Sequential Nucleophilic Aromatic Substitution Reactions of Activated Halogens

Building blocks have been identified that can be functionalised by sequential nucleophilic aromatic substitution. Some examples are reported that involve the formation of cyclic benzodioxin and phenoxathiine derivatives from 4,5-difluoro-1,2-dinitrobenzene, racemic quinoxaline thioethers, and sulfones from 2,3-dichloroquinoxaline and (2-aminophenylethane)-2,5-dithiophenyl-4-nitrobenzene from 1-(2-aminophenylethane)-2-fluoro-4,5-dinitrobenzene. Four X-ray single-crystal structure determinations are reported, two of which show short intermolecular N–O…N “π hole” contacts.

Int. J. Mol.Sci.2024, 25, x FOR PEER REVIEW 2 of 15 Figure 2 shows some products that can be made from compounds 5 or 6, respectively.Compound 7 is an easily made cyclophane [14], and macrocycle 8 is a precursor to an energetic substance [15].Phthalonitrile 9 is a phthalocyanine precursor for optical limiting in polished polycarbonate discs [16].

Results and Discussion
New studies are being reported with building block 2 and catechol, 10, dithiocatechol, 11, and 2-hydroxythiophenol, 12, to make dioxin 13, dithiin 14, and phenoxathiin 15, respectively (Figure 3).In the supplementary section charts for proton and carbon NMR data for all new compounds are reported.
The two nitro groups activate both halogens to sequential nucleophilic displacement by phenoxide and thiolate anions.The yields are good for these syntheses.The synthesis of compound 14 was reported by us previously, but it is included here for comparison with other data.Figure 4 shows the synthesis of racemic S-oxide, 16.Although the yield was good, the yield for the synthesis of the precursor heterocycle 15 was poor, which restricted the amount of material made.Further detailed studies were only carried out on compound 14.Compound 15 was oxidised with meta-chloroperbenzoic (mcpba) acid in DCM at room temperature to S-oxide 16 on a small scale.Owing to the racemic nature of this Soxide, it was difficult to obtain good crystals, possibly due to the disorder of the S-oxide grouping.The oxidation of cyclic sulphide 15 to sulfoxide 16 stopped at the sulfoxide without over-oxidation to a sulfone.
X-ray single-crystal structure determinations were carried out on compounds 13-15.

Results and Discussion
New studies are being reported with building block 2 and catechol, 10, dithiocatechol, 11, and 2-hydroxythiophenol, 12, to make dioxin 13, dithiin 14, and phenoxathiin 15, respectively (Figure 3).In the supplementary section charts for proton and carbon NMR data for all new compounds are reported.

Results and Discussion
New studies are being reported with building block 2 and catechol, 10, dithiocatechol, 11, and 2-hydroxythiophenol, 12, to make dioxin 13, dithiin 14, and phenoxathiin 15, respectively (Figure 3).In the supplementary section charts for proton and carbon NMR data for all new compounds are reported.
The two nitro groups activate both halogens to sequential nucleophilic displacement by phenoxide and thiolate anions.The yields are good for these syntheses.The synthesis of compound 14 was reported by us previously, but it is included here for comparison with other data.Figure 4 shows the synthesis of racemic S-oxide, 16.Although the yield was good, the yield for the synthesis of the precursor heterocycle 15 was poor, which restricted the amount of material made.Further detailed studies were only carried out on compound 14.Compound 15 was oxidised with meta-chloroperbenzoic (mcpba) acid in DCM at room temperature to S-oxide 16 on a small scale.Owing to the racemic nature of this Soxide, it was difficult to obtain good crystals, possibly due to the disorder of the S-oxide grouping.The oxidation of cyclic sulphide 15 to sulfoxide 16 stopped at the sulfoxide without over-oxidation to a sulfone.
X-ray single-crystal structure determinations were carried out on compounds 13-15.The two nitro groups activate both halogens to sequential nucleophilic displacement by phenoxide and thiolate anions.The yields are good for these syntheses.The synthesis of compound 14 was reported by us previously, but it is included here for comparison with other data.Figure 4 shows the synthesis of racemic S-oxide, 16.Although the yield was good, the yield for the synthesis of the precursor heterocycle 15 was poor, which restricted the amount of material made.Further detailed studies were only carried out on compound 14. Figure 2 shows some products that can be made from compounds 5 or 6, respectively.Compound 7 is an easily made cyclophane [14], and macrocycle 8 is a precursor to an energetic substance [15].Phthalonitrile 9 is a phthalocyanine precursor for optical limiting in polished polycarbonate discs [16].

Results and Discussion
New studies are being reported with building block 2 and catechol, 10, dithiocatechol, 11, and 2-hydroxythiophenol, 12, to make dioxin 13, dithiin 14, and phenoxathiin 15, respectively (Figure 3).In the supplementary section charts for proton and carbon NMR data for all new compounds are reported.
The two nitro groups activate both halogens to sequential nucleophilic displacement by phenoxide and thiolate anions.The yields are good for these syntheses.The synthesis of compound 14 was reported by us previously, but it is included here for comparison with other data.Figure 4 shows the synthesis of racemic S-oxide, 16.Although the yield was good, the yield for the synthesis of the precursor heterocycle 15 was poor, which restricted the amount of material made.Further detailed studies were only carried out on compound 14.Compound 15 was oxidised with meta-chloroperbenzoic (mcpba) acid in DCM at room temperature to S-oxide 16 on a small scale.Owing to the racemic nature of this Soxide, it was difficult to obtain good crystals, possibly due to the disorder of the S-oxide grouping.The oxidation of cyclic sulphide 15 to sulfoxide 16 stopped at the sulfoxide without over-oxidation to a sulfone.
X-ray single-crystal structure determinations were carried out on compounds 13-15.Compound 15 was oxidised with meta-chloroperbenzoic (mcpba) acid in DCM at room temperature to S-oxide 16 on a small scale.Owing to the racemic nature of this S-oxide, it was difficult to obtain good crystals, possibly due to the disorder of the S-oxide grouping.The oxidation of cyclic sulphide 15 to sulfoxide 16 stopped at the sulfoxide without over-oxidation to a sulfone.
X-ray single-crystal structure determinations were carried out on compounds 13-15.
The building blocks in Figure 1 are all commercially available, so more were investigated.Each chlorine atom of compound 3 is activated by a pyridine-type nitrogen atom.Compound 3 was reacted with a cheap optically pure (S) amine by a nucleophilic aromatic substitution reaction to give product 17 (Figure 9).This was reacted with a thiolate anion which is a strong nucleophile owing to its size and polarisability.Product 18 was treated with mcpba with a view to make the mono S-oxide (not drawn).Instead, the product was identified, with a clean mass spectrum, as sulfone 19 shown in Figure 9. Here, and in our previous studies, the oxidation of a cyclic sulphide stopped at the mono S-oxide, but here the acyclic sulphide smoothly converted to the sulfone.The oxidation of a cyclic sulfoxide is presumed to have a higher energy barrier.Previously, we discussed the enantiomeric fractionation of chiral sulfoxides from a silica column, which has been reported, but not for single enantiomers.The sulfoxide and sulfone have similar R f values, which might complicate the fractionation.No X-ray single-crystal structures were obtained on compounds 17-19.The asymmetry possibly inhibits the growth of good crystals.
well as disorder of the oxygen atoms of the N3 and N4 nitro groups in 0.715 (4):0.285(4) and 0.720 (6): 0.280 ( 6) ratios, respectively.The extensive disorder complicates the detailed interpretation of the ring conformations, but it may be stated that the molecules are close to planar, with dihedral angles between the C1-C6 and C7-C12 (major component) rings of 12.29 (12)° and C13-C18 and C19-C24 of 4.20 (8)°.In the extended structure of compound 15, the molecules are linked by weak C-H … O bonds, but there are no short contacts involving the nitro groups.The building blocks in Figure 1 are all commercially available, so more were investigated.Each chlorine atom of compound 3 is activated by a pyridine-type nitrogen atom.Compound 3 was reacted with a cheap optically pure (S) amine by a nucleophilic aromatic substitution reaction to give product 17 (Figure 9).This was reacted with a thiolate anion which is a strong nucleophile owing to its size and polarisability.Product 18 was treated with mcpba with a view to make the mono S-oxide (not drawn).Instead, the product was identified, with a clean mass spectrum, as sulfone 19 shown in Figure 9. Here, and in our previous studies, the oxidation of a cyclic sulphide stopped at the mono S-oxide, but here the acyclic sulphide smoothly converted to the sulfone.The oxidation of a cyclic sulfoxide is presumed to have a higher energy barrier.Previously, we discussed the enantiomeric fractionation of chiral sulfoxides from a silica column, which has been reported, but not for single enantiomers.The sulfoxide and sulfone have similar Rf values, which might complicate the fractionation.No X-ray single-crystal structures were obtained on compounds 17-19.The asymmetry possibly inhibits the growth of good crystals.Either one [10] or two chlorine atoms can be displaced from 2,3-dichloroquinoxaline, 3, with butylamine (Figure 10).Since the second Cl atom is harder to displace, and ideally requires a thiolate anion as a nucleophile, the reaction was carried out in a Parr PTFElined pressure vessel at a higher temperature of 150 °C.The product forms in low yield but was more polar and harder to purify.In our studies on potential porous organic materials, we found that polar compounds were harder to purify, so the polarity was reduced with butylamine substituents [1,2].For example, if butylamine was replaced with methyl, ethyl, or propylamine, no products were isolated with smaller compounds.Either one [10] or two chlorine atoms can be displaced from 2,3-dichloroquinoxaline, 3, with butylamine (Figure 10).Since the second Cl atom is harder to displace, and ideally requires a thiolate anion as a nucleophile, the reaction was carried out in a Parr PTFE-lined pressure vessel at a higher temperature of 150 • C. The product forms in low yield but was more polar and harder to purify.In our studies on potential porous organic materials, we found that polar compounds were harder to purify, so the polarity was reduced with butylamine substituents [1,2].For example, if butylamine was replaced with methyl, ethyl, or propylamine, no products were isolated with smaller compounds.
requires a thiolate anion as a nucleophile, the reaction was carried out in a Parr PTFElined pressure vessel at a higher temperature of 150 °C.The product forms in low yield but was more polar and harder to purify.In our studies on potential porous organic materials, we found that polar compounds were harder to purify, so the polarity was reduced with butylamine substituents [1,2].For example, if butylamine was replaced with methyl, ethyl, or propylamine, no products were isolated with smaller compounds.All four substituents on compound 2 are activated because each nitro group activates the other one as well as a para-fluorine atom (Figure 3) [21,22].An X-ray single-crystal structure determination was carried out on compound 24.All four substituents on compound 2 are activated because each nitro group activates the other one as well as a para-fluorine atom (Figure 3) [21,22].An X-ray single-crystal structure determination was carried out on compound 24.
Compound 24 crystallises in space group Pca2 1 with one molecule in the asymmetric unit (Figure 11).The morpholine ring adopts a normal chair conformation [displacements of N1 and O1 from C7 to C10 = -0.652(4) and 0.653 (4) Å, respectively] with the exocyclic N1-C5 bond in an equatorial conformation, although the bond angle sum at N1 of 354 • is suggestive of a tendency towards sp 2 hybridisation.The dihedral angle between the rings (all atoms) is 24.33 ( 11   Although these reactions are feasible because one fluorine atom is easily (Figure 13), the next reaction posed considerable difficulty (Figure 14).A TLC plate run after the reaction work-up showed three spots running gether.The middle spot was eventually isolated as the pure product after runn tiple number of long (12″ × 1″) columns.The data fits for structure 26 are sh fluorine atom must be the first group to be displaced; otherwise, two thioethers be formed.The nitro group conjugated to the amine is deactivated by this co After the fluorine atom, the more reactive nitro group is displaced next.This interesting and represents a formal addition-substitution of diphenyldisulfide 1 and 4 positions of a benzene ring, which we believe to be a new reaction.Th only about 10%, but the product is pure with good data.Although these reactions are feasible because one fluorine atom is easily displaced (Figure 13), the next reaction posed considerable difficulty (Figure 14).Although these reactions are feasible because one fluorine atom is easily displaced (Figure 13), the next reaction posed considerable difficulty (Figure 14).A TLC plate run after the reaction work-up showed three spots running close together.The middle spot was eventually isolated as the pure product after running a multiple number of long (12″ × 1″) columns.The data fits for structure 26 are shown.The fluorine atom must be the first group to be displaced; otherwise, two thioethers could not be formed.The nitro group conjugated to the amine is deactivated by this conjugation.After the fluorine atom, the more reactive nitro group is displaced next.This reaction is interesting and represents a formal addition-substitution of diphenyldisulfide across the 1 and 4 positions of a benzene ring, which we believe to be a new reaction.The yield is only about 10%, but the product is pure with good data.

Material and Methods
IR spectra were recorded on a diamond-attenuated total reflection (ATR) Fourier transform infrared (FTIR) spectrometer, Nicolet Summit Everest, (Thermo Fischer Scientific, 1 Ashley Road, Altrincham, Cheshire, England); Ultraviolet (UV) spectra were rec- A TLC plate run after the reaction work-up showed three spots running close together.The middle spot was eventually isolated as the pure product after running a multiple number of long (12 ′′ × 1 ′′ ) columns.The data fits for structure 26 are shown.The fluorine atom must be the first group to be displaced; otherwise, two thioethers could not be formed.The nitro group conjugated to the amine is deactivated by this conjugation.After the fluorine atom, the more reactive nitro group is displaced next.This reaction is interesting and represents a formal addition-substitution of diphenyldisulfide across the 1 and 4 positions of a benzene ring, which we believe to be a new reaction.The yield is only about 10%, but the product is pure with good data.

Material and Methods
IR spectra were recorded on a diamond-attenuated total reflection (ATR) Fourier transform infrared (FTIR) spectrometer, Nicolet Summit Everest, (Thermo Fischer Scientific, 1 Ashley Road, Altrincham, Cheshire, England); Ultraviolet (UV) spectra were recorded using a Perkin Elmer Lambda 25 UV-Vis spectrometer with EtOH as the solvent (LAS Chalfont, Seer Green, Beaconsfield, England); The term sh means shoulder. 1H and 13 C nuclear magnetic resonance (NMR) spectra were recorded at 400 and 100.5 MHz, respectively, using a Bruker 400 spectrometer (Bruker UK Ltd., Welland House, Westwood Business Park, Coventry, England); Chemical shifts, δ, are given in ppm and measured by comparison with the residual solvent.Coupling constants, J, are given in Hz.High-resolution mass spectra were obtained at the University of Wales, Swansea, using an Atmospheric Solids Analysis Probe (ASAP) (positive mode) instrument: Xevo G2-S ASAP (Waters Ltd., Stamford Avenue, Altrincham Road, Wilmslow, England); Melting points were determined on a Cole-Palmer MP-200D Stuart digital melting point microscope (CamLab, Norman Way Ind. Estate, Over, Cambridge, England).

Crystal Structure Determinations
The crystal structures of 13, 14, 15, and 24 (all recrystallised from the mixed solvents of dichloromethane/light petroleum ether) were established using intensity data collected at 100 K on a Rigaku CCD diffractometer using either Mo Kα radiation (13, 14, and 15) or Cu Kα radiation (24).The structures were routinely solved by dual-space methods using SHELXT [23], and the structural models were completed and optimised by refinement against |F| 2 with SHELXL-2019 [24].Extensive disorder was found for 15.The H atoms were placed in idealised locations (C-H = 0.95-0.98Å) and refined as riding atoms with U iso (H) = 1.2U eq (carrier).Full details of the structures and refinements are available in the deposited cifs.(11), ∆ρ min,max (e Å -3 ) = -0.17,+0.17, CCDC deposition number 2362028.

Conclusions
Further chemistry is developed for substrates with two halogens activated for nucleophilic displacement by strong electron withdrawing groups.The use of compound 2 gave dinitrated heterocyclic benzodioxin 13, dithiin 14, and phenoxathiine 15.All three heterocycles gave satisfactory X-ray single-crystal structure data, but phenoxathiine 15 was disordered.The cyclic thioether of compound 15 was readily oxidised with mcpba to racemic sulfoxide 16 without over-oxidation to the sulfone occurring.The chemistry of this intermediate was not developed [21] any further because of the low yield for the formation of heterocycle 15.The yield was lower than for the two symmetrical systems 13 and 14.Presumably, there is a molecular strain in the heterocycle because it is not planar but rather folded with a butterfly shape.As expected, one or two fluorine atoms are easily displaced with compound 2 [3] New aromatic derivatives 23, 24, and 25 are reported here.This leaves a further activated fluorine atom and two nitro groups, which both activate each other.A thiol was chosen to react with compound 23 because it is polarisable owing to its large size, making it a good nucleophile.The F atom was displaced, followed by the most reactive nitro group.This gave an interesting 1,4-bis(thiophenyl)benzene derivative 26, which might be a new reaction not requiring metallic catalysis such as Pd, Pd(II), or Cu(II).

Figure 1 .
Figure 1.Dihalogenated molecules that can undergo two sequential nucleophilic substitution reactions.
Copyright: © 2024 by the authors.Submitted for possible open access publication under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

Figure 1 .
Figure 1.Dihalogenated molecules that can undergo two sequential nucleophilic substitution reactions.

Figure 2 .
Figure 2. Products 7 and 8, or product 9, that can be made from compounds 5 or 6, respectively.

Figure 4 .
Figure 4.The oxidation of phenoxathiin 15 to form a racemic S-oxide 16.

Figure 2 .
Figure 2. Products 7 and 8, or product 9, that can be made from compounds 5 or 6, respectively.

Figure 2 .
Figure 2. Products 7 and 8, or product 9, that can be made from compounds 5 or 6, respectively.

Figure 4 .
Figure 4.The oxidation of phenoxathiin 15 to form a racemic S-oxide 16.

Figure 2 .
Figure 2. Products 7 and 8, or product 9, that can be made from compounds 5 or 6, respectively.

Figure 4 .
Figure 4.The oxidation of phenoxathiin 15 to form a racemic S-oxide 16.

Figure 4 .
Figure 4.The oxidation of phenoxathiin 15 to form a racemic S-oxide 16.

Figure 7 .
Figure 7. Short N-O … N contacts (black dashed lines) in the extended structure of compound 14, which generate [010] chains.Yellow is sulfur, red is oxygen and blue is nitrogen Compound 15 crystallises with two molecules (A containing C1 and B containing C13) in the asymmetric unit (Figure 8) of space group P1 , both of which display disorder:

Figure 7 .
Figure 7. Short N-O . . .N contacts (black dashed lines) in the extended structure of compound 14, which generate [010] chains.Yellow is sulfur, red is oxygen and blue is nitrogen.Compound 15 crystallises with two molecules (A containing C1 and B containing C13) in the asymmetric unit (Figure 8) of space group P1, both of which display disorder: in molecule A, 'flip' (~180 • rotational) disorder about the long axis of the molecule of the O and S atoms of the oxathiine ring [occupancy of S1/O2 = 0.493 (5); occupancy of S2/O1 = 0.507 (5)] occurs as well as positional disorder of the C7-C12 ring.The B molecule also shows flip disorder [occupancy of S3/O8 = 0.180 (4); occupancy of S4/O7 = 0.820 (4)]as well as disorder of the oxygen atoms of the N3 and N4 nitro groups in 0.715 (4):0.285(4) and 0.720 (6): 0.280 (6) ratios, respectively.The extensive disorder complicates the detailed interpretation of the ring conformations, but it may be stated that the molecules are close to planar, with dihedral angles between the C1-C6 and C7-C12 (major component) rings of 12.29(12) • and C13-C18 and C19-C24 of 4.20 (8) • .In the extended structure of compound 15, the molecules are linked by weak C-H . . .O bonds, but there are no short contacts involving the nitro groups.The building blocks in Figure1are all commercially available, so more were investigated.Each chlorine atom of compound 3 is activated by a pyridine-type nitrogen atom.Compound 3 was reacted with a cheap optically pure (S) amine by a nucleophilic aromatic substitution reaction to give product 17 (Figure9).This was reacted with a thiolate anion which is a strong nucleophile owing to its size and polarisability.Product 18 was treated with mcpba with a view to make the mono S-oxide (not drawn).Instead, the product was identified, with a clean mass spectrum, as sulfone 19 shown in Figure9.Here, and in our previous studies, the oxidation of a cyclic sulphide stopped at the mono S-oxide, but here the acyclic sulphide smoothly converted to the sulfone.The oxidation of a cyclic sulfoxide is presumed to have a higher energy barrier.Previously, we discussed the enantiomeric fractionation of chiral sulfoxides from a silica column, which has been reported, but not for single enantiomers.The sulfoxide and sulfone have similar R f values, which might complicate the fractionation.No X-ray single-crystal structures were obtained on compounds 17-19.The asymmetry possibly inhibits the growth of good crystals.

Figure 8 .
Figure 8.The molecular structure of compound 15 showing 50% displacement ellipsoids.Both disorder components of the oxathiine rings are shown, but for clarity, only the major disorder components of the C7-C12 ring and N3 and N4 nitro groups are drawn.

Figure 8 . 15 Figure 9 .
Figure 8.The molecular structure of compound 15 showing 50% displacement ellipsoids.Both disorder components of the oxathiine rings are shown, but for clarity, only the major disorder components of the C7-C12 ring and N3 and N4 nitro groups are drawn.Int.J. Mol.Sci.2024, 25, x FOR PEER REVIEW 6 of 15

Figure 11 .
Figure 11.The molecular structure of compound 24 showing 50% displacement ellipsoids.The extended structure of 24 features weak C-H … O and C-H … F interactions as well as notably short N2-O2 … N3 ii (ii = x, 1+y, z) contacts (Figure 12), which lead to [010] chains with adjacent molecules related by translation: the O … N separation is 2.839 (3) Å, the N-O … N angle is 132.20 (19)°, and the dihedral angle between the N2 and N3 ii nitro groups is

Figure 13 .
Figure 13.The displacement of one activated fluorine atom from compound 2 with differ

15 Figure 12 .
Figure 12.Short O … N contacts (black dashed lines) in the extended structure of compound 24, which generate [010] chains.

Figure 13 .
Figure 13.The displacement of one activated fluorine atom from compound 2 with different amines.

Figure 14 .
Figure 14.The sequential displacement of an activated fluorine atom followed by an activated nitro group on compound 23.