts derived from cyclic ketones are especially valuable with respect to their later application for clean Baeyer-Villiger oxidations.12,29-35 This contribution also provides further evidence that this class of materials can easily be synthesized and purified. The new representative adducts 1-4 are solid, safe, stoichiometric, and soluble oxidizing agents. Furthermore, a key intermediate for the mechanism of formation and decomposition of the adducts could be identified and characterized. Other applications besides the oxidation reactions described previously were tested to underline the importance and potential of the di(hydroperoxy)alkane adducts of phosphine oxides, especially in cases where abundant water or the nitric acid stabilizer are problematic. Specifically, in the following, the synthesis, characterization, and applications of the di(hydroperoxy)cycloalkane adducts of tricyclohexylphosphine oxide 1-3 and the hydroperoxy(hydroxy)cycloalkane adduct 4 (Scheme 1) will be described. With 4, for the first time a representative hydroperoxy(hydroxy)alkane could be fully characterized, including a single crystal structure. The adducts have successfully been applied to Baeyer-Villiger oxidations,12,29-35 and to a challenging diphosphine oxidation reaction.

RESULTS AND DISCUSSION Synthesis of Adducts 1-4. It has been demonstrated recently that di(hydroperoxy)alkane adducts of phosphine oxides can be synthesized in a variety of different ways.21 This also accounts for the syntheses of 1-4, which are amenable also to larger scale production. In this contribution, the adducts 1 and 3 have been obtained on a gram scale by combining the in situ formed hydrogen peroxide adduct (Cy3PO·H2O2)220,22 with cyclopentanone and cycloheptanone, respectively (Scheme 2). The unoptimized isolated yields were high, with 76% for 1 and 88% for 3. For the synthesis of adduct 2, the hydrogen peroxide in (Cy3PO·H2O2)220,22 is replaced by the preformed di(hydroperoxy)cyclohexane.52,53 Adduct 4 is obtained in 84% yield after the synthesis of 2 from (Cy3PO·H2O2)220,22 and cyclohexanone and exposing the biphasic reaction mixture to the atmosphere for several days. Alternatively, 4 can be generated quantitatively by thermal



decomposition of 2 in chlorobenzene at 110 °C within several hours. All new adducts are colorless solids that can easily be purified by crystallization. They are mechanically robust and do not release oxygen when ground or exposed to sudden impact. Furthermore, they melt cleanly without detonation tendencies. It should also be pointed out that no explosive di- or triperoxide species have been detected as side-products.

Scheme 2. Synthesis routes for the adducts 1-3.

The preliminary reaction mechanism suggested earlier20,21 for the formation of di(hydroperoxy)alkane adducts of phosphine oxides can now be refined by inserting hydroperoxy(hydroxy)alkane adducts as key intermediates (Scheme 3).

Scheme 3. Suggested mechanism for the formation of di(hydroperoxy)alkanes and hydroperoxy(hydroxy)alkanes, hydrogenbonded to phosphine oxides.


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In the first step of the reaction mechanism (Scheme 3) hydrogen peroxide performs a nucleophilic attack at the carbonyl carbon of a ketone. This step is facilitated by the presence of nitric acid in commercial aqueous H2O2 (see above). In case hydrogen peroxide is added stoichiometrically, the hydroperoxy(hydroxy)alkane is formed as an intermediate. It can be scavenged to generate a hydroperoxy(hydroxy)alkane adduct of a phosphine oxide. Hereby, the phosphine oxide also stabilizes the hydroperoxy(hydroxy)cycloalkane by two strong hydrogen bonds. Due to this stabilization, the adduct, containing only one hydroperoxy group, can be isolated, identified, and fully characterized, as exemplified for 4. Adduct 4 is the first literature known stabilized hydroperoxy(hydroxy)alkane that has also been characterized by single crystal X-ray crystallography (see below). This adduct is also an interesting addition to recently published mechanistic studies on the Baeyer-Villiger oxidation.35 4 can be further oxidized with aqueous H2O2 to the di(hydroperoxy)alkane adduct of a phosphine oxide, in this case 2. The hydroperoxy(hydroxy)alkane intermediate can also be oxidized in situ by an excess of H2O2 to the di(hydroperoxy)alkane, which can subsequently be scavenged to generate the stable adduct R3PO·(HOO)2CR'R" (Scheme 3). The decomposition of the di(hydroperoxy)alkane adducts of phosphine oxides in solution follows the reverse pathway, with consecutive loss of the oxygen atoms from the two hydroperoxy groups. When the adducts R3PO·(HOO)2CR'R" are heated up in solution, first R3PO·(HOO)(HO)CR'R" forms and the remaining oxidative power of the solution reaches a plateau at the 50% level.21 Although the monoperoxy adduct 4 is more stable than the diperoxy adduct 2, the one remaining peroxo group per adduct assembly is still able to oxidize Ph3P to Ph3PO in the standardized in situ NMR test reaction described previously.20 This feature of the adducts R3PO·(HOO)2CR'R" to release active oxygen in two steps might be interesting for future applications as radical initiators for polymerizations which incorporate two functions with different reactivities.

NMR Spectroscopy of 1-4. Since the adducts 1-4 (Scheme 1) are highly soluble in organic solvents (see below), they can be characterized by routine solution NMR spectroscopy. One- and two-dimensional NMR spectroscopy is used to identify and assign all 1H,

13

C, and

31

P resonances unequivocally. A large database on diverse pure

phosphine oxides20-23 as well as hydrogen peroxide20,22 and di(hydroperoxy)alkane adducts of phosphine oxides20,21 has been used additionally. The chemical shifts and J coupling values in the 1H and 13C NMR spectra of 1-4 that are characteristic for the signals of the phosphine oxide carriers, differ only minimally from the corresponding values of the pure phosphine oxides.22 Larger changes of the peroxyalkane moieties of the adducts are found, which follow the



trends observed earlier when transforming open-chain ketones to di(hydroperoxy)alkanes.20,21 Most indicative of the formation of the di(hydroperoxy)-cycloalkane adducts 1-3 is the resonance in the range of 109 to 121 ppm of the newly generated quaternary carbon atoms bound to two oxygen atoms (Table 1). This chemical shift range is very characteristic and not occupied by the typical signals of aryl or alkyl carbon nuclei. Furthermore, the signals for the quaternary carbon nuclei of the shock-sensitive diacetone diperoxide (DADP) and triacetone triperoxide (TATP) appear at about 105 ppm.68 Fortunately, the syntheses of 1-4 never resulted in any of these species according to 13C NMR. The presence of the phosphine oxides might prevent this peroxide oligomer formation. There is no obvious trend in the δ(13C) values of the quaternary carbon nuclei when proceeding from the five-membered ring in 1 to the seven-membered ring in 3. For 4, this value is lower (102.65 ppm), confirming that the di(hydroperoxy)cyclohexane moiety (109.52 ppm) has been transformed into hydroperoxy(hydroxy)cyclohexane. The 13C NMR resonances of the quaternary carbon nuclei are also easily identified by the absence of resonances in DEPT and cross peaks in 1H,13C COSY NMR spectra.

The 1H NMR spectra show broad resonances for the protons in the hydrogen bridges in the region from 10 to 12 ppm. While these signal positions are typically very sensitive to concentrations, solvents, and temperature, it is remarkable that for 4 two broad, but clearly distinct signals are found. One signal at 10.37 ppm corresponds to the OOH proton, and another one at 9.51 ppm to the OH group. This might be an indication that the proton exchange is slowed down by the strong hydrogen bonding to the phosphine oxide.

The

31

P NMR signals of the adducts 1-4 are shifted downfield as compared to that of the corresponding pure

phosphine oxide Cy3PO (49.91 ppm)22 (Table 1). The higher δ(31P) values indicate the deshielding of the phosphorus nuclei due to the two strong hydrogen bonds to the oxygen atom of the P=O group.20,21 The ∆δ values cover a relatively narrow range from 3.4 to 8.1 ppm. While there is no visible trend regarding the change of the ring size of the peroxyalkane moieties, the ∆δ value of 4 is less than half the value observed for 2. Obviously, there is less deshielding of the 31P nucleus if the hydrogen bridges are established between the P=O group and one OH and one OOH group, versus two OOH groups.


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Table 1. δ(13C) of the quaternary carbon signals Cq of the cycloalkane moieties in 1-4, 31P NMR chemical shifts of the adducts 31

and the 31P NMR chemical shift differences with respect to pure Cy3PO with δ( P) = 49.91.22 All values were obtained using CDCl3 as the solvent.

Adduct

δ(13C) of Cq (ppm)

δ(31P) (ppm)

∆δ (ppm)

1

120.92

57.14

7.23

2

109.52

58.01

8.10

3

114.34

56.63

6.72

4

102.65

53.34

3.43

X-Ray Crystallography of 1-4. All adducts 1 to 4 crystallize in large single crystal specimens that are suitable for X-ray diffraction. The structure of 2 has been communicated previously,21 the crystal structures of 169 and 370 are displayed in Figures 1 and 2.

Figure 1. Single crystal X-ray structure of 1.69 Two independent molecules are displayed. Thermal ellipsoids are shown at the 50% probability level. Only the hydrogen-bonded H are displayed for clarity.

Figure 3 demonstrates the ease of growing crystals of 4 and that the syntheses of all adducts of phosphine oxides can easily be scaled up. The single crystal X-ray structure of 4 is displayed in Figure 4.71 Overall, X-ray crystallography provides indisputable proof that all di(hydroperoxy)cycloalkane adducts of tricyclohexylphosphine oxide systematically form molecular assemblies with a reproducible ratio of 1 : 1 between the P=O groups and the (HOO)2C(CH2)4-6 moieties. This corresponds to the observation made earlier for other, open-chain di(hydroperoxy)alkane adducts of phosphine oxides.21



Figure 2. Single crystal X-ray structure of 3.70 The stacking of two independent molecules is displayed on the right. Thermal ellipsoids correspond to the 50% probability level. Only the hydrogen-bonded H are shown for clarity.

Furthermore, the general stacking motif of two adducts with the P=O groups pointing in opposite directions is further established in 1-4 (Figure 1, Figures 2 and 4, right). This packing theme in the single crystals even tolerates the reduced size of the ring containing the hydrogen bridges in 4 (Figure 4). In fact, this sterically favorable general stacking motif might be the reason why the di(hydroperoxy)alkane and hydroperoxy(hydroxy)alkane adducts of phosphine oxides crystallize so readily (Figure 3). Interestingly, the parallel stacking of the cyclohexyl substituents in 4 leads to a certain steric crowding that seems to render the orientation of the smaller hydroxy group towards the inside of a dimer assembly more favorable (Figure 4).

Figure 3. Single crystals of 4.


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Figure 4. Single crystal X-ray structure of 4.71 The stacking of two independent molecules is displayed on the right. Thermal ellipsoids correspond to the 50% probability level. Only the hydrogen-bonded H are shown for clarity.

The P=O bond lengths of 1-4 and their elongation upon adduct formation are reported in Table 2. As compared to the original P=O bond length in Cy3PO (1.490 Å),72 in the adducts 1-4 the bonds of the carrier phosphine oxide are between 1.505 and 1.513 Å long. This corresponds to substantial elongations between 0.015 and 0.023 Å. Obviously, the P=O bonds are weakened by sustaining two hydrogen bonds, as the IR data discussed below confirm. Although the P=O bonds appear less affected with increasing alkyl ring sizes of the alkane moieties, there is no linear trend on going from 1 to 3. Table 2. Comparison of the P=O bond lengths (Å) of the adducts 1-4 with the value for the pure phosphine oxide Cy3PO.72

Species

P=O Bond lengths (Å)

∆ Bond lengths (Å)

1

1.513

+0.023

2

1.51221

+0.022

3

1.505

+0.015

4

1.509

+0.019

Cy3PO

1.49068

-

Another indication for the presence of hydrogen bonds in 1-4 can be derived from the O···H distances (Table 3). According to the literature, typical O···H distances in hydrogen bonds lie within the range of 1.85 to 1.95 Å.73,74 All O···H distances in 1-4 are found in this range, in fact in the region of shorter distances, indicating strong hydrogen bonds. The hydrogen bond containing the hydroxy group assumes the largest value with 1.91 Å. Strong hydrogen bonds also manifest themselves in the form of comparatively short O···H−O distances between the oxygen atoms in 1-4 (Table 3). 2.75 to 2.85 Å is the range of distances that is recognized for hydrogen bond formation.73,74 Most O···H−O distances in the structures of 1-4 are even shorter, indicating again strong hydrogen bonding. Once more, the largest distance (2.76 Å) is found for the hydrogen bridge containing the hydroxyl group in 4.



Finally,

the

O−C−O

angles

in

the

di(hydroperoxy)cycloalkane

Page 12 of 35

units

of

1-3

and

the

hydroperoxy(hydroxy)cyclohexane moiety of 4, were considered as an indicator for strain in the assemblies due to the formation of the two hydrogen bonds.21 The O−C−O angles in 1-4 exceed those of the tetrahedral angle (109.5°), with most of the values being larger by about 1.8 to 3.8° (Table 3). Therefore, it seems like the O−C−O angles increase in order to accommodate the formation of the two hydrogen bonds per P=O group. However, no clear trend regarding the ring sizes of the alkyl moieties of the assemblies on going from 1 to 3 is discernible. Furthermore, the O−C−O angles in 4 (112.3°/112.1°) with the smaller ring containing the hydrogen bridges, are comparable to the 112° in 2.21

Table 3. Hydrogen bond lengths, O···O distances, and O−C−O angles of the di(hydroperoxy)alkane moieties in the adducts 1 to 4.

Adduct

O···H Distance (Å)

O···H−O Distance (Å)

O−C−O Angle (°)

1

1.854/1.878

2.700/2.727

111.8/ 111.3

2

1.864/1.87621

2.705/2.72321

112.021

3

1.865/1.872

2.704/2.706

109.90/ 113.3

4

1.917 (OH)/ 1.860 (OOH)

2.760 (OH)/ 2.628 (OOH)

112.3/ 112.1

IR Spectroscopy of 1-4. IR spectra provide valuable information about the new adducts. Importantly, all spectra differ substantially from those of the starting phosphine oxide, Cy3PO, and the cyclic ketones. Furthermore, IR spectroscopy can be used as a quick analytical check to confirm that there is no water in any of the materials. Water would manifest its presence with a hydroxyl stretching band at 3400 cm-1 and an overtone at 1647 cm-1.22 The analytically most relevant IR spectroscopy data for 1-4 and Cy3PO are given in Table 4, and representative spectra are displayed in Figure 5.


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The broad ν(O-H) stretching bands of the OOH groups in the new adducts appear close to 3200 cm-1,20,21 consistent with the wavenumber for the hydrogen peroxide ν(OO-H) stretching band.20,22 The largest deviations from the 3200 cm-1 value are found for 1 (3167 cm-1) and 4 (3246 cm-1). This indicates that the cyclopentyl ring of 1 allows for the strongest hydrogen bonds, diminishing the stretching band frequency in the OH group. This correlates well with the X-ray data discussed above, where 1 exhibits the longest P=O bond and the shortest O···H and O···H−O distances (Tables 2 and 3). On the other hand, the unsymmetric seven-membered ring containing the hydrogen bonds of 4 appear to be less favorable for the bonding to the P=O group. Like in 1H NMR spectroscopy (see above), where the OOH and OH signals of 4 can be distinguished, the ν(O-H) stretching bands in the IR spectrum are both discernible. Besides the band for the OOH group at 3246 cm-1, the second stretching band for the OH group in 4 is clearly visible at 3323 cm-1 (Figure 5, bottom). The high frequencies of ν(O-H) for the OH and OOH groups correlate with the largest O···H and O···H−O distances for the OH group found in the single crystal X-ray structure of 4 (Table 3). The ν(P=O) frequencies for 1-4 are lower than the corresponding wavenumber of neat Cy3PO.22 For 1-3 the difference amounts to 34 cm-1, for 4 it is only 13 cm-1. In general, the reason for the decreased wavenumbers is that the P=O bond is weakened by two hydrogen bonds in the adducts. Remarkably, the change of the ring sizes in the cycloalkane moieties of 1-3 does not have any impact on the ν(P=O) stretching bands which all appear at 1123 cm-1. For 4, however, the higher frequency of ν(P=O) of 1144 cm-1, which indicates weaker hydrogen bonding, nicely complements the higher frequencies of the ν(O-H) bands of the OOH and OH groups.

Table 4. Characteristic IR stretching bands ν(O-H), ν(P=O), and ν(C-O) of neat 1-4.

Cy3PO

ࣇ(O-H) [cm-1] -

ࣇ(P=O) [cm-1] 115722

ࣇ(C-O) [cm-1] -

1

3167

1123

1101

2

3196

1123

1103

3

3186

1123

1101

4

3323/3246

1144

1099/1111

Species

Based on the structures of 1-4, there should be another strong absorption in the IR spectra for ν(C-O). Acetals and ketals, for example, display IR bands between 1035 and 1190 cm-1.75 Secondary alcohols show IR bands



between 1090 and 1120 cm-1 for ν(C-O).75 Indeed, in the narrow region from 1099 to 1111 cm-1 in all IR spectra of the adducts 1-4 an additional strong absorption appears (Figure 5). The bands can be assigned to the ν(C-O) bands of the di(hydroperoxy)carbon moieties of 1-3 and the hydroperoxy(hydroxy)carbon unit in 4. In the latter case, the ν(CO) stretching band of the CqOOH group can be tentatively assigned to 1111 cm-1, that of the CqOH moiety to 1099 cm-1. This assignment is based on the fact that the ν(C-O) of neat (HOO)2C(CH2)6 appears at 1111 cm-1 in the IR spectrum. In summary, all IR stretching bands of 1-4 corroborate the structures displayed in Scheme 1 with their characteristic values and prove that all adducts are molecular and crystalline in nature, and well-defined throughout the bulk material.

Figure 5. IR spectra of the neat polycrystalline adducts 1-4 (top to bottom).


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Solubilities and Shelf Lives of 1-4. The adducts 1-4 are highly soluble in organic solvents. The solubilities in diverse solvents have been quantified and a graph of the data is displayed in Figure 6. The solubilities of 1-4 are remarkably high in chloroform and dichloromethane, with nearly 250 mg being fully dissolved in one mL of solvent. But even in aromatic solvents such as toluene and benzene, the solubilities are substantial. On the other hand, for purifying the adducts it is favorable that their solubilities in water and hexane are low. The presence of only one peroxy group per adduct assembly in 4, as compared to 2, increases the solubility slightly in polar solvents like alcohols and acetone. Interestingly, the adduct 3, incorporating a cycloheptane ring, displays the lowest solubility in many solvents, while still being only negligibly soluble in hexane. This attribute of high solubility of 1-4 in organic solvents is very important with respect to their application for many oxidation reactions. They can be performed in one organic phase, rendering a biphasic reaction mixture obsolete. This is especially favorable in cases where a large amount of water in the aqueous phase might lead to unwanted secondary products. Furthermore, reactions proceed faster and under milder conditions when all educts are dissolved in one phase as compared to reactions that only take place at phase boundaries. Naturally, no phase separation or cumbersome drying of the products is required when performing the reactions with 1-4 in organic solvents. The one water molecule formed when both peroxy groups have reacted remains firmly bound to the phosphine oxide carrier and will not interfere with the progress of the reaction.22,23 The water adducts of phosphine oxides can be transformed directly into hydrogen peroxide or di(hydroperoxy)alkane adducts, as demonstrated earlier.21 Therefore, the phosphine oxides carriers can easily be separated and reused.

Figure 6. Solubilities of the adducts 1-4 in representative solvents.



The adducts 1-4 are remarkably stable with respect to dry grinding and sudden mechanical impact. They do not detonate or show sudden release of gas. In the solid state, the adducts live very long. In order to test for longevity, the oxidative power of a sample is measured. The oxidative power can be determined by a standardized in situ 31P NMR test.20,21 For 4, 100% oxidative power corresponds to the one active oxygen atom per adduct assembly. For 13, two active oxygen atoms per assembly indicate 100% oxidative power. Using this method, it has been found that large single crystals of 1-4 stay intact over months. Even when polycrystalline 4 is ground and placed into the sun at a window, 99% oxidative power remains after 10 days of exposure. When the decomposition of the adduct 2 is monitored in toluene solution, 50% oxidative power is lost within about 8 days at 105 °C. The decomposition curve reaches a plateau at the 50% value, and 4 can be retrieved. Therefore, it can be concluded that 4 is less reactive than 2, which might lead to important future applications, for example, as radical initiators for polymerizations. In the following reactions, however, both active oxygen atoms of 1-3 are used up for the oxidation of a substrate.

Oxidation of Phosphines. Because the adducts R3PO·(HOO)2CR'R" (R, R', R" = alkyl, aryl) are stored as solids, it is easy to use them for reactions that require strictly air- and moisture-free conditions. Moreover, due to their high solubility in organic solvents, the oxidation reaction can occur in one phase, eliminating the need for phase transfer agents. The oxidation of PPh3 with aqueous H2O276 or its phophine oxide adducts (R3PO·H2O2)220,22 and R3PO·(HOO)2CR'R"20,21 is straightforward because PPh3 is not air-sensitive in the solid state and in most solvents, and Ph3PO is the sole product with no occurrence of overoxidation. Therefore, this reaction is used as in situ test for quantifying the oxidative power of peroxo adducts (see NMR above). In the case of alkyl- and other phosphines which are sensitive to overoxidation and hydrolysis,22,77 it is interesting to probe whether oxidation with the adducts of the type R3PO·(HOO)2CR'R" (R, R', R" = alkyl, aryl) can proceed in a stoichiometric manner. Furthermore, it needs to be tested whether the reaction conditions would remain sufficiently anhydrous to prevent hydrolysis in spite of the formation of one equivalent of water per adduct assembly.23 As an interesting, but challenging target in this respect, the oxidation of tetraphenyldiphosphine, Ph2P-PPh2,78 to 1,1,2,2-tetraphenyldiphosphine dioxide, Ph2P(O)-P(O)Ph2 (5),79,80 was chosen. In spite of its structural similarity to hypphosphoric acid, (RO)2P(O)-P(O)(OR)2, which exhibits anti-tumor activity, 5 has not been extensively studied due to the difficulty of synthesizing it selectively.80 Since the P-P bond of Ph2P-PPh2 is sensitive to hydrolysis, its


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oxidation to the dioxide has traditionally been performed in dry solvents with oxygen gas.79 In the presence of moisture, the P-P bond is cleaved to produce a mixture of oxidized species, including Ph2P(O)H and Ph2P(O)OH.80 Using dry air at low atmospheric pressure, the oxidation of Ph2P-PPh2 is extremely slow and incomplete, with diphosphine dioxide (5) and diphosphine monoxide Ph2P-P(O)Ph277 resulting in the product mixture.80 Therefore, this method of oxidation is also inconvenient, because it involves high pressures and the use of an oxygen gas cylinder, a potential safety hazard. Other recent approaches for the synthesis of 5 involve (a) the reaction between an electrophile, R2P(O)X (X = Cl, Br), and deprotonated R2POH, (b) an alkali metal reduction of R2P(O)X, and (c) the reaction of R2PCl with R2P(O)H and oxygen gas under anhydrous conditions.80 However, all of these methods result in a mixture of products, including R2P(O)-P(O)R2 and R2P(O)OPR2.80 On the other hand, the new adducts R3PO·(HOO)2CR'R" are dry, solid materials that can simply be weighed in and administered in a stoichiometric manner. Fortunately, the adducts are successful and provide a new and efficient way of selectively oxidizing 1,1,2,2,-tetraphenyldiphosphine to the diphosphine dioxide 5 (Scheme 4).

Scheme 4. Selective synthesis of Ph2P(O)-P(O)Ph2 (5) without hydrolysis of the P-P bond by using the di(hydroperoxy)alkane adducts R3PO·(HOO)2CR'R" (R, R', R" = alkyl, aryl) dissolved in benzene.

For example, when Cy3PO·(HOO)2CMe2 (6)20 and Ph2P-PPh2 were added in a 1 : 1 ratio to dry benzene, R2P(O)P(O)R2 (5) was obtained in 74% isolated yield. While the resulting water adduct of the phosphine oxide carrier, Cy3PO·H2O,23 is highly soluble in benzene, the diphosphine dioxide 5 is insoluble and precipitates, allowing for easy separation from the reaction mixture. Once synthesized selectively and purified, solid 5 is air-stable and can be stored for weeks without P-P bond cleavage due to hydrolysis or oxygen insertion. Therefore, this diphosphine dioxide (5) can serve as a low-weight phosphine oxide carrier for H2O2 and the peroxides (HOO)2CRR' in the future. Baeyer-Villiger Oxidation. The oxidation of ketones to esters typically require harsh reaction conditions, including catalysts and acidic media.12,29-35 Therefore, we sought to test whether the new di(hydroperoxy)alkane



adducts of phosphine oxides would be able to perform Baeyer-Villiger oxidations under milder conditions. The substrate conversion as opposed to isolated yields were determined (Table 5) in order to avoid blurring the resulting data by losses of yield due to purification procedures. In each di(hydroperoxy)cycloalkane adduct Cy3PO· (HOO)2C(CH2)n (n = 4-6) (1-3) there is a cyclic ketone inherently present, arranged favorably with respect to its oxidation with two active peroxide groups attached to the quaternary carbon of the carbonyl group. In the presence of only a catalytic amount of H2SO4, the hydrogen-bound (HOO)2C(CH2)n moieties are instantaneously and quantitatively transformed into the corresponding free lactones (Scheme 5, Table 5, entry 1), as determined by in situ

1

H NMR spectroscopy (Experimental Section). Hereby, the oxidation can take place while the

di(hydroperoxy)cycloalkanes are still attached to the phosphine oxide carriers, or they are released prior to the oxidation. Even though there are two peroxo groups per (HOO)2C(CH2)n moiety, no further oxidation of the lactones is observed, and the only other product remaining in the reaction mixture is Cy3PO·H2O (Table 5, entry 1).

Scheme 5. Baeyer-Villiger oxidation products δ-valerolactone, ε-caprolactone, and 2-oxocanone (n = 4, 5, 6, respectively), obtained by adding trace amounts of H2SO4 to the adducts 1-3.

For testing whether additional lactone could be oxidized by the second active oxygen of 1, one more equivalent of the free ketone (CH2)4CO was added to adduct 1 prior to starting the oxidation reaction with a trace amount of H2SO4. Interestingly, the yield of δ-valerolactone with respect to the overall amount of masked and free ketone was only 58% (Table 5, entry 2). This led to the initial assumption that there is at least an advantage for the oxidation of the hydrogen-bonded di(hydroperoxy)-cycloalkane versus the free cyclic ketone. In order to test whether the peroxo groups of the adducts react preferentially with the attached cycloalkyl group over added free cyclic ketone, an equimolar amount of cyclohexanone was added to 1 and the oxidation reaction was started with a trace amount of H2SO4 (Table 5, entry 3). A mixture of δ-valerolactone (21%) and ɛ-caprolactone (23%) was obtained, corresponding to conversion of about half the amount of masked and free lactone. Obviously the masked cyclopentanone in adduct 1 was not preferentially oxidized as compared to the free cyclohexanone.


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Table 5. Baeyer-Villiger oxidations of the adducts Cy3PO·(HOO)2C(CH2)n (1-3), (Cy3PO·H2O2)2 (7) and the free ketones (CH2)nCO (n = 4, 5) in the presence of catalytic amounts of H2SO4.

For testing the general validity of this result a crossover experiment was performed with adduct 2 (Scheme 1), incorporating a di(hydroperoxy)cyclohexane moiety. 2 was mixed with cyclopentanone in a 1 : 1 molar ratio (Table 5, entry 4). Again, a mixture of about equal amounts of δ-valerolactone (24%) and ε-caprolactone (22%) was obtained. Therefore, it can be concluded that there is no preference for the oxidation of phosphine oxide-bound di(hydroperoxy)cycloalkanes over the lactone formation starting from free ketone. But the question remained why the overall yield of lactone was limited to roughly 50% in all cases. This implied that only half of the active oxygen atoms in the di(hydroperoxy)cycloalkane adducts of Cy3PO was used for the lactone formation. Therefore, we sought to determine whether two peroxo groups were needed in the di(hydroperoxy)cycloalkane adducts of phosphine oxides in order to transform one equivalent of ketone into a lactone. Indeed, when the adduct 4 (Scheme 1), incorporating only one peroxo group, was combined with one equivalent of cyclopentanone, no conversion to δ-valerolactone was observed under the standard conditions. The 1H and

13

C NMR spectra showed

that the starting materials persisted. Therefore, it can be concluded that in the case of 1 and 2 the formed



intermediates with only one remaining peroxo group, Cy3PO·(HO)(HOO)C(CH2)4 and 4, respectively, remain hydrogen-bonded to the phosphine oxides and are not active enough to perform another Baeyer-Villiger oxidation cycle. It should be noted at this point, however, that 4 is a potent oxidizing agent that transforms one equivalent of triphenylphosphine to the corresponding phosphine oxide instantaneously. In order to explore whether the two peroxo groups attached to the quaternary carbon atom of the cycloalkane moiety were crucial or at least beneficial for the Baeyer-Villiger oxidation to proceed, a hydrogen peroxide adduct20,22 was employed in combination with a ketone. Specifically, the Baeyer-Villiger oxidation was performed with the hydrogen peroxide adduct (Cy3PO·H2O2)2 (7)22 and cyclopentanone in a 1 : 2 molar ratio, starting the reaction again with a trace amount of H2SO4. The corresponding δ-valerolactone was the sole product, however, the yield was only 55% (Table 5, entry 5). When the molar ratio of hydrogen peroxide adduct 7 to cyclopentanone is increased to 1 : 1, such that there are two peroxo groups per cyclopentanone, δ-valerolactone (52%) and a small amount of adduct 1 (5%) were obtained (Scheme 6, Table 5, entry 6). Therefore, overall it can be concluded that for the Baeyer-Villiger oxidation of one ketone molecule two peroxo groups are needed, irrespective of the nature of the starting peroxide, hydrogen-bound to a phosphine oxide carrier. The peroxo groups can be incorporated in a hydrogen peroxide adduct of a phosphine oxide, like in 7, or in a di(hydroperoxy)alkane adduct, as in 1-3. In case there is only one peroxo group like in 4, the oxidation does not take place.

Scheme 6. Baeyer-Villiger oxidation of cyclopentanone with (Cy3PO·H2O2)2 (7)22 to give δ-valerolactone (52%) and 1 (5%) after adding a trace amount of H2SO4.


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CONCLUSION In conclusion, in the course of this study, the following general and desirable features of the di(hydroperoxy)cyclo-alkane adducts of tricyclohexylphosphine oxide, Cy3PO·(HOO)2C(CH2)4-6 (1-3) and the hydroperoxy-(hydroxy)cycloalkane adduct Cy3PO·(HOO)(HO)C(CH2)5 (4) emerged. (a) The stoichiometry of all hydroperoxide adducts is well defined, with two hydrogen bonds per P=O group. (b) All adducts crystallize readily and reproducibly in large habits, facilitating purification. (c) Their structures and packing motifs show many similarities, also with structures obtained previously.20-23 (d) The solid adducts are safe and robust towards high temperatures and mechanical stress inflicted by hammering and grinding, with shelf lives of months at ambient temperatures. This is most probably due to the stabilizing effect of the hydrogen bonding to the phosphine oxide. (e) Several different and straightforward synthetic routes can be employed. (f) Potentially dangerous oligomeric species like TATP (triacetone triperoxide) have not been found in any of the preparations, indicating that phosphine oxides may prevent their formation. (g) Besides X-ray crystallography, NMR and IR spectroscopy have successfully been applied for characterizing 1-4. (h) The high solubility of all adducts in organic solvents allows for homogeneous oxidation reactions in one organic phase. (i) In the presence of suitable substrates, for example phosphines, the di(hydroperoxy)alkane moiety releases two active oxygen atoms in a consecutive manner. (j) As demonstrated by the successful selective oxidation of 1,1,2,2-tetraphenyldiphosphine, these adducts can be applied as oxidants in reactions that require air- and water-free conditions, as well as reactions with desired products that are sensitive to overoxidation. (k) The adducts incorporating two peroxo groups, 1-3, perform Baeyer-Villiger oxidations under mild conditions, with only catalytic amounts of acid. (l) Only one of the peroxo groups is used for Baeyer-Villiger oxidation with 1-3. With 4 the residual peroxide group oxidizes phosphines, but not ketones. The co-products of all oxidation reactions (ketones and phosphine oxides), are unreactive81,82 and practically non-toxic.83 However, in the future, the recovery and reuse of the phosphine oxide carriers will be optimized. They can be removed from the reaction mixtures by adsorption on silica,22,23 and retrieved by washing with acetone.22 Alternatively, one can immobilize the adducts on silica by covalent tethering of the phosphines,54-67 and subsequently oxidizing them to the phosphine oxides.22 The immobilized phosphine oxide carriers can easily be removed by settling of the silica support and reused as peroxide carriers by recharging them with a ketone and H2O2. In order to further reduce the weight of the phosphine oxide carriers, to improve their competitiveness with aqueous H2O2 with respect to transport, the diphosphine dioxide (5), or oxides of tripodal phosphines55,67,84 or



tetraphosphines64-66,85 will be applied. In conclusion, the presented work has greatly expanded the general accessibility, fundamental chemistry, and synthetic applications of a new important class of peroxides that are stabilized by a novel hydrogen bonding motif. They possess many of the most desirable attributes for oxidizing agents and are primed to have a significant impact on diverse problems in synthetic chemistry.

EXPERIMENTAL SECTION General Considerations. The 1H, 13C, and 31P NMR spectra were recorded at 499.70, 125.66, and 202.28 MHz on a 500 MHz Varian spectrometer. The 13C and 31P NMR spectra were recorded with 1H decoupling if not stated otherwise. Neat Ph2PCl (δ(31P) = +81.92 ppm) in a capillary centered in the 5 mm NMR tubes was used for referencing the 31P chemical shifts of dissolved compounds. For referencing the 1H and 13C chemical shifts, if not mentioned otherwise, the residual proton signals and the carbon signals of the solvents were used (C6D6: δ(1H) = 7.16 ppm, δ(13C) = 128.00 ppm; CDCl3: δ(1H) = 7.26 ppm, δ(13C) = 77.00 ppm). Virtual couplings are indicated by "virt".86,87 The signal assignments were based on comparisons with analogous phosphine oxides.20-23 All reactions were carried out using standard Schlenk line techniques and a purified N2 atmosphere, if not stated otherwise. The substrate conversion and raw yields in the Baeyer-Villiger reactions were determined based on the integration of the beta-protons on the remaining cycloketone compared to the newly emerging protons on the lactone neighboring the oxygen atom in the ring. Reagents purchased from Sigma Aldrich or VWR were used without further purification. Aqueous H2O2 solution (35% w/w) was obtained from Acros Organics and used as received. Solvents were dried by boiling them over sodium, then they were distilled and stored under purified nitrogen. Acetone (Aldrich, ACS reagent grade) and ethanol (200 proof) were dried over 3 Å molecular sieves (EMD Chemical Inc.) prior to use.

Synthesis of Cy3PO·(HOO)2C(CH2)4 (1). In a round bottom flask (Cy3PO·H2O2)2 (996 mg, 1.5 mmol) was dissolved in cyclopentanone (4.6 mL, 52 mmol). H2O2 (1 mL, 10 mmol) was added to the flask, the contents was stirred for 1 h, then left to crystallize by slow evaporation of the solvent. Cy3PO·(HOO)2C(CH2)4 (1) was obtained in the form of colorless, cubic crystals (1049 mg, 2.3 mmol, 76% yield).


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NMR (δ, CDCl3), 31P{1H} 57.14 (s); 1H 11.61 (br. s, 2H, OOH), 1.93 (t, 4H, 3J(1H-1H) = 7.58 Hz, CCH2), 1.951.81 (m, 15H, PCHaxCHeqCHeq), 1.75-1.71 (m, 3H, PCH(CH2)2CHeq), 1.70 (t, 4H, 3J(1H-1H) = 7.58 Hz, CCH2CH2), 1.47-1.37 (m, 6H, PCHCHax), 1.31-1.21 (m, 9H, PCHCH2CHaxCHax); 13C{1H} 120.92 (s, CCH2), 34.80 (d, 1J(31P13

C) = 60.5 Hz, PC), 33.14 (s, CCH2), 26.76 (d, 3J(31P-13C) = 11.6 Hz, PCHCH2CH2), 26.01 (d, 2J(31P-13C) = 3.3 Hz,

PCHCH2), 25.95 (d, 4J(31P-13C) = 1.4 Hz, PCH(CH2)2CH2), 24.66 (s, CCH2CH2). IR: ν(PO) = 1123 cm-1. mp 152 °C.

Synthesis of Cy3PO·(HOO)2C(CH2)5 (2). 0.3 mL of H2SO4 (5 mmol) and 13.5 mL of H2O2 (0.135 mol) were combined with THF (25 mL) in a round bottom flask. Cyclohexanone (1.00 mL, 9.7 mmol) was added dropwise over a period of 15 min, while stirring vigorously. After 5 h, 10 mL of CH2Cl2 was added, and NaHCO3 was used to neutralize the mixture to pH 7. The organic layer was collected, washed with H2O (4 times 3 mL) and dried with MgSO4. The solvent was removed from the filtrate in vacuo to produce (HOO)2C(CH2)5. The 1H and 13C NMR data of (HOO)2C(CH2)5 matched those in the literature.53 (Cy3PO·H2O2)2 (297 mg, 0.45 mmol) was dissolved in 5 mL of benzene and added to the flask. The mixture was stirred for 2 h and subsequently concentrated in vacuo to about 2 mL at ambient temperature. Cy3PO· (HOO)2C(CH2)5 (2) was obtained as clear, hexagonal crystals (235 mg, 0.53 mmol, 59% yield). NMR (δ, CDCl3), 3

31

P{1H} 58.01 (s); 1H 10.66 (br. s, 2H, OOH), 1.97-1.79 (m, 15H, PCHCHeqCHeq), 1.81 (t,

J(1H-1H) = 6.4 Hz, 4H, CCH2), 1.75-1.71 (m, 3H, PCH(CH2)2CHeq), 1.58 (quin, 3J(1H-1H) = 6.4 Hz, 4H, CCH2CH2),

1.47-1.37 (m, 8H, PCHCHax, CCH2CH2CH2), 1.31-1.22 (m, 9H, PCHCH2CHaxCHax);

13

C{1H} 109.52 (s, CCH2),

34.67 (d, 1J(31P-13C) = 60.5 Hz, PC), 29.68 (s, CCH2), 26.69 (d, 3J(31P-13C) = 12.1 Hz, PCHCH2CH2), 25.94 (d, 2

J(31P-13C) = 3.3 Hz, PCHCH2), 25.89 (d, 4J(31P-13C) = 0.9 Hz, PCH(CH2)2CH2), 25.55 (s, CCH2CH2CH2), 22.53 (s,

CCH2CH2). IR: ν(PO) = 1123 cm-1. mp 121 °C.

Synthesis of Cy3PO·(HOO)2C(CH2)6 (3). (Cy3PO·H2O2)2 (831 mg, 1.25 mmol) was weighed into a round bottom flask and dissolved in cycloheptanone (3.0 mL, 25 mmol). H2O2 (1 mL, 10 mmol) was added to the flask, the contents was stirred for 1 h, and then left to crystallize. Cy3PO·(HOO)2C(CH2)6 (3) was obtained as colorless, cubic crystals (1067 mg, 2.2 mmol, 88% yield). NMR (δ, CDCl3),

31

P{1H} 56.63 (s); 1H 11.57 (br. s, 2H, OOH), 1.93-1.81 (m, 19H, PCHCHeqCHeq, CCH2),

1.75-1.71 (m, 3H, PCH(CH2)2CHeq), 1.61-1.53 (m, 8H, CCH2CH2CH2), 1.47-1.36 (m, 6H, PCHCHax), 1.31-1.21 (m,



Page 24 of 35

9H, PCHCH2CHaxCHax); 13C{1H} 114.33 (s, CCH2), 34.80 (d, 1J(31P-13C) = 60.9 Hz, PC), 32.36 (s, CCH2), 30.23 (s, CCH2CH2), 26.75 (d, 3J(31P-13C) = 11.6 Hz, PCHCH2CH2), 26.00 (d, 2J(31P-13C) = 2.7 Hz, PCHCH2), 25.95 (d, 4

J(31P-13C) = 0.9 Hz, PCH(CH2)2CH2), 22.84 (s, CCH2CH2CH2). IR: ν(PO) = 1123 cm-1. mp 138 °C.

Synthesis of Cy3PO·(HOO)(HO)C(CH2)5 (4). 300 mg of (Cy3PO·H2O2)2 (0.45 mmol) was dissolved in 10 mL of cyclohexanone (97 mmol) in a 20 mL vial. 1.5 mL aqueous H2O2 (15 mmol) was added to the vial, and the mixture was stirred vigorously overnight, then left to crystallize via slow evaporation of the solvent. Colorless rhombic crystals appeared after three days (327 mg, 0.76 mmol, 84% yield). NMR (δ, CDCl3),

31

P{1H} 53.34 (s); 1H 10.37 (s, 1H, OOH), 9.51 (s, 1H, OH), 1.95-1.78 (m, 17H,

PCHCHeqCHeq, CCHeq) 1.74-1.68 (m, 3H, PCH(CH2)2CHeq), 1.67-1.60 (m, 2H, CCHax), 1.58-1.52 (m, 4H, CCH2CH2), 1.47-1.34 (m, 8H, PCHCHax, CCH2CH2CH2), 1.31-1.19 (m, 9H, PCHCH2CHaxCHax); 13C{1H} 102.65 (s, CCH2), 35.01 (d, 1J(31P-13C) = 60.6 Hz, PC), 34.15 (s, CCH2), 26.80 (d, 3J(31P-13C) = 11.8 Hz, PCHCH2CH2), 26.11 (d, 2J(31P-13C) = 3.4 Hz, PCHCH2), 26.00 (d, 4J(31P-13C) = 1.7 Hz, PCH(CH2)2CH2), 25.40 (s, CCH2CH2CH2), 22.93 (s, CCH2CH2). IR: ν(PO) = 1144 cm-1. mp 33 ºC.

Oxidation of 4 to adduct 2. 40 mg (0.09 mmol) of Cy3PO·(HOO)(HO)C(CH2)5 was dissolved in 1 mL of cyclohexanone in a 20 mL vial. Once completely dissolved, 0.1 mL (1 mmol, 10 eq.) of 35 wt% aqueous H2O2 was added. The reaction mixture was stirred for 4 h, then left undisturbed to crystallize. After 2 days Cy3PO·(HOO)2C(CH2)5 was obtained in the form of large single crystals (37 mg, 0.08 mmol, 92%).

Oxidation of Ph2P-PPh2. 1,1,2,2-Tetraphenyldiphos-phine (Ph2P-PPh2) was synthesized according to a literature procedure in 83% isolated yield.78 The 1H and

13

C NMR signals were assigned using

13

C,1H HMBC and COSY

NMR spectra and following the general trends for δ(13C) and J(31P-13C) in arylphosphines.20-23 The 1H and 31P NMR signals are in agreement with the literature values,78 the 13C NMR data have not been reported previously. NMR (δ, CDCl3), 31P -14.84 (s); 1H 7.39-7.35 (m, 8H, Ho), 7.26 (m, 4H, Hp), 7.20 (m, 8H, Hm); 13C 135.64 (virt. t, J(31P-13C) = 5.1 Hz, Ci) 134.30 (virt. t, J(31P-13C) = 12.6 Hz, Co), 128.66 (s, Cp), 128.20 (virt. t, J(31P-13C) = 3.3 Hz, Cm). mp 96-98 °C.


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41 mg (0.11 mmol) of Ph2P-PPh2 and 47 mg (0.12 mmol) of Cy3PO·(HOO)2CMe2 were filled into an NMR tube flushed with N2 as the inert gas. 0.4 mL of C6D6 was added to the tube, which heated up immediately. Initially, the sample turned into a cloudy solution. However, after a few minutes, Ph2P(O)-P(O)Ph2 precipitated as white powder and settled at the bottom of the NMR tube. The water adduct of the phosphine oxide carrier, Cy3PO·H2O, remained dissolved in C6D6, allowing for easy separation of the product 5 via filtration (32 mg, 74%). The solid Ph2P(O)P(O)Ph2 (5) was redissolved in 0.5 mL of CDCl3 and characterized with 1H, 13C and 31P NMR spectroscopy. The 1H and

31

P NMR signals were in agreement with literature values.80 The

13

C NMR values have not been reported

previously, but they follow the general trends for arylphosphines.20-23 NMR (δ, CDCl3), 31P 23.71 (s); 1H 7.93 (dd, 3J(31P-1H) = 12.5 Hz, 3J(1H-1H) = 7.6 Hz, 8H, Ho), 7.49 (t, 3J(1H-1H) = 7.6 Hz, 4H, Hp), 7.40 (t, 3J(1H-1H) = 7.6 Hz, 8H, Hm); 13C 132.43 (virt. t, not resolved, J(31P-13C) < 2 Hz, Ci), 131.80 (virt. t, J(31P-13C) = 5.1 Hz, Co), 128.57 (virt. t, J(31P-13C) = 6.1 Hz, Cm), 128.32 (s, Cp).

Baeyer-Villiger Oxidation. 23 mg (0.05 mmol) of Cy3PO·(HOO)2C(CH2)4 (1) was dissolved in 3 mL of benzene in a 20 mL vial and one drop of H2SO4 (98 wt%) was added. The contents of the vial was stirred for twenty minutes, then an NMR sample was prepared for 1H and

13

C NMR analyses. δ-Valerolactone was produced in 100% crude

yield, with respect to di(hydroperoxy)cyclopentane. For the purification of the lactone, 1 g of silica (Merck 40, dried for 3 days at 300 °C under vacuum) was added to the vial and the mixture was stirred for 10 minutes. Under these conditions, the phosphine oxide and traces of water were adsorbed on the silica.23 The supernatant containing the lactone was stripped from the solvent in vacuo, and the residue was subjected to microdistillation (110 to 120 °C bath temperature) under high vacuum. Pure δ-valerolactone was obtained as a clear liquid in 85% yield (4 mg, 0.04 mmol). δ-Valerolactone NMR (δ, CDCl3), 1H 4.35-4.31 (m, 2H, OCH2), 2.58-2.51 (m, 2H, (CO)CH2), 2.15-1.63 (m, 4H, OCCH2, OCCCH2); 13C 172.01 (C=O), 69.45 (OC), 29.53 (CC=O), 21.96 (OCC), 18.68 (OCCC), in correspondence with the literature.88 (Cy3PO·H2O2)2 (33 mg, 0.05 mmol) was mixed with 10 mg (0.12 mmol) of cyclopentanone and one drop of H2SO4 (98 wt%) in 1.0 mL of CDCl3. After stirring for twenty minutes, δ-valerolactone was produced in 55% yield with respect to the starting amount of (HOO)2C(CH2)4, as determined by 1H NMR spectroscopy. When double the amount of (Cy3PO·H2O2)2 (66 mg, 0.11 mmol) was reacted with 10 mg (0.12 mmol) of cyclopentanone and one drop



of H2SO4 (98 wt%), 100% conversion occurred, but a product mixture resulted that consisted of δ-valerolactone and traces of adduct 1. 92 mg (0.2 mmol) of Cy3PO·(HOO)2C(CH2)4 (1) and 17 mg (0.2 mmol) of cyclopentanone were dissolved in CDCl3 (1.0 mL) in a vial. 1 drop of H2SO4 (98 wt%) was added, and the contents was stirred for 20 min. Both, (HOO)2C(CH2)4 and cyclopentanone were oxidized to δ-valerolactone in 58% yield as determined by 13C NMR.

Cy3PO·(HOO)2C(CH2)4 (1) (46 mg, 0.1 mmol) was reacted with 10 mg (0.1 mmol) of cyclohexanone and one drop of H2SO4 (98 wt%) in 1.0 mL of CDCl3. A mixture of δ-valerolactone (21% yield) and ε-caprolactone (23% yield) was produced. Reacting the adduct Cy3PO·(HOO)2C(CH2)5 (2) with cyclopentanone in a 1 : 1 ratio resulted in a mixture of δ-valerolactone (24% yield) and ε-caprolactone (22% yield). ε-Caprolactone NMR (δ, CDCl3), 1H 4.24-4.20 (m, 2H), 2.65-2.61 (m, 2H), 1.88-1.82 (m, 2H), 1.79-1.70 (m, 4H);

13

C 176.22 (C=O), 69.30 (OC), 34.57 (CC=O), 29.34 (OCCC), 28.93 (OCC), 22.99 (CCC=O), in

correspondence with the literature.89

AUTHOR INFORMATION Corresponding Author *J.B.: e-mail, [email protected]; tel, (979)845-7749. Author Contributions The manuscript was written through contributions of all authors. All authors have given approval of the final version of the manuscript. Notes The authors declare no competing financial interest.

ACKNOWLEDGEMENT This work was supported by the National Science Foundation (CHE-1300208).


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Graphical Abstract

Synopsis: The new peroxides stabilized by hydrogen-bonding to Cy3PO are safe and easy to synthesize, and they perform catalyst-free Baeyer-Villiger oxidations efficiently under mild conditions in one organic phase.


Di(hydroperoxy)cycloalkanes Stabilized via Hydrogen Bonding by

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