Stereochemistry of electrophilic and nucleophilic substitution at phosphorus

Article abstract of DOI:10.1080/10426507.2018.1521409

Stereochemistry and mechanisms of nucleophilic [S_N2(P)] and electrophilic [S_E2(P)} reactions have been analyzed, discussed and confirmed by experimental studies. S_E2(P) reactions proceed with the retention of absolute configuration, while the S_N2(P) reactions react with the inversion of the configuration at the phosphorus atom.

Full text of DOI:10.1080/10426507.2018.1521409

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
Stereochemistry of electrophilic and nucleophilic
substitution at phosphorus
Oleg I. Kolodiazhnyi
To cite this article: Oleg I. Kolodiazhnyi (2018): Stereochemistry of electrophilic and nucleophilic
substitution at phosphorus, Phosphorus, Sulfur, and Silicon and the Related Elements, DOI:
10.1080/10426507.2018.1521409
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PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
https://doi.org/10.1080/10426507.2018.1521409
Stereochemistry of electrophilic and nucleophilic substitution at phosphorus
Oleg I. Kolodiazhnyi
Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences, Kiev, Ukraine
ABSTRACT
ARTICLE HISTORY
Stereochemistry and mechanisms of nucleophilic [S
been analyzed, discussed and confirmed by experimental studies. S 2(P) reactions proceed with
N
2(P)] and electrophilic [S
E
2(P)} reactions have
Received 15 July 2018
Accepted 31 August 2018
E
the retention of absolute configuration, while the S
configuration at the phosphorus atom.
N
2(P) reactions react with the inversion of the
KEYWORDS
Electrophilic substitution;
nucleophilic substitution;
stereochemistry; halogeno-
philic reactions; mechanism
GRAPHICAL ABSTRACT
N
of S 2(P) reaction
R
SN
R
SE
Y
R
P
Y
X
R
P
X
R
R
Introduction
of ligands at the phosphorus center (Scheme 3). In the case
of a diastereoselective reaction of a chiral reagent with a
racemic substrate, the existing chiral center influences the
stereochemistry of new formed asymmetric center, therefore
the formation of a more stable diastereomer is controlled by
thermodynamic factors (Scheme 4). As a result, the reaction
passes with partial racemization, the asymmetric induction
at the phosphorus atom is also possible.
The reaction of P(III)-compounds with tetrahalomethanes
plays an important role in chemical and biochemical synthe-
Nucleophilic and electrophilic reactions are the most com-
monly used in organic chemistry. They are closely intercon-
nected, because in a reacting pair always one reagent is an
[1, 2]
electrophile, and the other is a nucleophile.
The electro-
philic attack on the P(III) reaction center occurs from the
front side, where a free pair of electrons and negative charge
is localized, therefore the bond of electrophile with phos-
phorus is formed with retention of configuration. On the
contrary, the negatively charged nucleophile is repulsed by a
pair of electrons from the front-side, and therefore the
attack occurs from the backside. As a result, the electrophilic
attack proceeds with the retention of configuration, and the
nucleophilic attack is accompanied by Walden inversion
[4, 5]
sis, various versions of this reaction were described and
[6–11]
used in organic and organophosphorus chemistry.
The
most important versions of these reactions are the Atherton-
Todd reaction, the Appel reaction, the Corey-Fuchs reaction,
and the tertiary phosphine reaction proceeding with the
[3]
(Scheme 1).
[11, 12]
formation of P-halogenylides.
These reactions consist of two steps. In the first step, an
electrophilic attack of positivized halogen on a trivalent
phosphorus atom is carried out to form a quasiphospho-
Results and discussion
The bimolecular S 2(P) mechanisms of electrophilic substitu-
E
nium intermediate containing a CX -anion. In the second
3
tion reactions at phosphorus is similar to the S 2 mechanism step, the intermediate reacts with the nucleophile or a
N
in the sense that new bonds form, when old bonds break rearrange with the formation of CX -phosphonium salt. The
3
(Scheme 2).
Appel and Atherton-Todd reactions are two-step processes
Usually the reaction of phosphorus (III) compounds with resulting in the final product with inversion of absolute con-
[
8–10]
strong nucleophiles (Nu ¼ Grignard reagents, alcoholates, figuration.
The formation of the intermediate 3 con-
alkyl lithium) proceeds stereospecifically via the formation taining the CX -anion was proved by chemical and physical
3
of short-living intermediate 1 with inversion of absolute methods.[
12]
For example, the CX -intermediate 3 reacts
3
configuration. In the case of weak nucleophiles (Nu ¼ with trimethylchlorosilane to afford CX SiMe , or forms
3
3
alcohols in the presence of organic bases or primary alkyl halides with alcohols under Appel reaction conditions.
amines), the reaction proceeds through the formation of a Optically active alcohols, in this case afford optically active
long-living pentacoordinated intermediate 2, which under- alkyl halides with inversion of configuration (Scheme 5).
goes the Berry pseudorotation with a change in the position Optically active tertiary phosphines under Appel reaction
CONTACT Oleg I. Kolodiazhnyi
olegkol321@gmail.com
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/gpss.
ß 2018 Taylor & Francis Group, LLC

2
O. I. KOLODIAZHNYI
conditions give optically active phosphine oxides with inver- presence of (-)-L-menthol led to the formation of chiral
sion of absolute configuration. An asymmetric version of the tertiary phosphine oxides (Scheme 6).
[
8]
Appel reaction was developed. The oxidation of trivalent
Reaction of chiral tertiary alkylphosphines with tetra-
phosphorus compounds with alkane polyhalides in the chloromethane leads to the formation of P-halogenylides.
These ylides are interesting reagents for organic synthesis.
Scheme 7 shows the reaction mechanism. The deprotonation
R
SN
R
of the alkyl group in the phosphonium cation occurs by tri-
chloromethyl anion, that leads to the formation of chloroform.
As a result, the chiral P-halogenoylides, previously unknown,
were obtained. These P-halogenylides can be used to prepare a
number of novel chiral phosphorus compounds. The P-halo-
genylides react with aldehydes, ketones, CO and CS to form
SE
P
Y
R
Y
X
R
P
X
R
R
Scheme 1. Electrophilic and Nucleophilic attacks on the Phosphorus center.
2
2
5
X
1,2k -oxaphosphetanes, some of which were isolated as stable
compounds, as well as vinylphosphonates, allyl phosphonates,
phosphoric ketenes and thioketenes. In this work, we synthe-
sized some chiral P-halogenoylides. These compounds are
analogs of the racemic P-halogenylides, which we have
R
X
P
R-X
X
SE
X
+
P
P
R1
L
R1
L
–LX
R1
R
R2
R2
R
2
Retention
Scheme 2. Mechanism of electrophilic substitution of P(III)-compounds.
[
12–14]
described earlier.
The sequential treatment of chiral
X=2e, BH ; R-X= AlkCl, AlkBr, AlkTs, etc; L=Li, Na
3
alcoxylphosphine boranes with tetrachloromethane and
(
(
a)
b)
X
X
X
SN
Nu
P
L
Nu
P
L
Nu
P
–L
R1 R2
R1 R2
R2
R1
inversion
1
Backside attack
Nu=Strong nucleophile
short-living intermediate
X
P
X
P
X
X
Nu
SN
P
L
Nu
P
Nu
L
Nu
L
–
L
R1
R1
R2
R2
R2
R1
R1
R2
2
X= e pair or BH3
long-living intermediate
Nu -Weak nucleophile, L -Leaving group
Scheme 3. The mechanism of nucleophilic substitution in P(III).
B
P
B
P
R
B
R*XH
R
R
R'
R
X
–
P
X
P
X
X
–
:
R'
R'
B=Base
R'
B
XR*
a
XR*
b
–B.HX
–B.HX
R*X
R*X
R'
*
*
P
R'
P
R
R
Scheme 4. The mechanism of nucleophilic substitution at the trivalent phosphorus atom.
Cl
CCl3
Cl
O
P
(
R)
CCl4
(
R)
(R)
−
HOMe
(S)
Bu-t
P
P
P
Cl C
3
Bu-t
Me
Bu-t
Me
Bu-t
Me
H C
3
Retention
Ph
Ph
inversion
Ph
Ph
3
.
Scheme 5. Stereochemistry of the Appel reaction.

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
3
O
P
OR
3
R
R
R1
P
R3
2
+
2
R1
R*Cl
R*Cl
R1
R1
...
Cl
R
Cl CCl
3
CCl4
R*OH
P
R3
P
R2
R2
R3
O
OR
R3
+
R1
P
R3
R1
P
R2
R2
Cl
Scheme 6. The mechanism of asymmetric induction at the Phosphorus atom.
H B
3
O
t-Bu
Ph
Cl
Et NH
CCl4
2
MeOH
P
P
P
P
Bu-t
Me
Bu-t
Me
H C
Bu-t
CH2
3
Ph
Retention
inversion
Ph
Ph
R5
R4
O
Y
P
R
O
P
t-Bu
R1
P
R
H
t-Bu
H
H
C
R1
R2
Z
H
R'
X (Cl, Br, F)
Y=O, S; Z=O, S
4
5
6
Scheme 7. Reaction of chiral tertiary alkylphosphines with tetrachloromethane.
+
1) BuLi
BuLi
Ph
3
P
CBr
4
Br
O
Br
2
) H
2
O
ClCO Me
2
7
8
H
9
Ph P
H NR
2
3
CO Me
2
C(O)NHR
CO Me
2
10
11
R=Alk
M: 273,21 m/z; 274.21 (M+1) (R=Bu-i),
Scheme 8. The Cory-Fuchs reaction and the Trost-Kazmaier methodology in the organic synthesis.
R2
R1
R2
R1
R*OH
R*OH
P
OR*
P
OR*
13
P
Cl
R1
Py
THF
R2
Et3N
Toluene
-
12
(
SP)
0-70% de
Scheme 9. Example of diastereoselective reaction of chiral alcohols with chlorophosphines.
13
(
RP)-
6
78-90% de
R*OH=1,2:5,6-Diisopropyliden-D-glucofuranose
carbon dioxide or carbon disulfide leads to the formation of acids and their amides, in particular of tetradecapentaenoic
chiral ketenes and thioketenes.
acid derivatives, which attract attention as bioregulators of
[
17]
The considerable interest from the point of view of apoptosis.
The treatment of dibromoalkene by triphenyl-
organic synthesis represent also the Corey-Fuchs reaction as phosphine using the method of Trost-Kazmaier led to the
[
15, 16]
a method for the synthesis of terminal alkynes.
The rearrangement of alkyne to 1,3-diene 10 and formation of
reaction of tertiary phosphines with tetrabromomethane tetradecapentaenoic acid 11 (Scheme 8).
gives dibromomethylenephosphorane 7, which reacts with
The reaction of asymmetric chlorophosphines with chiral
aldehydes to form dibromalkenes 8. The treatment of dibro- nucleophiles proceeds with asymmetric induction and lead
malkenes 8 with butyl lithium gives terminal alkynes 9. This to the formation of enantiomerically enriched phospho-
[18]
reaction is used for the total synthesis of a number of nates.
The reaction of chlorophosphines 12 with gluco-
important natural compounds. Using the Corey-Fuchs reac- furanose allows the production of phosphinites 13 with a
tion on a key step, we obtained some polyunsaturated fatty high enantiomeric excess (Scheme 9). By changing the

4
O. I. KOLODIAZHNYI
Table 1. Diastereoselectivity of reaction of tert-butyl (phenyl)chlorophosphine
with 1-methylbenzylamine depending on reaction conditions.
(1) stereoselectivity of reaction depends on the nature of
solvent; (2) stereoselectivity of reaction depends on nature
of organic bases; (3) increase in amount of chlorphosphine
in the reaction mixture increases the stereoselectivity of
reaction, while increase of methylbenzylamine concentration
reduces stereoselectivity; (4) lowering temperature decreases
the stereoselectivity of reaction; (5) the reaction of chloro-
phosphine with (S)-1-methylbenzylamine afforded phosphin-
ites of (R)-configurations while (R)-1-methylbenzylamine
gives a product having (S)-configuration.
ꢁ
IIII
Solvent
Base
Temp. C
1:2:Base
dr
1
2
3
4
5
6
7
8
9
Benzene
Benzene
Benzene
Toluene
Toluene
Toluene
Toluene
Hexane
THF
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
3
3
3
3
3
3
3
3
3
3
3
3
3
3
N
N
N
N
N
N
N
N
N
N
N
N
N
N
20
20
20
30
20
0
ꢀ20
20
20
20
20
20
20
20
20
20
20
1:1:1
1:1:2
1:1:10
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
2:1:1
4:1:1
1:1:4
1:1:1
1:1:1
1:1:1
8:92
13:87
21:79
10:90
16:84
20:80
26:74
20:80
38:62
36:64
75:25
15:85
14:86
18:82
25:75
1
0
Ether
The obtained results show significant effect of tertiary
!
1
Benzene
Toluene
Toluene
Benzene
Toluene
Toluene
Toluene
1
1
1
1
1
1
2
3
4
5
6
7
organic bases on stereochemistry of S 2P reaction. The
N
dependence of stereoselectivity on temperature shows that
the reaction is not kinetically controlled because usually the
DABCO
PEA
DBU
17.5:82.5 decrease of temperature increases the stereoselectivity of kinet-
42:58
[19, 20]
ically controlled reactions.
The dependence of the
stereoselectivity on temperature shows that the mechanism of
nucleophilic substitution at the trivalent phosphorus atom
involves the Berry pseudorotation and the exchange of ligands
in the pentacoordinated phosphorane intermediate, leading to
the formation of a more stable diastereomer under thermo-
dynamic control (Scheme 4). This mechanism was confirmed
in the case of trivalent phosphorus compounds 15 containing
a 1,3,2-oxazophospholane ring. Chloriminophosphoranes 16
stereoselectively add methanol to form pentacoordinated
reaction conditions, it is possible to obtain the phosphinites
of both absolute configurations (S )-13 and (R )-13. The
P
P
reactions of chlorophosphines with primary amines or with
amino acid esters, or alpha-methylbenzylamine proceeds
with the transfer of chirality from the chiral amine to the
[
5–7]
phosphorus atom (Scheme 10).
We have used these
reactions as the object for investigation of mechanism of
diastereoselective reaction at phosphorus. First of all we
have found that the stereochemical result does not depend
on the chirality of chlorophosphine, since the same diaster-
eomeric values of aminophosphines were obtained with
racemic and optically active chlorophosphines. The effect of
various factors on stereochemistry of reaction of tert-butyl-
phenylchlorophosphine with 1-methylbenzylamine in the
presence of the organic bases shown in the Table 1 allowed
to make some conclusions concerning the mechanism
of reaction:
3
1
intermediate 17 (dr 96: 4), which is stable in solution. The
P
NMR spectrum confirmed the presence of signals belonging to
31
the diastereoisomers 17 in the negative field of the P NMR
spectra at d ꢀ56 and ꢀ58 ppm, in accordance with the penta-
P
coordinate state of phosphorus atom.
Upon heating, alkoxyphosphorane 17 was converted into
cyclic amidophospholane 18 (dr 75:25). The (S ,S)- and
P
(RP,S)-diastereomers 18 were separated and obtained in pure
state (Scheme 11).
R3
R3
R1
P
R3
H N
H
H N
2
H
R2
P
R3
2
H
R4
H
R4
R1
(R)
(S)
R1
N
R4
R2
N
R4
P
Cl
H
H
R2
Et
N
3
Et N
3
(
R,S )-14
(S,R )-14
P
P
8
5-95%
12
85-95%
8
0-85% de
80-85% de
1
2
3
4
R =Me, t-Bu, Mes; R =Ph, Me, i-Bu; R =Me; i-Pr, i-Bu; R =Ph, An, 4-ClC H , Nphth, CO Me
6
4
2
Scheme 10. Example of diastereoselective reaction of chiral amines with chlorophosphines.
O
O
NR*
X
O
P
O
CCl4
MeOH
0
O
NHR* >20 C
P
NHR*
P
P
EtN
CHCl3
N
NHR*
N
N
o
Et
OMe
-MeX
Et
Et
ether, -80 C
X
17
1
6
15
18
–
13.5; –14.4 ppm.
–
56.0; –59.8 ppm
2
1.9; 21.86 ppm
δP
δP
dr =96 : 4
δP
dr =75:25
dr =3:4
X=Cl, Br; R*= (S)-CH(R)CO Me
2
Scheme 11. S
N
2(P) Mechanism of addition of methanol to chloriminophosphoranes.

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
5
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[
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