A fast catalytic process of transfer of a phosphorus atom: How folding of the reagent is related to its catalytic activity. a possible correlation with rna behavior

Article abstract of DOI:10.1080/10426507.2014.883625

A simple and very fast process of transfer of a phosphorus atom, performed by a simple molecule acting as catalyst in an almost infinite catalytic cycle is described. The catalyst donates a P atom to a mixture of two different Grignard reagents giving, in a very fast and in a highly selective manner, only one phosphorus-containing compound with an enormous rate enhancement with respect to the corresponding no-catalyzed reaction which gives a final cluttered mixture of many organophosphorus products. The focal factor to explain this highly selective process of P transport lies in the folded structure of the reagent with particular angles around the phosphorus atom which can facilitate the formation of cyclic trigonal bipyramidal pentacoordinated species and then its catalytic activity. In a similar manner, RNA can adopt, in a precise position, a particular three-dimensional structure that might facilitate the formation of pentacoordinated species leading to the catalytic function.

Full text of DOI:10.1080/10426507.2014.883625

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Phosphorus, Sulfur, and Silicon and the
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A Fast Catalytic Process of Transfer of
a Phosphorus Atom: How Folding of
the Reagent is Related to its Catalytic
Activity. A Possible Correlation with Rna
Behavior
Graziano Baccolinia & Gabriele Michelettia
a Dipartimento di Chimica Industriale “Toso Montanari”, ALMA MATER
STUDIORUM - Universita’ di Bologna, Viale Risorgimento, 4-40136
Bologna, Italy
Accepted author version posted online: 30 Apr 2014.Published
online: 04 Aug 2014.
To cite this article: Graziano Baccolini & Gabriele Micheletti (2014) A Fast Catalytic Process of
Transfer of a Phosphorus Atom: How Folding of the Reagent is Related to its Catalytic Activity. A
Possible Correlation with Rna Behavior, Phosphorus, Sulfur, and Silicon and the Related Elements,
189:7-8, 1254-1265, DOI: 10.1080/10426507.2014.883625
To link to this article: http://dx.doi.org/10.1080/10426507.2014.883625
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Phosphorus, Sulfur, and Silicon, 189:1254–1265, 2014
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2014.883625
A FAST CATALYTIC PROCESS OF TRANSFER
OF A PHOSPHORUS ATOM: HOW FOLDING
OF THE REAGENT IS RELATED TO ITS CATALYTIC
ACTIVITY. A POSSIBLE CORRELATION
WITH RNA BEHAVIOR
Graziano Baccolini and Gabriele Micheletti
Dipartimento di Chimica Industriale “Toso Montanari”, ALMA MATER
STUDIORUM − Universita’ di Bologna, Viale Risorgimento, 4-40136 Bologna,
Italy
GRAPHICAL ABSTRACT
Abstract A simple and very fast process of transfer of a phosphorus atom, performed by a
simple molecule acting as catalyst in an almost infinite catalytic cycle is described. The catalyst
donates a P atom to a mixture of two different Grignard reagents giving, in a very fast and
in a highly selective manner, only one phosphorus-containing compound with an enormous
rate enhancement with respect to the corresponding no-catalyzed reaction which gives a final
cluttered mixture of many organophosphorus products. The focal factor to explain this highly
selective process of P transport lies in the folded structure of the reagent with particular angles
around the phosphorus atom which can facilitate the formation of cyclic trigonal bipyramidal
pentacoordinated species and then its catalytic activity. In a similar manner, RNA can adopt, in
a precise position, a particular three-dimensional structure that might facilitate the formation
of pentacoordinated species leading to the catalytic function.
Keywords Phosphorus pentacoordinate; phosphorus trichloride; Grignard reagents; benzoth-
iadiphosphole; RNA
INTRODUCTION
Generally, thereactions occurringthroughorganophosphorus intermediates aredrived
by the ability of the phosphorus to form “hypercoordinate” species, mainly penta- and
Received 25 November 2013; accepted 7 January 2014.
Dedicated to Professor Dr. Louis D. Quin on occasion of his 86th birthday.
Address correspondence to Prof. G. Baccolini, Dipartimento di Chimica Industriale “Toso Montanari”,
ALMA MATER STUDIORUM − Universita’ di Bologna, Viale Risorgimento, 4-40136 Bologna, Italy. E-mail:
graziano.baccolini@unibo.it
1254

HOW FOLDING OF REAGENT IS RELATED TO ITS CATALYTIC ACTIVITY
1255
hexa-coordinate.1,2 For example, phosphoryl transfer reactions, which are fundamental in
biological processes, are generally assumed to involve pentacoordinated intermediates,
that influence the outcome of the reactions.3 The trigonal bipyramidal geometry (TBP)
represents the most common structure of pentacoordinated phosphorus intermediates.
Their stability strongly depends from their structure; in particular, when it is possible,
the formation of a cycle around the pentacoordinate phosphorus atom is favoured over that of
the corresponding acyclic intermediate by a factor of 106–108, as reported by Westheimer.4
Then any other possible collateral reaction in which the phosphorus atom belongs to an
acyclic pentacoordinate intermediate is practically minimized or annulled.
From these considerations, it can be deduced that the super-activated formation of
cyclic pentacoordinate phosphorus intermediates might be a possible candidate for a “self-
organized or autocatalytic mechanism” acting either on simple molecules or on complex
molecules in processes in which phosphorylation or dephosphorylation reactions are in-
volved, processes which are the centrepiece for the evolution of life. In fact, many studies
reveal that several enzymatic phosphoryl transfer processes such as decomposition of RNA
and DNA, and many others processes involving the so-called high-energy biomolecules
(e.g., phosphoenol pyruvic acid, PEP5 or cyclic adenosyl monophosphate, cAMP6) take
place via pentacoordinate phosphorus transition states or intermediates.7,8
Recently, we studied5b the nonenzymatic hydrolysis of PEP by following the re-
action course through 31P NMR spectroscopy. We have demonstrated that PEP in water
exists prevalently as a very stable cyclic pentacoordinated phosphorus compound TBP1
in equilibrium with other cyclic pentacoordinated forms (Scheme 1). This explains the
PEP stability in water. In contrast, after addition of an alcohol to a PEP aqueous solution,
other very unstable cyclic pentacoordinated intermediates are formed which immediately
collapse giving a feasible phosphorylation of the alcohol. In other words, we have ex-
plained why PEP is very resistant to hydrolysis while it is, in apparent contrast, a powerful
phosphorylating agent of alcohols.
Scheme 1
An intramolecular nucleophilic attack, via b, by the hydroxyl oxygen atom of the
carboxyl group to the P O group of PEP (1) forms a cyclic pentacoordinate phosphorus
intermediate such as TBP1 which is reported4 to be more stable by a factor of about 106–8
with respect to the corresponding acyclic pentacoordinate intermediate acTBP1 deriving
from the attack of water, via a, on the same P O group. As a consequence of this huge
rate difference between intra- and intermolecular pathways a and b, water cannot attack
P O group of PEP and this explains the great stability of PEP in water. Decomposition

1256
G. BACCOLINI AND G. MICHELETTI
of TBP1, via c, by elimination of water, gives, in very small amount, the cyclic phosphate
intermediate 2 which is the crucial product of this process. In fact, now it is possible
an addition of water to 2 to obtain again intermediate TBP1 together with TBP2 which
decomposes to give products of hydrolysis, pyruvic acid and phosphoric acid.
Mechanism of Non-Enzymatic Hydrolysis of RNA
The emphasis of the recent investigations on RNA hydrolysis was focused on the
study and the role of the factors that govern the formation, isomerisation, and breakdown
of the pentacoordinated phosphorus intermediates such as B (Scheme 2) involved in this
process.9 Now we re-propose this generally accepted9 mechanism but on the light of the
results obtained on the hydrolysis of PEP. In particular, intermediates B and C, are very
similar to intermediates TBP1 and 2, involved in PEP mechanism depicted in Scheme 1.
Scheme 2
As shown in the proposed mechanism (Scheme 2), the 2ꢁ-oxygen of the ribose
ring firstly attacks the phosphorus atom (Scheme 2, structure A) acting as an internal
nucleophile to generate the cyclic pentacoordinate intermediate or transition state B. This
attack should be more activated by a factor of ∼106 fold with respect to any other external
nucleophilic attack, such as that with water, which would give formation of a disfavored
acyclic pentacoordinate transition state4 The cyclic phosphodiester C can be obtained by
collapse of the pentacoordinate intermediate B after departure of the group O-5ꢁ which
is the most apicophilic group in B. Then, the formed C can easily undergo an attack,
activated by its cyclic form, by the nucleophile H2O, with formation of the stabilized cyclic
pentacoordinate intermediate D, which then collapses, giving the product of hydrolysis E.
It should be noted that the O-2ꢁ group is more apicophilic and leaving group than
O-3ꢁ in all pentacoordinate cyclic intermediates as those shown in Scheme 2. This is due to
the presence of the N group (N represent one of the four natural nucleotide base moieties),

HOW FOLDING OF REAGENT IS RELATED TO ITS CATALYTIC ACTIVITY
1257
which is more electron-withdrawing than C-5ꢁ. In this manner is explained the almost
exclusive ligation of phosphoryl group in O-3ꢁ position in the RNA chain.
In addition, this mechanism might explain the RNA catalytic ability to facilitate
chemical transformations such as its elongation process as well as transesterification.10
It is evident that in RNA polymers there are further factors, such as metal ions, the acid
and basic effect, which permit the easy formation of intermediate or transition state B and
consequently the formation of the cyclic phosphate C. However, as reported,11 the folding
structure of RNA molecules play very important roles in its behavior which enables the
regulation of their function diversities.
How a Three-Dimensional Structure is Related to the Catalytic Activity
An RNA polymer is structurally very flexible and it can often adopt a multitude of
possible three-dimensional structures. Only a single or a few possible structures usually lead
to function, therefore, the RNA polymer must avoid the problem of folding into alternative,
nonfunctional structures.
In other words, RNA must adopt complex three-dimensional folds that create specific
sites adapted for a chemical catalysis. Only a precise position of a RNA polymer might be
in such a conformation to facilitate a trigonal bipyramidal intermediate or transition state
and then only in this position catalysis or ligand rupture can occur.
RESULTS AND DISCUSSION
Now we report a simple and very fast process of transfer of a phosphorus atom,
performed by a simple molecule acting as catalyst in an almost infinite catalytic cycle.
The molecule which transfers the phosphorus atom has a particular folded structure in
which the angles around the phosphorus require only a small deformation as the structure is
transformed from a tetrahedral to the pentacoordinated trigonal bipyramidal intermediate.
The focal factor to explain this high selective process of P transport lies in the consequent
easy and fast formation of a stable poly-cyclic phosphorus pentacoordinated intermediate
and of a corresponding unstable hexacoordinated intermediate. In fact, the hexacoordinate
state3 exhibits greater instability than pentacoordinate analogous and this permits a facile
collapse of this intermediate or transition state giving the final products in very fast manner.
The “transport” system (Scheme 3, run a) is formed by two molecules. The first
is a benzothiadiphosphole derivative (1a),12 which we called “Butterfly reagent’ for its
particular bicyclic and folded structure, which donates13,14 a P atom to incoming different
Grignard reagents (i.e., bis-Grignard BrMg(CH2)4MgBr (2) and CH3MgBr) forming easily
cyclic tertiary phosphines as 3a. The second molecule (4)15a is the remainder of the reagent
1a, produced after expulsion of the phosphorus atom that resides between the two sulfur
atoms. This molecule 4 is easily re-transformed into the starting reagent 1a by the simple
addition of PCl3 to the final reaction mixture. It is important to note that the molecule 4 is
the true carrier of the P element and can be considered a “catalyst” both, for its ability to
obtain products which are quite difficult to synthesize by other methods, and for the fact
that it can be completely recovered at the end of the process.
In fact, this process provides an enormous rate enhancement for the formation of 3a
compared to the uncatalyzed reaction (Scheme 3, run c). Performing the reaction under
the same conditions but in the absence of 4 resulted in a mixture of many products, with
only a very low yield (∼0.01%) of compound 3a after 3 days of reaction. The mechanism

1258
G. BACCOLINI AND G. MICHELETTI
PCl3
H3C
H3C
CH3
MgBr
+
BrMg(CH2)4MgBr (2)
P
S
P
P
P
CH3
H3C
CH3MgBr
S
S
1
80%
BrMg
S
MgBr
1a
3a
4
Run a
2
+ 4
80%
1a
PCl3
+
4
P
CH3
3a
CH3MgBr
Run b
+
Me2PBut
MePBut2
PMe3
PCl3
+
2 + CH3MgBr
many others
products
3a (0,01% after
+
PBut
+
Without catalyst 4
+
3
3 days of reaction)
Run c
Scheme 3
of this process is shown in Scheme 4 and involves the intervention of cyclic pentacoordi-
nate and hexacoordinate phosphorus intermediates A and B, respectively. The particular
bicycle and folded structure of reagent 1a strongly stabilizes hypercoordinated phosphorus
intermediates involved in the reaction and favours their formation. Recently,14b in a similar
reaction it has been possible to detect, by 31P NMR spectroscopy, both pentacoordinate A
and metastable hexacoordinate species B and to follow their evolution during the course of
the reaction.
These findings prompted us to use 4 to obtain similar transport processes with other
elements in which the formation of such hypervalent species is easy as in the case of the
P element. These element are As and Sb which have atom electronic configuration similar
to the P atom. If 4 is treated with AsCl3, or SbCl3 and BiCl3 and the two above Grignard
reagents we have a catalytic process obtaining 3b (60% yield), or 3c (50% yield) and 3d
(20% yield), respectively, and consequent regeneration of catalyst 4.15a (See Scheme 5).
In the case of As we have also carried out the reaction between AsCl3 and the two
Grignard reagents without catalyst 4, obtaining a mixture of many products with only very
small traces of cyclic arsine 3b (see Scheme 6).
The gradual decrease of the yields of cyclic products on going from P, As, Sb, Bi
could be explained by the increasing stability of the corresponding hypervalent species of
Sb and Bi that make difficult for them to collapse to form the final products. In particular
penta- and hexacoordinated species of bismuth have been often reported15b to be very stable
or substituted by ionic species).15c
In contrast, when the same process was carried out using the carbon deriva-
tive of 1a (2,5a,9-trimethyl[1,3]benzothiaphospholo[2,3-b][1,3]benzothiaphosphole) by
adding CH3CCl3 to 4 we did not obtain the transport of the carbon atom giving 1-
methylcyclopentane. This is in accord with the fact that in the case of carbon atom the
hypervalent species, penta and hexacoordinated, are very unstable or impossible. These

HOW FOLDING OF REAGENT IS RELATED TO ITS CATALYTIC ACTIVITY
1259
Scheme 4
results indicate that only the phosphorus and, in minor amount, the arsenic among these
elements gives easily hypervalent metastable species which then decompose to give final
products. But these processes in which the phosphorus is involved with these hypercoordi-
nations are essential for biological processes and perhaps also for the processes regarding
the origin of life.
The process described here clearly demonstrates that the facile formation of the cyclic
pentacoordinated phosphorus intermediate is the driving force that allows the disorder of
the corresponding uncatalyzed process (run c) to be overcome. This agrees with the results
showing the formation of only cyclic compound 3a in the presence of catalyst 4 (run b),
whereas a very complex mixture of acyclic organophosphorus compounds is formed in its
absence (run c).

1260
G. BACCOLINI AND G. MICHELETTI
ECl3
MgBr
H3C
P
S
S
P
ECl3
H3C
BrMg
MgBr
4
S
E
4
S
+
1a–d
BrMg(CH2)4MgBr,
E
E = P (a), As (b), Sb (c), Bi (d)
CH3MgBr
CH3
3 a–d
Scheme 5
The folded structure of reagent 1a provides a clear explanation for the easy formation
of pentacoordinate intermediate such as A. Using X-ray analysis of 1, we found that the
two P2–P1–S angles are 96◦ and that the S–P1–S angle is 107◦.12a These angles were also
found in solution by comparing the 31P NMR results in the solution and solid states.12b The
values of the angles indicate only a small deformation around the phosphorus atom as the
structure is transformed from 1a to the pentacoordinated trigonal bipyramidal intermediate
A, wherein the two P–P1–S angles must be 90◦ and the S–P1–S angle must be 120◦. Thus,
there is an overall angle deformation of 6◦ + 6◦ + 13◦ = 25◦. In a hypothetical acyclic
compound R2PP(SR)2, the two angles P–P1–S and the S–P1–S angle must all be equal to
the tetrahedral angle of 109.5◦. In this case, the overall angle of deformation to form the
trigonal bipyramidal intermediate must be 19.5◦ + 19.5◦ + 10.5◦ = 49.5◦. Therefore, the
folded bicyclic structure of 1a permits a net economy of 24.5◦ in the overall angle expansion
with respect to hypothetical acyclic compound R2PP(SR)2, activating the formation of a
trigonal bipyramidal intermediate such as A.
Correlation with RNA
This mechanism may be helpful to explain the relation between the three-dimensional
structure of RNA in a specific position and its catalytic function. The 2ꢁ-oxygen first
attacks the phosphorus atom, acting as an internal nucleophile, to generate the cyclic
pentacoordinated intermediate or transition state B (see Scheme 2). But this attack is
possible only in a precise position of RNA in which its conformation facilitates a trigonal
bipyramidal intermediate or transition state B and then only in this position catalysis can
occur. In other words, in A in Scheme 2 the three groups 2ꢁ-OH, 3ꢁ-P and 5ꢁ-O must be
aligned and the three angles around the P atom must be preferential in the same plane (the
three angles must be near to 120◦). This attack should be activated by a factor of ∼106
AsCl3
(CH3)3As + nBu3As + nBu2AsCl
2 + CH3MgBr
3b
+ traces of
+many other products
Without
4
catalyst
Scheme 6

HOW FOLDING OF REAGENT IS RELATED TO ITS CATALYTIC ACTIVITY
1261
compared to any other external nucleophilic attack, such as with water, which would result
in the formation of a disfavored acyclic pentacoordinated transition state.
It is interesting to note that the nucleolytic ribozymes typically accelerate their
transesterification reactions by around a million-fold relative to the uncatalyzed reaction in
a dinucleotide, similarly the rate constant for RNA transesterification under representative
physiological conditions is 100,000-fold greater that the estimated rate constant for the
hydrolysis of DNA under similar reaction conditions.16 This catalytic power could be
explained by the above mechanism where it is expected by Westheimer4 rule to be activated
by a factor of ∼106. We suspect that the cyclic phosphate C is the true “catalyst” or
“activated catalyst” form of the ribozyme, similar to cyclic reagent 1a in Scheme 3 or
compound 2 in PEP hydrolysis (Scheme 1).
Then, the particular folding structure in a specific position of RNA favoring the
structural geometry of intermediates, is fundamental for its catalytic function, as occurs
with activated catalyst 1a.
The same factors also are important in many enzymatic phosphoryl transfer
processes.17
Based on the above mechanism, it is clear that the high catalytic activity of RNA
molecules is due to its specific three-dimensional structure which facilitate the attack of
the 2ꢁ-hydroxyl group on the 3ꢁ-P with consequent easy formation of cyclic pentacoordi-
nated intermediates by a factor of ∼106 compared to all other acyclic pentacoordinated
intermediates or transition states. RNA is similar to DNA but, unlike DNA, has a hydroxyl
group at the 2ꢁ-position of the ribose sugar. This hydroxyl group makes RNA less stable
but permits to RNA to catalyze many tranformations without the presence of enzymes but
with the intervention of a cyclic phosphate such as C (see Scheme 2).
Conclusions
In conclusion, the simple high selective process of a P atom transport described
here suggest that the focal factor to explain this lies in the particular folded structure of
the reagent 1 with particular angles around the phosphorus atom which can facilitate the
formation of cyclic trigonal bipyramidal pentacoordinated species and then its catalytic
activity. In a similar manner a particular three-dimensional structure that RNA can adopt in
a specific position might facilitate the formation of pentacoordinated species and then lead
to the catalytic function.
EXPERIMENTAL
General experimental details. NMR spectra were recorded at 400 and 121.45 MHz
1
for H and 31P respectively. Chemical shifts are referenced to internal standard TMS
(1H NMR), and external standard 85% H3PO4 (31P NMR). J values are given in Hz.
THF was distilled from sodium benzophenone ketyl. All Grignard reagents used, both
commercially available and prepared from the corresponding alkyl halide and magnesium
turnings, were titrated immediately prior to use by standard methods.18 Air and mois-
ture sensitive solutions and reagents were performed under dry argon atmosphere using
standard Schlenk-type techniques. All solvents were purified appropriately before use and
degassed immediately prior to use. Benzothiadiphosphole 1a was synthesized as previously
described.12c

1262
G. BACCOLINI AND G. MICHELETTI
Preparation and Isolation of ‘Catalyst’ 4:15a
A solution containing BrMg(CH2)4MgBr (2) (2.0 mmol) and CH3MgBr (2.0 mmol) in
THF was added, at room temperature, to a solution of benzothiadiphosphole (1a) (2.0 mmol)
in anhydrous THF (35 mL) and under an argon atmosphere. The reaction was monitored
by GC–MS and 31P NMR spectrometry:19 when the signals of reagent 1a disappeared, with
concomitant appearance of those of cyclic phosphine 3a and of compound 4, the solvent
was partially removed (reduction to about 1/5 of the starting volume) under vacuum, and
the resulting suspension was filtered under argon atmosphere. The white salt 4 was washed
one time with 1–2 mL of anhydrous THF and it can be stored as suspension in anhydrous
THF under argon (in this way it can be preserved for 2–3 days). It should be noted that the
reaction can be carried out also at lower temperature (i.e., 0 – −5 ◦C) with the same yields
after the same reaction time. This indicate that the reaction is a very energetically favored
process.
Tris[bromomagnesium(1+)] bis(5-methyl-2-sulfidophenyl)phosphate(1-) (4)15a
:
1
White solid; H NMR (400 MHz, THF d8): δ = 7.50–7.38 (m, 1H), 7.33–7.20 (m, 1H),
7.11–6.92 (m, 2H), 6.60–6.40 (m, 2 H), 2.20 (s, 3 H), 2.11 (s, 3 H); 31P NMR (161.9 MHz,
THF d8) δ = −79.4 (m).
Preparation of Compounds 1b–d: 15a
AsCl3 (or SbCl3, or BiCl3, 1.0 mmol) was added, at room temperature, to a solution of
compound 4 (0.278 g, 1.0 mmol) in dichloromethane (30 mL) under argon atmosphere. After
about 20 m. the solvent was removed giving quantitatively the corresponding compound 1.
2,10-dimethyl[1,3,2]benzothiaphospharsolo[2,3-b][1,3,2]benzothiaphospharso-
le (1b): 1H NMR (400 MHz, [D8]THF, 25◦C): δ (ppm) = 7.54 (d, J = 9.5 Hz, 2H), 7.26 (d,
J = 8.2 Hz, 2H), 6.96 (d, J = 8.10 Hz, 2 H), 2.28 (s, 6H, CH3); 13C NMR (100.56 MHz,
[D8]THF, 25◦C): δ (ppm) = 145.3, 143.8 (d, J = 33 Hz), 137.0 (d, J = 9 Hz), 134.8 (d,
J = 30 Hz), 132.3, 127.6 (d, J = 3 Hz), 22.2; 31P NMR (161.9 MHz, [D8]THF, 25◦C,
1
31
H3PO4 ext. st.): δ (ppm) = 78.6 (br.s., line width ∼15Hz); { H} P NMR (161.9 MHz,
[D8]THF, 25◦C, H3PO4 ext. st.): δ (ppm) = 78.6 (t, JPH = 8.7 Hz); GC–MS: m/z (%): 350
(35) [M+], 243 (100), 107 (14).
2,10-dimethyl[1,3,2]benzothiaphosphastibolo[2,3-b][1,3,2]benzothiaphosphast-
1
ibole (1c): H NMR (400 MHz, [D8]THF, 25◦C): δ (ppm) = 7.54 (d, J = 10.3 Hz,
2H), 7.22 (d, J = 8.1 Hz, 2H), 6.84 (d, J = 8.0 Hz, 2H), 2.26 (s, 6H, CH3); 13C NMR
(100.56 MHz, [D8]THF, 25◦C): δ (ppm) = 147.6, 137.6 (d, J = 31 Hz), 135.5 (d, J =
10 Hz), 133.7 (d, J = 69 Hz), 131.4, 130.7, 21.9; 31P NMR (161.9 MHz, [D8]THF, 25◦C,
H3PO4 ext. st.): δ (ppm) = 52.7 (br. s., line width ∼42 Hz); GC–MS: m/z (%): 396 (23)
[M+], 243 (100), 153 (6), 121 (12).
2,10-dimethyl[1,3,2]benzothiaphosphabismolo[2,3-b][1,3,2]benzothiaphospha-
bismole (1d): 1H NMR (400 MHz, [D8]THF, 25◦C): δ (ppm) = 7.71 (d, J = 14.0 Hz, 2H),
7.25–7.08 (m, 4H), 2.29 (s, 6H, CH3); 31P NMR (161.9 MHz, [D8]THF, 25◦C, H3PO4 ext.
1
31
st.): δ (ppm) = 35.0 (s, line width ∼23 Hz); { H} P NMR (161.9 MHz, [D8]THF, 25◦C,
H3PO4 ext. st.): δ (ppm) = 35.0 (t, JPH = 14.0 Hz). MS: m/z = 484 [M+], 275, 243, 211,
153, 121.
Preparation of Compounds 3a–d:15a
ECl3 (2.0 mmol, E = P, As, Sb, Bi) was added to a suspension of 5 (2.0 mmol) in
THF (20–30 mL).

HOW FOLDING OF REAGENT IS RELATED TO ITS CATALYTIC ACTIVITY
1263
After about 20 min the formation of compound 1 a–d was complete. Then, a solution
containing BrMg(CH2)4MgBr and CH3MgBr (2.0 mmol) in THF was quickly added, at
room temperature. The reaction course was monitored by GC–MS and 31P NMR spec-
troscopy. After about 40 min. the signal of the starting reagent 1 disappeared, and concomi-
tantly appeared those of 4 and 3 a–d.
1-methylphospholane (3a): Colourless oil, bp 122–125◦C (760 mmHg), Lit.;20 80%
1
yield; H NMR (300 MHz, CDCl3): δ (ppm) = 2.20–1.20 (m, 8 H), 1.28 (d, 3 H, J =
2.7 Hz); 31P NMR (121.45 MHz, CDCl3) δ (ppm) = −38.2; GC–MS (m/z,%): 102 (M+,
85).
1-methylarsolane (3b): Colourless oil, 60% yield; 1H NMR (300 MHz, CDCl3): δ
(ppm) = 1.75–1.25 (m, 8 H), 0.83 (s, 3 H); GC–MS (m/z,%): 146 (M+, 100), 131 (39), 132
(23), 118 85, 103 (57), 90 (18), 55 (31).
1-methylstibolane (3c): Colourless oil, 50% yield; 1H NMR (300 MHz, CDCl3): δ
(ppm) = 1.80–1.00 (m, 8 H), 0.52 (s, 3 H); GC–MS (m/z,%): 192 [194] (M+, 75), 177 (44),
149 (58), 136 (100).
1-methylbismolane (3d): Colorless oil, 20% yield; 1H NMR (300 MHz, CDCl3): δ
(ppm) = 2.60–1.80 (m, 8 H), 0.87 (s, 3 H); GC–MS (m/z,%): 280 (M+, 20), 265 (15), 252
(10), 224 (48), 209 (100).
Reaction between PCl3 and Grignard Reagents
in the Presence of Catalyst 4
PCl3 (freshly distilled, 0.17 mL, 2.0 mmol) was added, under an argon atmosphere
and at room temperature, to a suspension containing catalyst 4 (2.0 mmol) in THF (20 mL).
After about 20 minutes the reaction mixture turned pale-yellow and clear, so indicating that
the formation of compound 1a was complete, as confirmed by 31P NMR spectroscopy of the
reaction mixture. To this mixture, a solution containing BrMg(CH2)4MgBr (2) (2.0 mmol)
and CH3MgBr (2.0 mmol) in THF was quickly added, at room temperature. The reaction
course was monitored by GC–MS and 31P NMR spectrometry. After about 20 minutes
the signals of the starting reagent 1a disappeared, and concomitantly appeared those of
1-methylphospholane (3a) and reformation of 4. This latter was separated by filtration as
above described and compound 3a, present in the filtrate, was purified, after removal of the
reaction solvent, by distillation.
Identification of Intermediates A and B
To a magnetically stirred solution of benzothiadiphosphole 1a (0.306 g, 1.0 mmol) in
THF (20 mL), kept under argon atmosphere, an equimolar amount of BrMg(CH2)4MgBr
(in THF) was added. The solution immediately turned golden-yellow and after 15 minutes
its 31P NMR spectrum showed disappearance of signals of the starting reagent and con-
comitant appearance of a new couple of doublets at δ = −27.0 ppm (d, J = 207 Hz), and
δ = −44.4 ppm (d, J = 207 Hz), ascribed to the pentacoordinated intermediate A. After
about 30–40 minutes an equimolar amount of CH3MgBr was added and the 31P NMR spec-
trum of the resulting reaction mixture showed appearance of a new couple of very weak
transient signals tentatively ascribed to hexacoordinated intermediate B [δ = 85 ppm (d, J
= 118 Hz), and δ = −58 ppm (d, J = 118 Hz)], together with those of 1-methylphospholane
(3) (δ = −37.8 ppm in THF) and of the compound 4 (δ = −79.4 ppm).

1264
G. BACCOLINI AND G. MICHELETTI
Other intermediates such as A and B were identified and reported in previous arti-
cles.14
Reaction between PCl3 and Grignard Reagents without Catalyst 4
To a freshly distilled solution of PCl3 (0.86 mL, 10 mmol) in anhydrous THF (75 mL),
kept under argon atmosphere, a solution containing Grignard reagent 2 (10 mmol) and
CH3MgBr (10 mmol) in THF (25 mL) was quickly added at room temperature. The
reaction course was monitored by GC–MS and 31P NMR spectroscopy (after quenching
with water). The mass spectra recorded after 40 min revealed formation of a disordered
mixture of organophosphorus compounds with only very small traces of phospholane 3a.
The reaction, analyzed after more time (3 days) showed increasing of compound 3a (about
0.01% yield) but also formation of several others phospho-organo compounds such as PMe3,
PBut3, MePBut2 (PMe3 = −61.5 ppm, PBut3 = −31.6 ppm, MePBut2 = −42.3 ppm). The
reaction was repeated several times, and the relative ratio of the reaction products changed
each time, as in a disordered process, but in every case only very small traces of 3a were
detected by GC–MS spectroscopy, (m/z,%) [102 (M+, 48), 101 (34), 87 (5), 75 (100), 74
(84), 57 (49)] compared with data obtained in the reaction with catalyst 4.
Reaction between AsCl3 and Grignard Reagents without Catalyst 4
To a solution of AsCl3 (0.42 mL, 5 mmol) in anhydrous THF (40 mL) was quickly
added, at room temperature and under argon atmosphere, a solution containing Grignard
reagent 2 (5.0 mmol) and CH3MgBr (5.0 mmol) in THF (10 mL). The reaction course was
monitored by GC–MS spectrometry. The mass spectra recorded after 40 minutes revealed
formation of a clutter mixture of compounds as acyclictrialkyl arsines, mono- and dialkyl
chloroarsines, and compounds bearing two arsenic atoms in their structure, but only very
small traces of arsolane 3b. The reaction was repeated several times and with more longer
time of reaction (3–4 days), and the relative ratio of the reaction products changed each
time, as in a disordered process, but in every case only very small traces of arsolane 3b
were detected by GC–MS spectroscopy, (m/z,%) [146 (M+, 100), 131 (39), 132 (23), 118
85, 103 (57), 90 (18), 55 (31)] compared with data obtained in the reaction with catalyst 4.
FUNDING
Work supported by ALMA MATER STUDIORUM–UNIVERSITA’ DI BOLOGNA
(ex 60% MIUR).
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