Medium-sized cyclic bis(anisylphosphonothioyl)disulfanes and their corresponding cyclic sulfane-structures and most characteristic reactions

Article abstract of DOI:10.1039/c9nj03682b

Cyclic 8-, 9-, 10-, and 12-membered bis(anisylphosphonothioyl)disulfanes were synthesized. Next, structurally related 7 to 9-membered cis and trans sulfanes were isolated as a result of sulfur atom extrusion from the parent cyclic disulfanes. The results of the desulfurization of the disulfanes using triphenylphosphine were compared to the results obtained for desulfurization of the respective bis(anisylphosphodithioates) with the aid of 2-chloro-N-methylpyridinium iodide. Cyclic disulfanes predominantly provide trans-sulfanes, and the expansion of their ring sizes causes the cis/trans isomer ratio of the cyclic sulfanes to increase. Moreover, bis(anisylphosphodithioates) mainly afford cis-sulfanes, and the cis/trans isomer ratio is greater than 3 : 1. Mechanistic and stereochemical aspects of cyclic disulfane desulfurization have been presented to elucidate the above findings. Although it was suggested by calculations that cis-sulfanes are more thermodynamically stable than their respective trans isomers, the cyclisation is a kinetically controlled reaction, which results in predominance of trans-sulfanes in the case of trans-disulfane desulfurization. Disulfanes exhibit thermal and solvolytic stability (except in wet DMSO). A characteristic persistent deep-blue coloration of methanolic ammonia solutions is an unusual feature of cyclic disulfanes. The mechanism of their ammonolysis has been studied and has been compared to that of the respective reaction performed on acyclic disulfanes. Ammonia solution of an acyclic disulfane is colourless and contains phosphosulfenamide and dithiophosphate, while the respective mixture of cyclic disulfane consists of thiophosphonoamide-phosphonodithioate, O-methyl thiophosphonate-phosphonodithioate and deep blue sulfur-ammonia species. Detailed X-ray structural analysis was performed for all trans-disulfanes and cis-and trans-sulfanes. They were compared to each other and to their acyclic or cyclic known analogs that comprise common subunits. 8-, 9-, 10-, and 12-membered disulfanes exist as trans isomers exclusively both in the solid state and in solution. They are significantly more stable than their hypothetical cis isomers, as shown by DFT calculations. The PSSP torsion angles of cyclic disulfanes lie in the range of 94° to 125° and increase with the size of the ring. These values are greater than the typical torsion angles found for the respective non-cyclic disulfanes. The greater stability of the cis-sulfanes was confirmed by calculations and can be ascribed mainly to the characteristic anisyl-anisyl stacking. Special attention was paid to the importance and the role of weak hydrogen bonds (CH..O/S) in conformational stabilization and intermolecular interactions. The conformations of cyclic disulfanes and cyclic sulfanes found in the crystalline state were also preserved in solution (variable temperature NMR). A Karplus relationship has been established between the dihedral angles and vicinal H-P coupling constants for all disulfanes and sulfanes. The effects of solvent on the ¹H NMR chemical shifts (ASIS) were determined and were associated with the dipole moments of the sulfanes.

Full text of DOI:10.1039/c9nj03682b

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Medium sized cyclic bis(anisylphosphonothioyl)disulfanes and the corresponding
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DOI: 10.1039/C9NJ03682B
related cyclic sulfanes - structure and the most characteristic reactions
Witold Przychodzeń a*, Jarosław Chojnacki b, Łukasz Nierzwicki c
aDepartment of Organic Chemistry, Gdańsk University of Technology, G. Narutowicza 11/12, 80233-PL, Gdańsk, Poland, bDepartment
of Inorganic Chemistry, Gdańsk University of Technology, G. Narutowicza 11/12, 80233-PL, Gdańsk, Poland, and cDepartment of
Physical Chemistry, Gdańsk University of Technology, G. Narutowicza 11/12, 80233-PL, Gdańsk, Poland. *Correspondence e-mail:
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witold.przychodzen@pg.edu.pl
ABSTRACT
Cyclic 8-, 9-, 10-, and 12-membered bis(anisylphosphonothioyl)disulfanes were synthesized. Next, structurally related 7 – 9-membered cis
and trans sulfanes were isolated as a result of sulfur atom extrusion from parent cyclic disulfanes. Results of desulfurization of disulfanes
with the use of triphenylphosphine have been compared to results obtained for desulfurization of the respective bis(anisylphosphodithioates)
with the aim of 2-chloro-N-methylpyridinium iodide. Cyclic disulfanes predominantly provide trans-sulfanes and expansion of their ring size
causes a cis/trans isomer ratio of cyclic sulfanes to increase. On the other hand bis(anisylphosphodithioates) give mainly cis-sulfanes and the
cis/trans isomer ratio is greater than 3:1. Mechanistic and stereochemical aspects of cyclic disulfanes desulfurization have been presented to
elucidate the above mentioned findings. Although it was suggested by calculation that cis-sulfanes are more thermodynamically stable than
the respective trans isomers, the cyclisation is kinetically controlled reaction, which results in the predominance of trans-sulfanes in the case
of trans-disulfane desulfurization.
Disulfanes exhibit thermal and solvolytic stability (except wet DMSO). A characteristic persistent deep-blue coloration of methanolic
ammonia solutions is an unusual feature of cyclic disulfanes. Mechanism of their ammonolysis have been studied and have been compared to
the respective reaction performed on acyclic disulfanes. Ammonia solution of an acyclic disulfane is colourless and contains
phosphosulfenamide and dithiophosphate while the respective mixture of cyclic disulfane consists thiophosphonoamide-phosphonodithioate,
O-methyl thiophosphonate–phosphonodithioate and deep-blue sulfur-ammonia species.
The detailed X-ray structural analysis was performed for all trans-disulfanes and cis- and trans-sulfanes. They were compared to each other
and their acyclic or cyclic known analogs that comprise common subunits. 8-, 9-, 10-, and 12-membered disulfanes exist as trans isomers
exclusively, both in the solid state and in solution. They are significantly more stable than their hypothetical cis isomers as shown by DFT
calculations. The PSSP torsion angle of cyclic disulfanes lies in a range 94-125o, increasing with the ring size. These values are greater than
a typical torsion found for the respective non-cyclic disulfanes. The greater stability of cis-sulfanes was confirmed by calculation and can be
ascribed mainly to the characteristic anisyl-anisyl stackings. Special attention was paid to the importance and the role of weak hydrogen
bonds (CH...O/S) in conformational stabilization and intermolecular interactions. The conformation of cyclic disulfanes and cyclic sulfanes
found in the crystalline state is also preserved in the solution (variable temperature NMR). A Karplus relationship has been established
between the dihedral angles and vicinal H-P coupling constants for all disulfanes and sulfanes. The effect of solvent on 1H NMR chemical
shifts (ASIS) has been determined and associated with dipole moments of sulfanes.
.
1. INTRODUCTION
Simple acyclic bis(dialkylphosphorothioyl)disulfanes (RO)2P(S)SSP(S)(OR)2 find use in the industry as sulfur donors
and as fast accelerators for natural and synthetic rubbers vulcanization 1 , as efficient sulfurization agents for oligo(nucleoside
phosphorothioates) synthesis 2 as well as ligands forming stable complexes with a plethora of metal ions in coordination
chemistry. 3 Due to synthetic difficulties, literature on respective phosphonodithioates R(RO)PS2 chemistry is not as
comprehensive as it is the case with their analogues, i.e. phosphorodithioates (RO)2PS2 and phosphinodithioates R2PS2.
However, diverse applications of phosphonodithioates R(RO)PS2 in the lubricant industry (multifunctional additives), the
mining industry (agents for flotation and ore extraction), agriculture (pesticide derivatives), as potential antibacterial agents are
highly valued. 4 Being efficient bidentate chelating agents bis(phosphonodithioic) acids are particularly interesting in this
respect since they form much more stable complexes with metal ions than monodentate phosphonodithioic acids RP(OR)SSH.
5,6 On the other hand, related acyclic bis(phosphothioyl)sulfanes are a rare and unexplored class of phosphorus-sulfur organic
compounds. In the past they were used occasionally as fungicides. 7
Conformational and stereochemical analysis of phosphorus heterocycles having more than six members is still relatively
unexplored. More than a decade ago, we used the reaction between Lawesson’s reagent (LR) and diols/diphenols for the
efficient synthesis of bis(anisylphosphonodithioic) acid 1 derivatives and among them the unique 8-, 9-, and 10-membered
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cyclic disulfanes 2a and 2b. It seems to be evident that a high-yielded formation of our medium-sized heterocycles without
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oligomeric by-products was connected with their fixed structure containing the most preferred a zig-zag motif of the SPSSPS
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unit. A similar procedure has been applied recently by Van Zyl’s group for successful synthesis of the related cyclic
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bis(ferrocenylphosphonothioyl)disulfanes 2 (2e as an example).
Therefore, P-ferrocenyl instead P-anisyl containing
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heterocycles were obtained in the reaction between ferrocenyl analog of Lawesson’s reagent (FcLR) DaOndI: 110,.120-3d9i/oCl9sN(Je0t3h6y8l2eBne
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glycol, trans-1,2-cyclohexanediol, and pentaerythritol) followed by subsequent oxidation. Next, they were characterized by H,
31P NMR, single-crystal X-ray analysis and their electrochemical properties were investigated using cyclic voltammetry.
Unfortunately, cyclic voltammetry was used only to test the reversibility of the ferrocenium-ferrocene and not disulfide-thiol
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redox couple. Previously, Woollins
prepared analogous eight-, nine-, and ten-membered diselenides starting from the
selenium analog of LR (―Woollin’s reagent‖) following a similar protocol. Quite recently, he has elaborated and applied one-
pot procedure for obtaining 8- to 10-membered cyclic disulfanes using FcLR. 11
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The constitution of cyclic medium-sized bis(anisylphosphonothioyl)disulfanes 2a and 2b was confirmed earlier by means of
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spectroscopic methods (1H and 31P NMR). We have already presented the preliminary results on crystal structure of 8- and
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10-membered disulfanes 2a and 2d with comparison to the structure of their ferrocenyl analogues.
So far, there is no
comparative study of the crystal structure of cyclic disulfanes and their structure in solution. Similarly, the effect of ring size
on the basic structural parameters of cyclic disulfanes 2 has not been investigated. Their conformation in solid state as well in
solution is not yet completely understood. In addition, the chemistry of cyclic bis(phosphonothioyl)disulfanes 2 is still not fully
explored, albeit some of our previous experimental results confirm their similar behaviour to acyclic disulfanes.13 For example,
we have shown that 9-membered bis(anisylphosphonothioyl)disulfane 2b undergoes nucleophilic substitution exclusively at
the phosphorus atom when it reacts with sodium N-methyl benzohydroxamate. We have proved that the reaction proceeds
with the inversion of the configuration at phosphorus and the resulting unstable >P(S)SS- anion rapidly loses its sulfur atom in
statu nascendi at a rate faster than the rate of its trapping by methyl iodide. On the other hand, we have observed that the
sterically more demanded sodium N-tert-butyl benzohydroxamate already results in the reduction of disulfane 2b giving,
among others, the respective benzamide, as Lawesson’s reagent does. 14 Next, we affirmed that sodium diethyl malonate attack
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preferably a soft sulfur atom of the disulfide bridge of 2b giving the respective 2-phosphonothioylsulfenyl malonates , i.e.
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behave as other simple carbanions against acyclic disulfanes 2.
Our research on the reactivity of cyclic
bis(phosphothioyl)disulfanes 2 described above suggests that their behavior with respect to other nucleophilic reagents should
be consistent with the HSAB theory.
It is well known that disulfanes, including diorganyl RSSR, can be desulfurized to the respective sulfanes using P(III)
reagents. However, it would be important and interesting to verify whether such a transformation performed on cyclic
bis(phosphonothioyl) disulfanes 2 will lead to cyclic sulfanes 3 (as a result of intramolecular reaction) or to polysulfanes (as
a result of intermolecular ring opening).
The results of previous works dealing with the formation of cyclic sulfanes 3 are given in Scheme 1 and 2. So far, only few
cyclic cyclic bis(anisylphosphonothioyl)sulfanes 3 have been isolated. In the reaction between ethylene glycol and 1-aryl-1,3-
propanediols with LR in boiling acetonitrile where the respective 5-membered 2-anisyl-1,3,2-dioxaphospholane 2-sulfide 4a
and and 6-membered 2-anisyl-1,3,2-dioxaphosphorinane 2-sulfide were principal heterocycles, traces of 7-membered 3a (6%)
and 8-membered sulfanes (3-6%) were obtained. 17,18 Unfortunately, due to limited spectroscopic data (a low resolution 1H
NMR spectrum) the stereochemistry of cyclic sulfane 3a was not further assigned. Herein, our structural studies (based on
comparison of 1H and 31P NMR spectra as well as melting point of both authentic isomers of 3a) confirm unequivocally that
Shabana 14 obtained merely trans-3a (see section 2.7). On the other hand, NMR spectra reported by Hue 15 proved to be
insufficient to give unambiguously the geometry of 8-membered sulfanes using our spectroscopic data.
A similar condensation of bis(methylphosphonodithioic) acids derivated from 1,2-, 1,3- and 1,4-diols leading to related cyclic
sulfanes 3 (with P-methyl instead of P-anisyl substituents) was described by Pudovik. 19 As a result 7- and 8-membered
sulfanes 3 were obtained albeit in very low yields (25 and 7%, respectively) and characterized (IR, NMR). The largest 9-
membered sulfane, namely 2,4-dimethyl-1,5,3,2,4-dioxathiadiphosphonane 2,4-disulfide, was not detected due to its alleged
rapid oligomerization. Because apparently a mixture of cis and trans isomer was formed in the above mentioned reaction
conditions, Pudovik had to isolate only one isomer of 7-membered 2,4-dimethyl-1,5,3,2,4-dioxathiadiphosphepane 2,4-
disulfide. Unfortunately, also in that case, the data we have obtained below does not allow us to determine which of the isomer
was actually isolated. Almost twice the smaller value of the geminal P-P coupling constant (2JPP = 7.5 Hz vs 13.0 Hz for trans-
3a as we report below) may indicate that the key effect on coupling in cyclic sulfanes 3 may, however, be the size of the P-
substituent.
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Scheme 1 Cyclic 7- and 8-membered bis(phosphonothioyl)sulfanes 3 of unknown geometry formed as by-products from the
corresponding bis-phosphonodithioic acids 1. 17-19
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It seems also interesting to note, that in 1991 a Japanese group obtained a mixture of stable, sterically protected small ring
analogous heterocycles. 20 Sulfurization of diphosphalene ArP=C=PAr (Ar = 2,4,6-But3C6H2) with elemental sulfur afforded
the respective cis- and trans isomers of 4-membered sulfanes accompanied by trans 5-membered disulfane (Scheme 2). Next,
every compound was isolated, characterized, and their crystal structure was successfully solved. It was found that the
corresponding cis-sulfane was the main product of ArP=C=PAr sulfurization. Additionally, desulfurization of trans-3,5-
bis(2,4,6-tritertbutylphenyl)-[1,2,3,5]dithiadiphospholane 3,5-disulfide yielded trans-2,4-bis(2,4,6-tritertbutylphenyl)-
[1,2,4]thiadiphosphetane 2,4-disulfide sulfane (and vice versa). No information was provided about the reaction mechanism or
diagnostic 3JPP and 2JPP coupling constant values in this report.
Scheme 2 Examples of stable small ring heterocycles of containing P-S-P and P-S-S-P linkages. 20
The experimental results on small and medium-sized cyclic bis(phosphothioyl)sulfanes described above confirm our
below-stated statements (see infra) that cis-sulfanes 3 can be generally more thermodynamically stable than their opposite
isomers, and that mainly trans-sulfanes 3 are formed from small rings of trans-disulfanes 2.
2. RESULTS AND DISCUSSION
2.1 Synthesis of cyclic disulfanes 2 and sulfanes 3
New cyclic 9-membered 2b’ containing ethoxycarbonyl moiety (as suitable starting material for further functionalization or
tethering, 85% yield) and 12-membered 2d (18% yield) as well as previously studied 8-membered 2a, 9-membered 2b and 10-
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membered 2c disulfanes have been obtained using our modified procedure 8 without isolation of di-tert-butylammonium
bis(anisylphosphodithioates) 1 x 2 ButNH2 precursors (Scheme 3). Also, larger i.e. 14-, 16- and 20-membered disulfanes
2 synthesis has been essayed, but without success. In this case, complex mixtures of respective oxidation products of bis-
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phosphonoditioates 1 were tentatively attributed to cyclic disulfane macrocyclic oligomers (based on 31P NMR analysis; see
DOI: 10.1039/C9NJ03682B
Figure S27).
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Scheme 3 Structures of cyclic anisyl disulfanes 2a-d under the study and related known cyclic and acyclic disulfanes 2e-2i that
have been used for a comparison study.
Next, cyclic disulfanes 2a-2d have been treated with triphenylphosphine in acetonitrile – dichloromethane (1:1 v/v)
and the corresponding cyclic sulfanes 3a-3d as a mixture of cis/trans stereoisomers were formed quantitatively as a result of
the S-S bond splitting and desulfurization. Just a few minutes after 2a-2c and triphenylphosphine dissolution, the recorded 31
P
NMR spectra mixtures consisted only three signals of both isomers of cyclic sulfanes 3a-3c and triphenylphosphine sulfide (δP
43 ppm) (Figure 1 a-c). The presence of two additional broad phosphorus peaks in the spectrum of the 2d–Ph3P mixture
(Figure 1d) probably indicates the formation of 22-membered dimeric bissulfane 3d’ as a mixture of isomers (Scheme 4).
Scheme 4 Postulated intermolecular dimerization of Ph3P-activated disulfane 2d leading to bissulfane 3d’.
To obtain cyclic sulfanes 3a-c we also used another method developed for the first time by Kato. 7 In this way, treating the
appropriate di-tert-butylammonium salts of 1 with Mukaiyama’s condensation agent (M.R.) afforded both isomers of 3a and
3b. As a result 3b isomers were separated but a slight dominance of the cis over the trans isomer was noted. Also, the reaction
leading to 3a starting from ethylene glycol derivative 1a gave even more significant predominance of cis-3a over trans-3a.
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However, in that case the reaction mixture consisted up to 40% of 5-membered phospholane 4a (see below) as a by-product (a
40:20:40 cis-3a:trans-3a:4a ratio).
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All routes to cyclic sulfanes 3 under the study are presented in Scheme 5. The mechanism of these interesting desulfurization–
cyclisation reactions, and their stereoselectivity is discussed below. Next, the cis and trans isomers of cyclic sulfanes 3a-3c
obtained according to above mentioned procedures were successfully separated chromatographically and their careful
crystallization gave good quality crystals to perform X-ray crystallography for solving their structure. Unfortunately, attempts
to isolate 3d isomers were unsuccessful.
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Scheme 5 Synthetic routes to cyclic sulfanes 3 of which 3a is an exceptional example: (a) from disulfane 2a using Ph3P
(method A), (b) from bis(phosphonodithioate) 1a using Mukaiyama’s reagent (Method B), (c) sulfane 3a as a side product
during dithio acid 1a condensation, leading exclusively to 4a according to Shabana 17 and Pudovik 19 works.
2.2. Mechanism of desulfurization of cyclic disulfanes 2 with triphenylphosphine
The reaction of open-chain bis(phosphoyl)disulfanes with P(III) compounds, including phosphines, has been already
described 21 and spectroscopic properties of acyclic bis(phosphorothioyl) sulfanes 3 as desulfurization products were studied
by Grossman. 22 Perlikowska et al 23 used such a transformation for preparation of optically enriched phosphine sulfides and
phosphine oxides, where three acyclic enantiomerically pure bis(phosphorothioyl)disulfanes 2 were used as sulfur atom
donors. Unfortunately, the fate of PSP sulfanes 3, which were by-products of this reaction, was not followed and the sulfides
3 themselves were not isolated or characterized.
Based on a generally accepted mechanism described for related acyclic bis(phosphinoyl)disulfanes 2 (e.g. 2g) 24, it
was assumed that at the crucial step of the reaction phosphonium intermediate arises immediately (even at -100 oC) after the
nucleophilic attack of phosphine on one bridged sulfur atom. In the next step, nucleophilic phosphodithioate (a leaving group)
attacks phosphonium salt giving phosphine sulfide and trithioanhydride sulfane 3 (see Scheme 6).
The intriguing results of our preliminary experiments using cyclic disulfanes 2 indicated that their behavior towards
phosphines may be slightly different. We suspected the special role of liberated nucleophilic anisylphosphonodithioate on the
course of the reaction due to its proximity. Therefore, we decided to investigate in detail the mechanism of the extrusion of
sulfur from 2.
Since the phosphodithioic acids 1 salts (liberated in the reaction) are not optically active as they are a hybrid of two
energetically equivalent resonance structures, the desulfurization reaction carried out on one disulfane 2 diastereomer should
give an equal mixture of two sulfane diastereomers, cis-3 and trans-3. The question remains why the cis/trans isomer ratio of
sulfanes 3 never reaches unity and why its value increases nearly proportionally with increasing ring size of disulfane 2.
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Scheme 6 Proposed mechanism of desulfurization-cyclisation of cyclic disulfanes 2 (in which 2a is an exceptional example) as a special case
of the more general desulfurization mechanism supplemented with the postulated specific contribution of acetonitrile in the formation of
cyclic five-membered phospholane 4a.
Therefore, the problem associated with the desulfurization mechanism of our cyclic disulfanes 2 in its stereochemical aspect
remains unresolved due to the lack of strong stereochemical proof. It was not known whether the reaction runs via
pentacoordinated trigonal bipyramidal phosphorus and whether its mechanism is concerted or stepwise. If both isomers of
3 are formed in unequal amounts and their mutual interconversion is not possible then there is a need to reconsider the
unquestioned mandatory reaction mechanism and propose a different reaction pathway.
At first, quantitative analysis of reaction mixtures of cyclic disulfanes 2a, 2b and 2c and Ph3P (by means of 31P NMR) was
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carried out. Next, a much more reliable quantitative analysis based on integration of all signals in H NMR spectra followed by
chromatographic isolation of both isomers of 3 was done. All three approaches used showed that the populations of
diastereomers of 3 can be accurately estimated both by 31P NMR and 1H NMR techniques. In this way, we have found that
only the desulfurization of the largest 10- and 12-membered disulfanes (2c and 2d) yields both diastereoisomers of the
corresponding sulfanes 3 in almost equal amounts (see Figure 1). On the other hand, in the case of desulfurization of disulfane
2a and 2b, the corresponding cis/trans isomer ratio was 0.24 and 0.50. Thus, if triphenylphosphine mediated desulfurization of
2a provides four times more of trans-3a, it may mean that the key rate-determining step proceeds in an SNi-like manner with
retention of configuration at the phosphorus atom. On the other hand, a dissociative SN1(P) mechanism should be excluded
because it would have to supply equal amounts of cis- and trans-3a (vide infra).
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Fig. 1 202 MHz 31P NMR spectra of reaction mixtures of disulfanes 2a-2d with Ph3P showing the presence of cis and trans isomers of cyclic sulfanes (a) 3a,
(b) 3b, (c) 3c, and (d) 3d (δP 87.0 and 87.1 ppm). Additional broad signals of dimeric 22-membered bissulfane isomers 3d’ (δP 85.3 and 85.9 ppm)
accompanying both 3d isomers (d). The peak at δP 43 ppm corresponds to the signal of triphenylphosphine sulfide which is the only by-product of the
desulfurization.
Thus, the above mentioned results indicate that the electrophilic phosphorus atom and the nucleophilic
dithiophosphonodithioate anion >P(S)S- being generated from trans-disulfane 2 begin to move away gradually from each other
since the moment of the S-S bond heterolysis during the desulfurization. Since the likelihood of finding of two ends of the
bifunctional chain decreases with increasing the length of the chain, it is obvious that in the case of 2d desulfurization the
spacing between both reactive ends reaches the maximum. Therefore, the open-chain intermediate derived from 2d has much
more time to preorganization, because its cyclisation is the slowest step of the reaction. As a result, populations of cis and trans
isomer are nearly equal for 2d as well as for 2c. Besides, in the case of twelve-membered 2d the probability of reactive centers
contact is so low that the probability of intermolecular dimerization also increases (see Scheme 4). At least two of three above
postulated and described desulfurization steps (i.e.: the S-S bond splitting, preorganization and cyclisation) have different rates
for different ring sized disulfanes 2. Because it is well known that the S-S bond cleavage is the fastest process during disulfane
2 desulfurization, the rate of cyclisation and the preorganization step dependent on it should affect the isomeric distribution.
Thus, there is a correlation between the cis/trans ratio and the size of cyclic disulfane 2 ring.
To prove that the cyclisation rate affects the cis/trans isomer ratio, we decided to slow it down by lowering the pH of the
reaction medium. We have found that the addition of 2,4-dinitrobenzoic acid to a mixture of 2a and Ph3P causes a slight
increasing of the cis/trans isomer ratio of 3a (from 0.26 to 0.31) apparently due to a reverse protonation of phosphodithioate
anion that is formed in the first stage of the reaction (Figure S26). This result strongly suggests that cyclisation step rate
determinates the cis/trans ratio of cyclic sulfanes 3 during cyclic disulfanes 2 desulfurization.
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Page 8 of 27
On the other hand, we have found that desulfurization-condensation experiments performed on bis-anisylphosphonodithioic
acids 1 salts with the aim of Mukaiyama’s reagent give the preference of cis isomers of 3a and 3b (the cis/trans ratio: 2.0 and
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3.8, respectively, see Figure 2). Almost two-fold increase in the cis/trans isomer ratio for 3b compared to 3a is most likely
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caused by the formation of 5-membered 4a in a competitive reaction during 1a desulfurization. CertainlDyOinI: 1t0h.a10t3c9a/sCe9NthJ0e3d6i8r2eBct
precursors of cyclic sulfanes 3 are fully preorganized because they have been formed from acyclic 1 rather than cyclic
2 starting materials. Additionally, the lower reactivity of 2-(anisylphosphonothioylsulfenyl)-1-methylpyridinium chlorides in
relation to (anisylphosphonothioylsulfenyl) triphenylphosphonium salts (both are the reactive intermediates and direct
precursors of 3) could have a significant influence on the preferential formation of the cis isomers in the process of
bisdithiophosphonic acids 1 salts desulfurization. Evidently, the results of experiment performed on bisdithiophosphonic acids
1 salts are proof that cis-3 isomers are more thermodynamically stable than their trans isomers. This statement will be further
supported by DFT calculations (see below).
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Fig. 2 31P (a) and 1H (b) NMR spectrum of the reaction mixture of 1b and M.R. in C6D6 after chromatographic separation from two byproducts, namely, 1-
methylpyridine-2-thione and tert-butylammonium iodide.
It was also necessary to explain the mechanism of the formation of a 5-membered by-product 4a that accompanied the
7-membered sulfane 3a isomers. It was found that when we performed the desulfurization of 2a using Ph3P in pure acetonitrile
comparative amounts of cis-3a, 5-membered phospholane 4a and thioacetamide were formed next to the main product i.e.
trans-3a (55%) (see Scheme 5). On the other hand, desulfurization of 1a salt in pure CH2Cl2 gave 40% of 4a. Therefore,
acetonitrile (as a competitive nucleophile) taking part in a reversible exchange with the thiotriphenylphosphonium cation (in
method a), and to a larger extent the already formed preorganized intermediate with remote reactive end groups (in method b)
are both responsible for the side-product (i.e., 4a) formation during sulfane 3 synthesis trials.
2.3 Cyclic disulfanes 2 stability and decomposition
Among cyclic disulfanes 2a-2d, disulfane 2b seems to be the most stable. After 10 years of storage of its samples, there was
no characteristic unpleasant sulfur-like odour of decomposition products and its melting point did not change. Detailed analysis
of the recorded 1H NMR spectra did not show any conformational changes, trans-cis isomerization, ring destruction or
oxidation of 9-membered disulfane 2b for a broad temperature range. 2b stays intact in dichloroetylene at 90 oC for 3 hrs as
well as in nitrobenzene-d5 solution at 190 oC for 0.5 h. The polymerization processes start only above 200 oC and are initiated
by homolytic scission of the disulfide bridge (see: Figure S24 and 25).
Ring strain energy calculations (the 6-311G* basis set with MN12SX functional) based on hypothetical hydrogenolysis of
cyclic disulfanes 2 revealed that both 2c and 2b are the most stable and have a stability advantage of 1.2 and 4.4 kcal/mol over
2a and 2d, respectively. It should be stressed that the calculated stability order of R10 ~ R9 > R8 >> R12 for cyclic disulfanes
2 is inverse than that for medium-sized cycloalkanes (R12 > R8 > R9 ~ R10) and the respective energy differences are twice
smaller (Table 1).
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It is known that in medium-sized carbocycles an additional stress occurs due to the presence of transannular hydrogen atoms
pointed inwards (so-called transannular strain). On the other hand, the atomic radius of phosphorus and sulfur atoms present in
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cyclic disulfanes 2 causes that the length of bonds between them and thus the "ring surface" increases. Thus, in consequence,
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also distances the transannular hydrogen atoms from each other. Inspection of the data in Table S8 leads to the conclusion that
DOI: 10.1039/C9NJ03682B
transannular hydrogens causes unfavorable H-H repulsive interactions only in the case of both isomers of the largest 12-
membered disulfane 2d, where the corresponding pairs of transannular hydrogens are placed on the same side of the ring.
Disulfane 2a is free of transannular hydrogens and in other disulfanes 2 that contain one or two transannular hydrogens, they
approach the sulfur ring atoms and can rather form attractive intramolecular H-bonds.
9
Table 1 Relative (in kcal/mol) energies of cyclic disulfanes 2 (MN12SX/6-311*/PCM) and the respective cycloalkanes (E. V.
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Anslyn and D. A. Dougherty, Modern Physical Organic Chemistry, University Science Books, Sausalito, 2006, p. 108).
Compd
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cycloalkane
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As can be clearly seen, cyclic bis(phosphothioyl)disulfanes 2 are much more thermally stable than dialkyl, diaryl, and
especially dithiocarbamoyldisulfanes (thiurams). Since the later ones are used in vulcanization processes as sulfur donors and
ultra-accelerators (the vulcanization initiation temperature in the range of 70-150 oC), there is a need to discover and study
appropriate organic disulfanes, which decompose in a controlled manner in the range of 200-300 oC. Thanks to the generation
of thiyl radicals, they are effective halogen-free flame retardants in various polymer compositions. 25 Thus, exceptional thermal
durability is a very valuable property of cyclic disulfanes 2 that can also be potentially promising reagents or additives used in
polymer industry.
Some of the cyclic disulfanes 2 under the study exhibit improved hydrolytic stability compared to their acyclic analogs. And
so, 2b preserves intact crystal structure after a few months of storage in an open vessel, while acyclic 2i shows substantial
deterioration after just a few days. On the other hand, we have noticed that disulfane 2b is rapidly decomposed in DMSO-d6
solutions due to oxidation and subsequent hydrolysis. On 31P NMR spectrum of 2b solution in DMSO-d6 within a few minutes
at 80 oC there appear additional well-resolved multipletes (Figure S28). Their splitting patterns and integration correspond,
with all probability, to both diastereomers of 2b S-oxide (48%) in a 1:1 ratio. Unfortunately, all attempts to isolate 2b S-oxide
were unsuccessful probably due to its higher polarity and susceptibility to further hydrolysis. 2b S-oxide hydrolysis starts
already in a NMR tube and is caused by the presence of residual water in standard DMSO-d6. As a result, originally colourless
solution of the starting disulfane 2b turns pale yellow and opaque due to precipitation of elemental sulfur, and there is also
a strong odour of dimethylsulfane. At this stage of 2b deterioration, 31P NMR analysis showed the presence of an additional
signal (δP = 84 ppm) from the endproduct of 2b S-oxides hydrolysis containing the >P(S)OH fragment (Scheme 7). Although
a similar redox reaction between simple diorganyl disulfanes RSSR and DMSO is already described in literature, there are no
reports on the analogous reaction for bis(phosphoryl)disulfanes 2.
Scheme 7 Proposed mechanism of cyclic disulfane 2b decomposition caused by wet DMSO.
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Page 10 of 27
2.4 Cyclic disulfanes 2 ammonolysis
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It turned out that the most intriguing and characteristic reaction of cyclic disulfanes 2 is their ammonolyVsiiesw,AwrtihcliecOhnlcinaen
be performed in liquid ammonia at -33 oC as well as in methanolic ammonia solutions at ambient tempeDraOtIu:r1e0..1U03n9l/iCk9eNtJh0e3i6r82B
open-chain acyclic analogs 2h and 2i, all cyclic disulfanes 2a-2d under the study give deep-blue solutions immediately after
their dissolution in ammonia. In both cases, different ammonolysis products are also formed. At first, we decided to investigate
acyclic disulfane 2h reactivity toward ammonia using 31P NMR. Based on NMR analysis we have confirmed that
bis(diisopropylphosphorothioyl)disulfane 2h treated with a saturated methanolic ammonia in excess gives a colourless solution
of the respective sulfenamide (iPrO)2P(S)SNH2 5h (δP = 81.3 ppm, ca 90%) which is the only product of the nucleophilic
substitution on the bridged sulfur atom of 2h after 1h at room temperature. Later the sulphenamide 5h slow-rate decomposition
reactions start leading after two weeks to the formation of a stable end-product, namely ammonium
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diisopropylphosphorothioylthioate 1h (δP = 109.1 ppm, >95%) (Figure 3).
Fig. 3 {1H} 31P NMR spectra of [(iPrO)2P(S)S]2 2h in 10 M methanolic NH3 recorded after 16 h, 48 h, 3 days and 2 weeks (from a bottom to a top) showing
slow decomposition of (iPrO)2P(S)SNH2 5h δP = 81.3 ppm (t, J = 11.5 Hz) into (iPrO)2P(S)S-NH4+ 1h δP = 109.1 ppm (t, J = 13.2 Hz). Minor signals at 82.21
ppm (t, J = 12.4 Hz) and 70.40 ppm (tt, J1 = 11.1 and J2 = 4 Hz) correspond to unreacted starting material 2h and amide (iPrO)2P(S)NH2 6h, respectively.
As was mentioned above, cyclic disulfanes 2 dissolved in saturated methanolic ammonia give solutions with a long-
lasting deep-blue coloration (the color last over two months in a screw vial). EPR experiments performed with these blue
solutions did not reveal any signal of radicals and the UV-Vis absorption peak position (λmax = 563 nm, ε = 6528) was constant
for all disulfanes 2a-2d. Therefore, we assumed that one type of ―NS‖ species that is formed is responsible for the deep-blue
coloration. 26 As the concentration of ammonia decreases due to evaporation from a semi-open UV cuvette, the color loses its
intensity and eventually disappears (Figure 4).
Fig. 4 UV spectrum of 7.2 x 10-5 M solution of 2b in 10 M methanolic NH3 recorded in open cuvette showing a decay of
absorbance in time (2 min → 45 min).
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New Journal of Chemistry
The recorded 31P NMR spectrum of the deep-blue 2b ammonia-methanolic solution confirmed that the main ammonolysis
product 6b has the same structure as the sulfane 3b ammonolysis product and posses two functional groups, i.e. >P(S)NH2 (δ
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4
= 77.2 ppm) and >P (S)S- (δ = 105.3 ppm) (Figure 5).
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DOI: 10.1039/C9NJ03682B
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Fig. 5 202 MHz 31P NMR spectra of the reaction mixture between methanolic ammonia in excess and (a) disulfane 2b and (b)
sulfane cis-3b recorded 1 h after the reactants were mixed.
Thus, at first sight, ammonia behaves as previously tested hydroxamates attacking preferably the hard phosphorus atom of
cyclic disulfane 2 to release the phosphodisulfane anion >P(S)SS-. 13 However, it should be stressed that such a statement
would be totally contrary to our results of ammonolysis experiments on disulfane 2h (vide supra) and to Khaskin 27 results.
Khaskin claimed that the corresponding phosphorothioyl sulfenamides 5 >P(S)SNH2 alone are products of acyclic
bis(phosphorothioyl) disulfanes 2 ammonolysis and that ammonia prefers a soft sulfur atom of the disulfide bridge in
disulfanes 2. It is worth mentioning Michalski’s results 28 here, who noted that related primary phosphoryl sulfenamides
>P(O)SNH2 are labile and decompose quickly to give phosphoramides >P(O)NH2 and elemental sulfur. Apparently,
phoshorothioyl sulfenamides 5 are much more stable than the respective phosphoryl sulfenamides.
A more careful analysis of the 31P NMR spectrum of the deep-blue solution of 2b in methanolic ammonia after 1 h showed that
the formation of phosphorothioyl sulfenamide >P(S)SNH2 5b as an intermediate should not be excluded. Besides the amide 6b,
the presence of small amounts of the the respective methyl ester 7b and diammonium salt of 1b, i.e. the product of reduction of
the starting disulfane 2b was corroborated by doping of authentic samples into the reaction mixture. The yields of individual
disulfane 2 ammonolysis products were estimated based on the intensity of the phosphodithioate residue signal for 6b (57%),
7b (18%) and 1b (25%) (Figure 6).
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Fig. 6 31P NMR spectrum of a solution of disulfane 2b in 10 M methanolic ammonia recorded after 1 h and enriched with 1b. The presence of diammonium
dithioate 1b (CH3)2C[CH2OP(S)(An)SH]2 . 2 NH3 (δP = 105.25 ppm) was thus confirmed. The presence of amide ammonium thioate
.
NH2P(S)(An)POCH2C(CH3)2CH2OP(S)(An)SH . NH3 6b (δP = 75.3 ppm and δP = 105.19 ppm) and methyl ester ammonium thioate NH3
CH3OP(S)(An)OCH2C(CH3)2CH2OP(S)(An)SH . NH3 7b (δP = 83.0 ppm and δP = 105.64 ppm) was also unequivocally verified by doping of authentic
samples.
On the other hand, we have found that 2b stays intact in triethylamine methanolic solution for three days, but it reacts with it
smoothly in the presence of DBU (1 equiv) yielding exclusively the methanolysis product 7b (δP1 = 88.2 ppm, δP2 = 105.6
ppm). Because ammonia is much weaker base than triethylamine, we have concluded that the mechanism of disulfane 2b to 7b
conversion in methanolic ammonia is not direct and must be more complex. At first, we postulate that the reaction proceeds via
the formation of reactive sulfenamide >P(S)SNH2 5b, which is prone to intermolecular nucleophilic substitution at phosphorus
atom by neighbouring phosphodithiolate group yielding cyclic sulfane 3b. Next, a reactive ring of sulfane 3b (formally cyclic
anisylphosphodithioic acid anhydride) undergoes a fast opening in methanolic ammonia to give the respective
phosphorothioamide 6b and traces of methyl ester 7b. As stated above, the same main product 6b was formed when pure
sulfane cis-3b was subjected to the action of ammonia in methanol. More accurate inspection of the recorded 31P NMR
spectrum (see Figure 8) showed that trace amounts of the respective methyl ester salt 7b were also formed (<2%) from 3b. The
formation of 6b and 7b directly from sulfenamide 5b is excluded as sulfenamide (iPrO)2P(S)SNH2 5h described above did not
undergo either ammonolysis or methanolysis under the same reaction conditions.
In summary, the formation of 6b as the main product of cyclic disulfane 2 ammonolysis is the result of three
consecutive steps, namely, the nucleophilic attack of ammonia at the bridged sulfur atom of 2b (A), the cyclisation to
trithioanhydride 3b (B) and finally ammonolysis/methanolysis of 3b (C/C’). Methyl ester 7b is formed from cyclic 3b and its
yield depends on the concentration of methanol (i.e. decreases significantly when freshly saturated methanolic ammonia is
used). We believe that the appearance of 1b among the reaction products is the result of the reduction of sulfenamide
>P(S)SNH2 5b (route E) or disulfane 2b (route D-F), which occurs with the participation of ammonium salt of
thiohydroxylamine NH2SNH4. Ammonia alone can not effectively reduce sulfenamide 5b, because a similar process on a
simple sulfenamide 5h carried out under the same conditions takes place very slowly within two weeks (vide supra). On the
other hand, it is well known that the trivalent nitrogen atom in hydroxylamine derivatives is characterized as a fairly soft base
center in terms of the HSAB principle. Thus, ammonium sulfenamide NH2SNH4 as a supernucleophile and a soft base is able
to replace 1b (a very good leaving group) on sulfenamide 5b nitrogen atom or even cause starting disulfane 2b ring opening.
The proposed sequence of reaction steps D-E-F can be repeated to furnish a more complex NS species such as blue S4N-
(Scheme 8).
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Scheme 8 Postulated transformations of cyclic disulfane 2b in methanolic ammonia leading to three organic end-products: thiophosphonoamido-
phosphonodithioate 6b, O-methylthiophosphonato-phosphonodithioate 7b and 1b, accompanied by S4N anion, which is probably responsible for a
characteristic deep-blue-coloration.
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The above reported experimental results also strongly suggest that analogous intermolecular contribution of 1h to the
formation of acyclic trithioanhydride 3h has an inconspicuous effect on splitting of the respective sulfenylamide >P(S)SNH2
5h considering ammonolysis as a whole process. The lack of a characteristic deep-blue coloration of acyclic disulfides (e.g.
2h) ammonia solutions is caused by very low concentration or even the absence of any colored SN species. Therefore, we
confirmed simultaneously a plausible mechanism of specific cyclic disulfanes 2 ammonolysis (see Scheme 8) and a significant
stability of simple sulfenamides (e.g 5h) those stay intact in the presence of ammonia in excess (Scheme 9).
Scheme 9 A proposed mechanism for the transformation of acyclic disulfide 2h in methanolic ammonia solution.
2.5. Crystal structure of cyclic disulfanes 2
The geometry and conformations of the main ring of cyclic disulfanes 2 and especially of its PSSP unit have been determined
and tested using a combination of X-ray crystallographic analysis and NMR spectroscopy (see section 2.7).
All cyclic disulfanes 2 are formed from the respective bis-anisylphosphonodithioates 1 as trans isomers and exist solely as
trans isomers. It is well known that the zig-zag geometry of P2S4 unit is the most common in acyclic disulfanes 2. It was
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imposed by cyclisation and obviously provides an extra stabilization for the trans-geometry of disulfanes 2. That special shape
of SPSSPS motif must be much more attractive than π−π interactions in hypothetical cis-2. Anisyl-anisyl stackings were
observed in both polymorphs of acyclic trans-disulfane 2i (R=iPr; intercentroid distances = 3.725 and 3.828VAiew, AirntitcelerOpnlalinnear
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angles = 10.6 and 18.2o) 28, but not in trans-disulfane 2j (R = L-menthyl) 11. It follows that these types of interactions can exist
DOI: 10.1039/C9NJ03682B
among acyclic disulfanes 2 where rotation around the S-S bond is free and alkoxy substituents do not provide (as in 2j) more
favorable van der-Waals attractive forces. Indeed, the predicted free energy difference were 3-5 kcal/mol more favorable for
cyclic trans-2 are of
that for cyclic cis-2.
8
9
It should be added that acyclic disulfanes 2 are usually formed as mixtures of two diastereomers, as was observed, inter alia,
29
by Woollins.
After oxidation of the corresponding anisylphosphonodithioate 1i, the presence of both (RP,SP)/(SP,RP) and
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(RP,RP)/(SP,SP) stereoisomers of 2i were confirmed and two polymorphs of the other one in the crystal were characterized. We
postulate that both Woollins’s stereoisomers are solely trans-disulfanes, but one contains anisyls arranged in π-stackings and
the second has trans-oriented anisyls. As we will explain below, the diagnostic effect of anisyls π-π interactions is a significant
deshielding of ortho-protons as well as C-1' carbons that is observed in NMR spectra of cyclic disulfanes 2. This tendency can
29
also be found in the spectroscopic description of Woollins' disulfanes.
In addition to the larger distance separating both
anisyl rings in linear disulfane 2i, an additional feature that differentiates their mutual position is that they are arranged
convergently in 2i but divergently in hypothetical cyclic cis-2 as well as in cis-3 sulfanes (see below).
All crystal structures of cyclic disulfanes 2, except 2d, have fixed geometry of both rotable methoxyl groups. In 2a, 2b, 2b’
methoxyls are anti-oriented and in 2c syn-oriented. For 2d where both polymorphs were isolated independently, energy
calculations showed insignificant preference of anti-2d (ΔG0
= 0.05 kcal/mol, ΔH0 = -0.14 kcal/mol). Apparently for
syn-anti
smaller rings (8 - 10-membered) optimal packing of molecules requires a suitable (syn or anti) methoxyl orientation, while in
the case of the largest 12-membered ring of 2d allows the existence of two forms slightly differing in packing efficiency in
their crystals. Since methoxyl pairs of all tested cyclic disulfanes 2 were involved in the formation of weak hydrogen bonds in
crystal state (both as donors and acceptors), their mutual arrangement certainly affects the strength of intermolecular
interactions.
A specific structural feature of acyclic chairlike thiophosphates such as 2g is their preference for a conformation with axial
P=S substituent due to stabilizing anomeric effect. 30 For our disulfanes 2a-2d this preference is not observable at all. As was
mentioned above, both the anisyl and the P=S adopt usually intermediate, inclinal positions. For syn-2d only anisyl groups (not
P=S) prefers to be in a pure axial orientation and in the case of 2b (closely related to 2g) also anisyl shows greater tendency to
choose an axial than equatorial position (RC-P-C angle of 67o vs RC-P=S angle of 51o). Undoubtedly, the preference of the
axial position by the anisyl groups, which are much steric bulkier than sulfur atom (A-values: 3 vs 1.3, respectively), is
connected with a more energetically favorable anomeric stabilization with an aromatic ring participation. The shielding of C-1
atoms in anisyls expressed by observed lower 13C chemical shift values for 2b and 2d (Δδ = 1 ppm) is an indirect proof for this
statement.
We expected that the lengths of P-S and S-S bonds in disulfanes 2a-2d may be important in explaining the observed
differences in their reactivity toward nucleophilic reagents, including their hydrolytic stability. However, both bonds only
slightly increase in length with increasing size of the disulfane 2a-2d ring (by 0.016 and 0.08 A, respectively). In addition, the
dependence of the S-S bond length on the PSSP torsion angle, as established by Potrzebowski 31 for acyclic
bis[phosphoro(thio)yl]disulfanes, is not met. For this relationship, similar in the course of the curve to the appropriate
dependence for diorganyl disulfanes RSSR 32, there is a minimum at the torsion angle PSSP 90o, which explains the particular
stability of bis(phosphothioyl)disulfanes 2 (e.g. 2g) with this structure. Significant discrepancies occurring for disulfanes 2a
and 2b, for which the S-S bond lengths are longer than anticipated by about 0.04 Å, presume that such a relationship does not
exist for cyclic disulfanes 2a-2d, where it is not the PSSP torsion angle but the ring closure defines the S-S bond distance.
A lack of correlation was also noted for relating Raman stretching frequencies of S-S bonds to their respective S-S bond
distances and PSSP torsion angles in our disulfanes 2 (484, 476 and 482 cm-1 for 2a-c respectively; Figure S32-36). However,
according to the literature, these relationships are rare, because too many structural factors affect the frequency of stretching
vibrations of S-S bonds in disulfanes. 33
Thus, the the above-mentioned exceptional hydrolytic stability of 2b as compared to other cyclic 2 under the study can be
mostly due to steric protection (branching at β-carbon; 2b is a neopentyl ester) and/or so-called the gem-dimethyl effect. 34
Similarly, we did not notice remarkable differences in the P=S bond length for disulfanes 2 under the study. We found that
none of their individual molecular parameters significantly affect the P=S bond length. These values are similar to those given
by Woollins 28 for linear disulfane 2i.
The complete structural parameters of all cyclic disulfanes 2 are listed in Tables S3 and S7.
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Crystal Packing and intermolecular interactions of Cyclic Disulfanes 2
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DOI: 10.1039/C9NJ03682B
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Non-classical hydrogen bonds in disulfanes 2. For cyclic disulfanes 2a and 2c weak hydrogen bonding of the C—H…O or
C—H…S type were found and were already described in our previous work.12 Detailed parameters of hydrogen bonding for
the other disulfanes 2 are presented in Table S6. No significant intramolecular hydrogen bonds were found. Since O-atoms
from the macrocycle are not involved as acceptors in the hydrogen bonding the conformation of the ring is not influenced by
this effect (unlike for described earlier 2a and 2c). Two C—H…O interactions can be noted in 2b and syn-2d mono, where
hydrogen bond donor is aromatic C-H bond from anisyl group (2b) or methoxy C-H bond (syn-2d mono) and the acceptor is
O-atom from methoxy anisyl residue in both cases. Hydrogen bonds of the C—H…S type are formed mainly with P=S type of
sulfur acceptors with the only exception of bonding to S2 in 2b’ which is also weak regarding the angle D—H···A of only
125°.
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Among disulfanes 2 studied, the most interesting crystal packing motif has 2b’. Molecules of 2b’ are connected to each other
using week non-classical H-bonds: C6—H6C… O3i (see Table S6) and centrosymmetric cyclic motif C15—H15…S3 thus
forming infinite rods spreading along the a axis. Bonding of the rods is accomplished by π – π stackings mentioned below
(Figure 7).
Fig. 7 Crystal packing of 2b’. Parallel stacking of anisyl rings are readily visible in the middle of the unit cell.
Stacking interactions in disulfanes 2. Minimal distances found between centroids of potentially stacking aromatic rings (anisyl
groups) are listed in the table 2 and are rather long indicating minor role of stacking for intermolecular interactions. All data
are based on calculations performed by PLATON program (A. L. Spek, Acta Cryst., 2015, C71, 9-18.)
Table 2
2a [Ref. 10]
2c [Ref.10]
anti-2d
syn-2d tri
2b
2b’
mono
Minimal
distance
5.0956(3)
5.0185(5)
4.4434(7) and 4.9213(4)
4.5143(7)
4.3778(8)
4.9208(6)
between ring
centroids, Å
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1
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Interaction
between
rings
Insignificant
Insignificant
C20-C25 and
its equivalent
(1-x,1-y,1-z);
C10-C15 and
equiv. (2-x,2-
y,-z)
Insignificant C10-C15 and Insignificant
its equiv.
( 1/2-x,1/2-
y,-z)
View Article Online
DOI: 10.1039/C9NJ03682B
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2.6. Crystal structure of cyclic sulfanes 3 and theoretical calculations
It has been proved by experiments, that cyclic sulfanes 3 derived from disulfanes 2 can exist both as cis and trans isomers.
It is important to note that every cis isomer of cyclic sulfides 3 have a higher melting point than its opposite isomer. Of course,
this feature may be related to their higher polarity (lower Rf values observed on silica gel TLC plates). However, the inverse
correlation between the melting temperature difference (Δmp) and the difference in retention coefficients (ΔRf) is much more
characteristic (for 3a isomers, Δmp is the lowest, while ΔRf is the highest).
On the other hand, it was found that none of the higher-melting crystals cis-3 is significantly denser (only cis-3c has about 5%
higher density), nor does not contain more strongly bound molecules compared to the crystals of the opposite isomer. It has
been proved by a standard calculation performed on sulfanes 3 involving their crystal data. Thus obtained lattice energy values
are significantly lower for trans isomers of 3a and 3b, but only slightly lower for trans isomer of 3c (see Table 3).
In the first approximation, the much larger dipole moment of each cis 3 isomer is caused by the presence of both polar P=S
groups directed by negative poles in the same direction, and the difference of the dipole moment values between the cis
isomers (ΔμD) by the angle of the P=S vectors. However, the estimation of the ΔμD of each cyclic sulfane 3 (as the sum of the
individual P=S bond vectors) on this basis leads to the opposite conclusion that the ΔμD increases with the expansion of the
sulfane 3 ring.
Fortunately, respective total dipole moments calculated for the optimized structures in DCM solutions are much more reliable.
Both dipole moments and differences for the isomer dipole moments ΔμD of 3 explain sufficiently their retention behaviour on
TLC plates. The dipole moment increases for trans isomers and decreases for cis isomers with sulfane 3 ring enlarging. Thus,
ΔμD values decreases also from 3a to 3c reflecting a characteristic retention on silica of every isomer (μD: 9.77 D, 1.87, 8.75,
5.01, 9.81, and 6.42 D for cis-3a, trans-3a, cis-3b, trans-3b, cis-3c, and trans-3c, respectively).
Performed calculations showed also that all cis-3 sulfanes are thermodynamically more stable than trans-ones
.
Such a statement supported by experiments (vide supra) is not common in literature, because cis isomers are usually less stable
than trans ones mainly due to steric hindrance. The structure of cis-3 sulfanes is similar only to the structure of hypothetical
cis-1,3-diaryl-1,3-dimethylcyclohexanes, which, according to calculations exist only in the conformations with diaxial
aromatic rings in the π-stacked orientation. 35 The π-stacking system in cis-3 sulfanes, however, more closely resembles the
structure of the 6-membered thiophosphine oxide trimer cyclo-(AnsPOS)3, where two of the three anisyl rings assume a
parallel orientation (intercentroid distance = 3.695 Å; interplanar angle = 8.7o). 36 In both described above examples, the 1,3-
diaxial adverse effect is usually beneficial due to the participation of aryl groups in it.
As was expected, a relative energy difference ΔGcis-trans diminishes with sulfane 3 ring size (Table 3). This trend can be
explained only by the energy differences among the trans-isomers, because the key geometric parameters of the mutual
orientation of the approximately coplanar anisyl rings in cis sulfanes 3 are not significantly different from each other (for cis-
3a, cis-3b and cis-3c the intercentroid distance is 3.637, 3.694, 3.528 Å and the interplanar angle is 4.1, 11.6, 2.3o,
respectively). As a reminder, the parent cyclic disulfanes 2 exist only as trans isomers, which results to a large extent from the
greater distance of P-anisyl rings in the hypothetical cis isomers caused by the presence of the disulfide bridge (see above).
Some relevant structural differences between the cis and trans isomers are detailed below when discussing the 1H and 13
C
NMR spectra of sulfanes 3. As has been mentioned above, the highest observed difference in relative energy for sulfane 3a
isomers (-1.57 kcal/mol) is not reflected in a desulfurization experiment where 4-fold more trans-3a is formed. Obviously, this
is caused by the fact that desulfurization of cyclic disulfanes 2 is an irreversible reaction under kinetic control.
Table 3 Calculated relative energies for hypothetical cis-disulfanes 2 and actual cis-sulfanes 3 in kcal/mol.
ΔGcis-trans
ΔH0
% cis
ΔElatt cis-trans*
cis-trans
4.77
5.40
-1.14
3.46
0.03
0.01
(87.5)
0.27
-
-
-
-
2a
2b
2c
2d
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-1.57
-1.14
-1.13
-2.08
-5.15
-3.48
93.6
87.5
87.3
6.8
3a
3b
3c
2
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5.8
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DOI: 10.1039/C9NJ03682B
1.5
(*) ΔElatt cis-trans were referenced to computed intermolecular potentials from crystal data using Mercury 3.8.
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Regarding the indication of transannular hydrogens effect on the stability of sulfanes 3, the analysis of the data from Table S8
shows that every cyclic sulfane 3 possess one or two transannular hydrogens. However, none of these causes unfavorable H-H
repulsive interactions, but rather forms attractive intramolecular H-bonds with the participation of the bridged sulfur atom,
especially for cis-3a and trans-3b. Therefore, the formation of transannular CH...S bonds can also be beneficial and
responsible for the exceptional stability all cis-3 beside attractive π-π stackings.
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The complete structural parameters of all cyclic disulfanes 3 are listed in Tables S4 and S7.
Analysis of the Crystal Packing and Intermolecular Interactions in cyclic Sulfanes 3
Stacking interactions in sulfanes 3. The shortest distances between centroids of potentially stacking aromatic rings (anisyl
groups) are listed in the Table S5 and are generally much shorter than for disulfanes 2, indicating the importance of stacking in
interactions among investigated sulfanes 3. It is expected for cis isomers to form parallel orientation of anisyl rings inside the
molecule and it is indeed so. The table indicates the number of molecules in the asymmetric unit Z’ to present the situation
properly. Nevertheless, also for trans-configuration intermolecular π – π stacking is observed in the cases of trans-3a and
trans-3b.
Intermolecular H-bonds forms both CH...S as CH...O systems. Among them one can found some strong bonds concerning the
corresponding distances of <2.9 Å and <2.5 Å, respectively. Detailed parameters of hydrogen bonding are presented in Table
S7.
2.7. Solution state structure of cyclic disulfanes 2 and sulfanes 3
8
As previously suggested based on standard NMR spectra, cyclic disulfane 2a and 2b rings are fairly rigid in solution.
1
Analysis of variable temperature H and 31P NMR spectra carried out as a part of this work fully confirmed the earlier
o
statement. All proton multiplets and phosphorus signals remain unchanged at higher temperatures (up to 185 C) in anhydrous
solvents (Figure S24 and S25). At low-temperatures (up to -80 oC) proton and phosphorus signals remain sharp too, but slight
changes in the position of CHeq, CHortho and OCH3 proton signals (2b: Δδ = +0.04, +0.06, and -0.02 ppm) as well as more
noticeable shielded phosphorus resonances (Δδ = -0.6 and -0.9 ppm for 2a and 2b, respectively) were observed (Figure S23).
On the other hand, the finding that the 2a and 2b phosphorus chemical shift values (δP) decrease proportionally with the
temperature agrees with the general theory of dishielding. 37
8
We also sustain our previous statement that axial alpha-protons are more deshielded than their equatorial counterparts (see
below) in cyclic disulfanes 2a-c (2d is the exception) and also in all cyclic sulfanes 3. This fact was confirmed by comparing
3
the HCOP torsion angles found in the crystal state with the observed JHCOP coupling constants (see below). At first glance, this
extraordinary deshielding of axial protons seems to contradict the general shielding theory arguing that in cycloalkanes (due to
the C-C bond anisotropy) and also in heterocycloalkanes (due to the n-ζ* delocalization) axial protons resonate rather at higher
38
fields than equatorial ones.
We postulate that the proximity of the P=S groups (anisyls are significantly distant), their
magnetic anisotropy and dispersion interactions, are the main factors that enhances deshielding of axial protons in cyclic
disulfanes 2. Additional proof for this statement we have found in disulfane 2 and sulfane 3 crystal state, where the respective
P=S…Hax distances are shorter as compared to P=S…Heq ones (see above). Another, but not less important reason for the
shifting of axial proton signals to lower field (especially for some sulfanes 3), is the possibility of forming CH...S
intramolecular hydrogen bonds with the participation of transannular inward-pointed hydrogens and ring sulfur atom (see
Table S8). According to the literature, systems where intramolecular CH...S hydrogen bonds play a key role in stabilization are
rare.39
The increase in conformational freedom of disulfane 2c and especially of 12-membered 2d is evidenced by, among others,
a much smaller difference in the chemical shifts of their axial and equatorial protons ΔδHax-Heq (see Figure S29). For disulfane
2d, assigning 1H NMR signals to axial and equatorial protons becomes ambiguous due to existence of a mixture of conformers
in dynamic equilibrium as in the case of acyclic disulfane 2g containing 6-membered dioxaphosphorinane rings. 40 For 2g, the
3
observed difference in chemical shifts of geminal protons (ΔδHgeminal = 0.37 ppm) was also small and additionally, both JHCOP
coupling constants were strongly dependent on the temperature (Δ3JHA-P = -3.5 Hz and Δ3JHB-P = +3.5 Hz in the range of -50 oC
to rt), which clearly indicates a rapid inversion of chair conformations.
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Despite the fact that 1H and 31P NMR measurements carried out at low temperatures (up to -80°C) did not show any dynamic
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behavior, which should result in line broadening or changing the coupling constants for 2a and 2b, small ring pseudolibrations
should not be excluded. Based on the observed consistency of the 3JHCOP coupling constants in the range of negative
View Article Online
temperatures, we assume that the respective HCOP torsion angles of disulfanes 2a, 2b and 2b’ in solutions undergo only minor
DOI: 10.1039/C9NJ03682B
changes and their values can be arithmetic averages of the respective angles measured in the crystal state. A comprehensive
study of relationship of 3JHCOP coupling constants with the HCOP torsion in acyclic disulfanes 2 in the range 70-180o was
reported by Potrzebowski. 31 Currently, we decided to determine the Karplus relationship 41 for cyclic disulfanes 2 (HCOP 1 -
143o), for cyclic sulfanes 3 (HCOP 1 - 165o) and 4a (Figure 8) with a much wider range of appropriate torsion angles.
Therefore, the torsion angles for axial and equatorial alpha-protons were taken from X-ray data (Tables S3 and S4) and were
9
1
averaged, and coupling constants values from the respective H NMR spectra. It should be stressed that for larger rings (10-
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and 12-membered), one should expect greater deviations from thus determined Karplus dependance.
Fig. 8 Karplus dependance (3JPOCH = 9.98 cos 2 ꢀ - 6.54 cos ꢀ + 13.85) for cyclic disulfanes 2, sulfanes 3 (for data see table
S4 and S5) and phospholane 4a (CCDC 1948450).
As already indicated above, the influence of the size of the disulfane 2 ring on the chemical shift of ortho-protons of anisyls is
also observed (Figure S29). This effect can be related to the magnetic anisotropy and the electric field effects of the P=S group,
which has a deshielding (+δ) region in the its plane. According to X-ray data the coplanarity of both residues occurs (the
smallest SPCC angle of 4o) only in disulfane 2a. Therefore, 2a has and should have the most strongly downfield shifted ortho-
proton among all cyclic disulfanes 2 under the study. Thus, the position of the ortho-proton signal can be correlated with the
torsion angles found in the disulfane 2a-2d crystal state (see section 2.5). On the other hand, the 13C NMR parameters of all
cyclic disulfanes 2 (chemical shifts and coupling constants of the carbon atoms in the main ring as well as the anisyls to
phosphorus) seem not to be influenced by their geometry or their ring size. However, the observable difference in chemical
shifts of alpha-carbons (Δδ 3.3 ppm) and geminal coupling constants 2JCP (6.3 vs. 4.8 Hz despite a similar COP angle of about
120o) between 10- and 12-membered 2c and 2d can be significant.
The 31P chemical shifts range for all cyclic disulfanes 2a-2d is rather narrow (88.0–90.0 ppm), and ring expansion results in
a proportional increase in phosphorus chemical shift values. Thus, a linear correlation exists between the P...P distance and the
δP value (4.334 Å, 4.483 Å, 4.615 Å and 4.695 Å , vs δP 88.0, 88.7, 89.2 and 90.0 ppm) for 2a, 2b, 2c, and 2d, respectively. It
may be the result of the increase of the OPS angle from 107o (for 8-membered 2a) to 109.2o (for 12-membered 2d), because it
is well known that any deviation from the angle of 107o (ideal pentagon angle) causes phosphorus deshielding effect.
42
Another reason for phosphorus downfield shift may be the aforementioned loss of the coplanarity of the P=S group with the
plane of the anisyl ring expressed by a gradual increase in the SPCC torsion from 4o for 2a to 37o for 2d. However, as we will
show below, the lack of coplanarity exhibited in the anisylphosphonothioyl residues shown in the crystal is of no importance in
the solutions of the compounds in question.
Comparison of 31P chemical shifts of cyclic disulfanes 2a and 2c with chemical shifts of their ferrocenyl analogs 2e
and 2f would allow to explain the effect of anisyl and ferrocenyl residue on the geometry of the main rings of 8- and 10-
18

Page 19 of 27
New Journal of Chemistry
membered disulfanes 2. Appropriate 31P increments of both aromatic P-substituents can be determined by comparing chemical
shifts of the respective model compounds described in the literature, i.e., anisylphosphonic acid (δP 19.5 ppm 43) and
ferrocenylphosphonic acid (δP 24.8 ppm 44). Exactly the same difference in 31P chemical shifts (ΔδP = 5.3 ppm) was noted for
8-membered 2a and 2e. This may indicate the structural similarity of both compounds at least in the sDpOhIe:r1e0.1o0f3V9eie/lwCec9ANtrtriJco0len3Oi6cn8l2ianBend
steric effects on their 31P chemical shifts. The difference of phosphorus shifts ΔδP for the corresponding 10-membered
analogues 2c and 2f is already smaller and amounts to only 3.4 ppm. As shown by the data for ferrocenyl disulfanes (2e and 2f)
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,
9 11 and anisyl disulfanes 2a-2d (current work) the change in phosphorus shifts at the size increase of the 8- to 10-membered
ring is -0.7 and +1.2 ppm, respectively. Therefore, it seems that they are not significant enough to find out the particular impact
of the structural differences of both classes of compounds. Thus, the aforementioned difference in phosphorus chemical shifts
ΔδP, and in particular the difference in chemical shifts of axial and equatorial alpha protons (Δδax-eq = 0.96 and 0.93 ppm, and
0.52 and 0.12 ppm, for the pair 2a and 2e and for the pair 2c and 2f, respectively) suggest close conformational similarity
between 2a and 2e, but also large structural differences between 2c and 2f in solution. It turns out that key structural
parameters describing the main ring conformation, i.e. CCCC, OCCC, POCC and PSSP torsion angles are surprisingly
convergent within pairs 2a-2e and 2c-2f, and the only factor clearly distinguishing crystalline structures of these compounds is
the coplanarity of P=S groups with planes of anisyl/ferrocenyl rings. The corresponding torsion angle is 3.8o and 32.9o for 8-
membered analogues 2a and 2e, while for the 10-membered 2c and 2f the mean value is 31.6o and 16.7o. These data 12 confirm
the above-mentioned suggestion that it is not the aromatic rings but exocyclic and bridge sulfur atoms that have the greatest
influence on differentiation of chemical shifts of axial and equatorial protons. However, as far as the influence of CCPS torsion
angles is concerned, it should be assumed that in the solution due to free rotation around the Caryl-P bond the degree of
coplanarity of the P=S and the OPS groups with aromatic rings is much larger than in the solid state, where the arrangement of
aromatic rings in space depends mainly on their participation in intermolecular contacts.
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Unsymmetrical from the point of view of magnetically and chemically inequivalent phosphorus atoms, disulfane 2b’
3
gives two distinct phosphorus resonances (ΔδP = 1 ppm), which reveals the P-P vicinal coupling constant JPP of 4.2 Hz.
Chemical and magnetic inequivalence of phosphorus atoms in 2b’(ΔδP = 1 ppm) enabled the measurement of the P-P coupling
constant directly from its proton-decoupled 31P NMR spectrum. However, in the case of other symmetrical disulfanes 2a-2d,
3
determination of the indirect JPP coupling constant by observation of C-13 satellites required long acquisition times, because
3
the 31P main signal is about 1000 times more intense. It turned out that the value of thus determined JPP vicinal coupling
constant decreases very slightly with increasing ring size (4.4, 4.2, 4.0 and 4.0 Hz for 2a, 2b, 2c and 2d respectively) despite
the significant increase in the PSSP torsion angle observed in the crystal state (from 94o to 125o). It should be mentioned that in
3
analogous open-chain disulfanes 2g and 2h, the vicinal coupling constants JPP have a slightly lower value (3 Hz and 0.7 Hz,
respectively). It is generally accepted that in the solution all non-cyclic bis(phosphorothioyl) disulfanes such as 2g and 2h are
in the conformation in which the PSSP torsion angle is about 90o, regardless of the fact that for some of them in the crystal
state this angle can be up to 180o. 21 In non-cyclic disulfanes, rotation around the S-S bond is possible over the full range of
angles (from 0 - 180o), while in cyclic disulfanes 2a-2d the change in the PSSP torsion angle is largely limited due to their ring
stiffness and the presence of bulky groups on phosphorus atoms. Grossmann reported the dependence of the P-P vicinal
coupling constant on the PCCP torsion angle in symmetrical bis-phosphonates. As expected, 3JPP assumes values close to 0 Hz
for angles close to 90o and reaches 30 Hz and 90 Hz for angles of 0o and 180o respectively. 45 Since cyclic disulfanes 2 must
3
comply with the general Karplus equation and the values of the vicinal coupling constant JPP do not change despite the ring
size change, we can speculate that their PSSP structural units tend to achieve the most optimal torsion in the solution. This has
been verified by calculation. In the optimized structures of 2a-2d, the PSSP torsion angle range is much narrower (99.5 -
114.6°) compared to that determined for their crystal structures. In the crystal and in the calculated structures, the
corresponding PSSP torsion angles for 8- and 9-membered disulfanes 2a, 2b and 2b’ are the closest to the optimal value (94-
3
105o) and the values of the JPP coupling constants in the solution correspond to an angle of 95-100o (according to the
dependence given by Grossmann 45). This indicates that the dominant conformations of these medium-sized disulfanes in the
solution are very similar to those in the crystal, which adain confirms their conformational rigidity.
In the initial stages of the study, 31P NMR spectra were recorded for disulfane 2 desulfurization solutions in the
MeCN-C6D6 system, which contained cis and trans isomers of cyclic sulfanes 3 and triphenylphosphine sulfide as the by-
product (see Figure 1). All cis-3 isomers gave signals in a very narrow range (δP 85.85 ppm +/- 0.25 ppm) while phosphorus
chemical shifts of trans-3 isomers decreased proportionally as the ring expanded, differing by a maximum of 2.54 ppm. Thus,
the largest 31P chemical shift difference between the cis and trans isomers of 3 (ΔδPtrans-cis) of 3.1 ppm was noted for the 7-
membered sulfane 3a. It should be added here that the position of the phosphorus signal of the cis-3 isomers is more strongly
dependent on the solvent used. In chloroform ΔδPtrans-cis are suppressed as compared to benzene solutions. For cis-3b
phosphorus resonance is shifted upfield (-0.8 ppm) in benzene as compared to trans-3b. This so called aromatic solvent-
induced shift (ASIS) effect found for individual sulfane 3 isomers as well as for sulfanes 3 of different ring size. This effect is
more pronounced for cis-3 phosphorus chemical shifts, because it is well known that benzene molecules interact stronger with
more polar solute molecules (cis-isomers) at their local electron-deficient sites (i.e phosphorus atoms in 3). The ASIS effect is
notable also in 1H NMR spectra although we found unexpectedly that selected protons of cis and trans isomers of 3b are
shielded to the same extent in benzene solution (Table 4). However, the most intriguing is the observed total lack of benzene
influence on the chemical shifts of axial protons and aromatic ortho-protons with simultaneous significant shielding of
equatorial protons, especially the meta (Hmeta) and even the methoxyl (OCH3) protons in both isomers of 3b. According to the
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ASIS theory Hmeta and OCH3 chemical shifts should not be affected by solvent change, because they are near the negative pole
of the respective dipole moments of 3 (see Figs S49-S54). Thus, it seems that the observed up-field shift of these protons
1
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3
indicates that some benzene molecules and the anisyl groups are arranged in the offset parallel π – π stacking interactions with
View Article Online
benzene molecules pointed toward methoxyls and can be caused by the hydrogen-like interaction betweDenOIt:h1e0.1O03C9H/C39NgrJo03u6p82aBnd
pi-electrons of benzene rings. On the other hand, the presence of bulky anisyl and sulfur substituents results in the exclusion of
space above and below the plane of the main ring for benzene molecules. Therefore, setting of the remaining benzene
molecules perpendicular to the plane of the main heterocyclic ring of 3b at its quaternary C-terminus reflects the shielding of
its equatorial protons and both methyl group protons. The existence of such arrangement of interactions of molecules 3 with
benzene molecules confirms the observed difference between two methyl groups for cis-3b, where the axial methyl protons are
two times strongly shielded and they show an unusual upfield shift of -0.88 ppm (δ = 0.13 ppm) with respect to the signal
recorded in chloroform.
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It is interesting to note, that all measured H-H and H-P coupling constants for sulfanes 3 do not change when the solvent is
changed from chloroform to benzene. Thus, the main ring conformation of cyclic sulfanes 3 is preserved in benzene solution.
Table 4 Δδ(ASIS) for sulfide 3b isomers.
CH3
OCH3
-0.69
Heq
Hax
Hortho
-0.03
Hmeta
-0.44
Cis-3b
-0.88
-0.46
-0.51
+0.04
Trans-3b
-0.53
-0.82
-0.37
+0.02
+0.14
-0.37
Δδ(ASIS) = δC6D6 - δCDCl3
In chloroform, the 1H chemical shift difference between aromatic protons for cis and trans sulfanes 3 is very characteristic, too.
A close proximity and parallel orientation of both anisyl groups (see section 2.6) lead to significant diamagnetic shifts of ortho
and meta proton resonances (ΔδHo = -0.51 - -0.59 ppm, ΔδHm = -0.20 - -0.45 ppm) in each cis-3. A similar tendency was
observed by analyzing the aromatic ranges of the 13C NMR spectra. C-1’ carbons are shielded in 3b and 3c by 0.5 and 2.1 ppm,
respectively, whereas they are surprisingly deshielded in cis-3a by 1.7 ppm. This fenomena can be explained by the fact that
the C1’-C1’’ distance in cis-3a is the largest (3.575 Å - no interaction between anisyls) and in cis-3c the smallest (3.444 Å - the
strongest interaction between the anisyls). Ortho-carbons are more shielded than meta-ones (-1.0 to -1.2 ppm vs -0.2 to -0.5
ppm) in all sulfanes 3 as expected. Clearly, the meta protons and the meta carbons are farther away from each other than the
atoms in the ortho positions, because the anisyl rings in the crystalline state are not ideally parallel but slightly divergent (the
measured angle between the C1'-C4 'and C1' '- C-4' 'axes is 2-5o) and, what is more important, they are flexible in solution.
The P-P geminal coupling constant value is characteristic and diagnostic feature of cyclic sulfane 3 isomers. It has a value of -
21 Hz and of -14 Hz for cis-3 and trans-3, respectively. The magnitude of 2JPP can be extracted from 31P NMR spectra
recorded after longer acquisition times, when 13C satellites become observable as doublets, with a splitting that is equal to the
2JPP coupling (Figure S30). Reported by Grossmann 40 the 2JPP coupling have values of -9 and -19 Hz for acyclic
bis(phosphorothioyl) sulfanes 3g and 3h, respectively. However, in the case of acyclic sulfanes, the free rotation around both
P-S bonds causes that we do not deal with cis-trans isomerism. While in our cyclic sulfanes 3a-3c the imaginary S=P…P=S
torsion angle is strictly defined (in the range of 3.6 - 23.6o and 155.4 - 176.5o for cis-3 and trans-3, respectively) and clearly
defines the cis-trans isomerism, for an acyclic sulfanes even in the crystalline state, there is an intermediate form (e.g. for the
3g, the angle is 117o). Geminal 2JPP is above 50% greater in cis-3 than in trans-3. Unfortunately, we have not been able to
relate the measured coupling constants to the corresponding differences in structural parameters or justify their magnitude by
means of NBO analysis. There is no the PSP bond angle dependance of the 2JPP magnitude found, although every trans-3 have
slightly larger PSP bond angle than cis-3 one (for 3c isomers, the difference in the PSP angles is even 5.8o; see section 2.6). On
the other hand, small changes of P-S bonds lengths for both isomers of 3 can not determine the 2JPP magnitude, therefore other
effects influencing 2JPP should be considered which make PP splitting more efficient for cis-3.
As with cyclic disulfanes 2, also for all cyclic sulfanes 3, 2JPC, 3JPC, and 4JPC couplings were observed as false triplets or
quintets, 46 indicating second-order effects (Figure S31).
Inspection of Table S1 shows that although calculated chemical shifts overestimate the 31P chemical shifts by 10-15 ppm, they
nevertheless agree with the observed trends of experimental values, so as such they can be useful for predicting chemical shifts
for similar systems. Calculations supported also the general notion that geminal 2JPP in cis-3 and trans-3 are larger (3-5 times)
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than the corresponding vicinal 3JPP for disulfanes 2. Although they have comparable values, clearly all coupling constants in
cis-3 isomers are larger by about 1 Hz than those calculated for trans-3. The calculated values of 2JPP geminal coupling
1
2
3
4
constants, however, are 2.5 - 3.3 times smaller than the experimental values.
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3. SUMMARIZED CONCLUSIONS AND OUTLOOK:
-
-
-
Despite the facility of the formation of disulfane 2/sulfane 3 medium rings, the proposed methods of their synthesis
are limited to the preparation of seven to ten-membered heterocycles (12-membered 2d was isolated in only 18%
yield).
Although cyclic sulfanes 3 can be efficiently obtained from disulfanes 2 or directly from bis-phosphonodithioates 1,
both desulfurization routes afford different cis/trans isomer ratio of sulfanes 3. Desulfurization of disulfanes 2 gives
predominance of trans-3, while cis-3 are mainly formed from bis-anisylphosphonodithioates 1.
Observed cis/trans selectivity of cyclic sulfane 3 formation was explained on the base of the results of experiments on
reaction mechanisms and also was confirmed by the respective calculations. The highest selectivity (cis/trans ratio
4:1) achieved for 1b desulfurization can be explained by either gem-dimethyl effect or suppression of sulfane 3
formation by competitive cyclisation to 5-membered 4a. On the other hand, the lowest selectivity (cis/trans ratio 1:4)
during disulfane 2a desulfurization is caused by their fixed trans-geometry and the shortest distance between the
reactive ends.
-
-
During the synthesis of 8-membered disulfanes (e.g. 2a) and 7-membered sulfanes (e.g. 3a) the use of acetonitrile
alone or in a combination with DCM should be avoided. In both cases acetonitrile takes a part in a competitive
reaction leading to the formation of a stable 5-membered phosphate 4a.
The most characteristic reaction of cyclic disulfanes 2 is their specific color ammonolysis. Thanks to the participation
of the neighboring group, this reaction is very fast and provides a high concentration of deep-blue unstable by-product
even in methanolic ammonia solutions. Generally, in their reactions with N- and P-nucleophiles all cyclic disulfanes 2
behave as their open-chain analogs, although their fixed SPSSPS structural motif responsible for the reactivity
determines kinetics as well as specific stereochemical course of the S-S bond splitting reactions.
-
-
It was confirmed that all cyclic disulfanes 2a-2d have trans configurations. Calculations confirmed that hypothetical
cis-2 are much more energetic.
Variable-temperature NMR spectra showed the outstanding thermal stability and conformational inertness of cyclic
disulfanes 2a and 2b. Calculation of ring strain energy indicates the following stability order: 2c > 2b > 2a >> 2d.
Exceptional hydrolytic stability of 2b is mostly due to branching at β-carbon and/or so-called the gem-dimethyl effect.
-
-
Unlike cyclic disulfanes 2, all cis-3 sulfides are more stable than trans-3. However, the difference in energy ΔEcis-trans
decreases with the increase in the size of the ring.
The P-S single bond length ranges (2.091-2.117 Å, and 2.103-1.149 Å) and P=S double bonds (1.916-1.946 Å and
1.917-1.938 Å) are consistent with the typical values for the P(=S)S moiety, 47 for cyclic disulfanes 2 as well as for
cyclic sulfanes 3, respectively.
-
The polar ethoxycarbonyl substituent is responsible for a better packing density (additional intermolecular week H-
bonds) and a higher symmetry in disulfane 2b’ as compared to 2b. The strength of intermolecular contacts in
disulfanes 2 represented by P=S…H3COAr distances decreases in order: 2d >> 2a > 2b ≅ 2c.
-
The Karplus-type dependance of the vicinal coupling constant on the dihedral angle is of particular importance in the
stereochemistry of cyclic systems. All measured vicinal 3JHCOP coupling constants have been correlated with the
respective average torsion angles for disulfanes 2 and sulfanes 3 under the study. Its allowed to find a suitable
relationship that could be useful for determining the conformation of other medium-sized heterocyclic rings.
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-
-
1H- and 13C-NMR spectra showed that solution state conformers closely resemble those present in the solid-state for 7
- 9 membered 2 and 3. 31P chemical shift increases proportionally with increasing ring size for cyclic disulfanes 2.
This phenomenon can be mainly correlated with the OPS bond angle value. As the size of the disulfane V2ierwinArgticle Online
increases, the conformational freedom increases especially for the 10- and 12-membered rings DoOf I2: c10a.1n0d392/Cd9.NTJh03e682B
observed difference in chemical shifts of axial and equatorial alpha-protons and a range of the HCOP torsion angle
corresponding to the observed 3JHCOP coupling constant are both a measure of the degree of conformational freedom
of the heterocycles tested.
1
2
3
4
5
6
7
8
An pronounced upfield shift for the aromatic protons of sulfanes 3 is a spectral evidence for the cis configuration and
additionally it shows that face-to-face stacking of the anisyl rings in crystals of cis-3a are preserved in solution. There
are also significant differences in 3JPP being ⅔ higher for cis-ones.
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-
-
Neither vicinal 3JPP value nor the S-S bond length is influenced by the PSSP torsion in cyclic disulfanes 2. These
findings do not agree with the corresponding relationships found in literature.
Specific solute-solvent interactions were evidenced in NMR spectra of cyclic sulfanes 3 measured in benzene
solutions. A significant negative ASIS effect for phosphorus in sulfanes 3 of different ring size as well as for Heq,
Hmeta, OCH3 and CH3 protons of individual sulfane 3b isomers was found. The ASIS effect is more pronounced for
cis-3 phosphorus chemical shifts, but selected protons of cis and trans isomers of 3 are shielded to the same extent.
Obtained results reveal that some benzene molecules and the anisyl groups are arranged in the offset parallel π – π
stacking interactions with benzene molecules pointed toward methoxyls of 3b and others perpendicular to the plane of
the main heterocyclic ring at its quaternary C-terminus. The main ring conformation of cyclic sulfanes 3 is preserved
in benzene solution, because coupling constants do not change with solvent.
-
-
Cis-3 are more polar than trans ones as expected. The largest difference in polarity (expressed as both ΔμD and ΔRf) is
found in the 3a isomers. It decreases with the increase in the size of the sulfane 3 ring. Calculated dipole moments are
always directed to anisyl end(s) of the molecules. The magnitude of the dipole moment depends both on the spatial
arrangement of the anisyl rings but also on the value of the CCPS torsion angle in sulfanes 3. The smaller the CCPS
torsion angle, the the higher value of the dipole moment. For trans-3b and trans-3b the negative pole of the dipole is
directed towards the equatorial anisyl whose ring plane is more coplanar with the P=S group. Trans-3a has the lowest
dipole moment, because both anisyls are pseudoequatorial and their vectors partly cancel each other out.
trans-3 cyclic sulfides have more deshielded phosphorus nuclei and their 31P chemical shifts are much more
differentiated (from 0.9 to 3.1 ppm for trans-3c and trans-3a, respectively) as compared to cis-3 which have 31P NMR
chemical shifts in the narrow range of 0.5 ppm. Additionally, an upfield shift of aromatic carbons of ca. 1 ppm was
observed that evidently confirms the existence of intramolecular face-to face interactions between anisyl rings in
every cis-3.
-
-
-
Medium-sized cyclic disulfanes 2 are redox active compounds. Unusual durability of disulfanes 2 and their reduction
products, bisanizylophosphonothioates 1, can ensure a high turnover number if someone use them in redox catalytic
cycles.
9-Membered 2b’, as containing ester functional group represents a relatively rare example of a redox‐active cyclic
disulfane that can be potentially used for grafting with a polymer matrix, tethering or conjugated with bioactive
compounds or other carriers.
Medium-sized cyclic disulfanes 2 and sulfanes 3 can not be used as monomers for anionic ROP polymerization due to
preferred ring-closing reactions as well as negligible reactivity of the resulting PSS- anion to the PSSP. The exception
is 12-membered disulfane 2d which undergoes desulfurization to give mainly macrocyclic oligomers. However, in
this case it is necessary to further optimize the conditions of this process.
-
The preliminary results of controlled thermolysis of disulfanes 2, which gives polymeric poly(disulfanes), are
promising and suggest that they can be useful in vulcanisation processes.
4. Experimental section
Synthesis of Disulfanes 2b’ and 2d: To a stirred solution of the corresponding diol (1 mmol) in THF (5 mL) Lawesson
Reagent (0.404 g, 1 mmol) was added in one portion at room temperature. After 15 min when the mixture became
homogeneous, tert-butyl amine (0.21 mL, 2 mmol) was added dropwise and the clear solution was concentrated in vacuo. The
residue was dissolved in ethyl acetate (15 mL) and a solution of iodine (0.254 g, 1 mmol in 10 ml of ethyl acetate) was added
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dropwise with ice-cooling to reach a persistent brown coloration. Next, the solution was washed with a 2% aqueous Na2S2O3
solution, water, and then with brine. The organic layer was dried with MgSO4 and concentrated. The crude product was
dissolved in chloroform (30 mL) and passed through a short pad of silica gel. After evaporation of the solvent, thVeieswoAlritdicle Online
1
2
3
4
precipitate was recrystallized to give the respective disulfane 2 as colorless crystals.
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Synthesis of Sulfanes 3a-c and phospholane 4a:
Using Ph3P as desulfurization agent (Method A): To a stirred suspension of disulfane 2 (0.2 mmol) in 2 ml of acetonitrile-
dichloromethane (1:1, v.v) triphenylphosphine (0.052 g, 0.2 mmol) was added in one portion at room temperature. The
reaction mixture immediately becomes a clear and colorless solution. After the 31P NMR spectrum of the reaction mixture had
been recorded. Next solvents were evaporated from the filtrate and the solid residue was fractionated by silica gel column
chromatography using hexane-ethyl acetate (7:3) or chloroform-hexane (1:1) as eluents.
Using Ph3P as desulfurization agent (Method A) with the additive 2,4-dinitrobenzoic acid: To a stirred solution of disulfane 2a
(0.023 g, 0.05 mmol) in dichloromethane (1 ml, 1/1, v/v) 2,4-dinitrobenzoic acid (0.013 g, 0.065 mmol) and
triphenylphosphine (0.013 g, 0.05 mmol) was added at room temperature. 31P NMR analysis showed increasing of the cis/trans
isomer ratio of 3a from 0.26 to 0.31.
Via Mitsunobu coupling (Method B): Di-tert-butylammonium O,O’-(2,2-dimethylpropane-1,3-diyl) bis[(4-
methoxyphenyl)phosphonodithioate 1b (0.654 g, 1 mmol) was dissolved in dichloromethane (5 ml) and 2-chloro-N-
methylpyridinium iodide (0.256 g, 1 mmol) was added. After 24 h at room temperature the homogeneous reaction mixture was
evaporated and the remaining yellow solid was filtered through a short pad of silica with ethyl acetate eluent to remove
tetrabutylammonium iodide and 1-methylpyridine-2-thione as byproducts. 31P and 1H NMR analysis showed the the cis/trans
isomer ratio of 3b was 3.8. Separation by silica gel column chromatography using hexane-ethyl acetate (7:3) gives, besides
both isomers of 3b, 0.075 g (30%) of phospholane 4a.
Ammonolysis of disulfanes 2: Disulfane 2b (0.01 g, 0.02 mmol) was added to 10 M NH3 in methanol (0.7 ml, 7 mmol) with
stirring (at the moment of 2b dissolution, the solution turned deep-blue). Next, the resulting solution was subjected to 31P NMR
analysis at different intervals and, after appropriate dilution, UV spectra were recorded to study absorbance changes with time.
31P NMR (crude reaction mixture after 5 min, 10% C6D6) 75.30 (100%) and 105.19 (80%) (6b), 83.0 (30%) and 105.64 (25%)
(7b), 105.25 (70%) (1b).
UV (10 M NH3 in MeOH): λmax = 563 nm (log ε = 3.81).
Keywords: Phosphorus and Sulfur heterocycles, Medium-ring compounds, Conformation analysis, Stacking and π-π
interactions, Reaction mechanisms, Nucleophilic substitution, Neighboring-group effects, Reduction, Solvolysis, Ring
contraction, X-ray diffraction, Solid-state structures, NMR spectroscopy, Ab initio calculations
Acknowledgements
This work was partially financed by a statutory activity subsidy from the Polish Ministry of Science and Higher Education for
the Faculty of Chemistry of Gdansk University of Technology.
Conflict of interest: The authors declare no conflict of interest.
†Electronic supplementary information (ESI) available: Disulfanes 2 and sulfanes 3 characterization data,
supplementary Figures, Schemes, Tables, crystallography data including ORTEP views of all compounds and their NMR
spectra.
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TOC
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A Family of cyclic medium-sized disulfanes and related sulfanes was synthesized
and characterized, followed by desulfurization and disulfane ammonolysis
mechanisms
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Page 27 of 27
New Journal of Chemistry
View Article Online
DOI: 10.1039/C9NJ03682B
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80x39mm (600 x 600 DPI)