Hydroxy- and Methoxybenzene Derivatives with Benzenediazonium Salts ― Chemical Behavior and Tautomeric Problems

A Journal of

Accepted Article

Title: Hydroxy- and Methoxy-Benzene Derivatives with

Benzenediazonium Salts: Chemical Behavior and Tautomeric

Problems

Authors: Gabriele Micheletti, Carla Boga, Luciano Forlani, Erminia del

Vecchio, Nicola Zanna, Andrea Mazzanti, and Magda Monari

This manuscript has been accepted after peer review and appears as an

Accepted Article online prior to editing, proofing, and formal publication

of the final Version of Record (VoR). This work is currently citable by

using the Digital Object Identifier (DOI) given below. The VoR will be

published online in Early View as soon as possible and may be different

to this Accepted Article as a result of editing. Readers should obtain

the VoR from the journal website shown below when it is published

to ensure accuracy of information. The authors are responsible for the

content of this Accepted Article.

To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601393

Link to VoR: http://dx.doi.org/10.1002/ejoc.201601393

Supported by

10.1002/ejoc.201601393

European Journal of Organic Chemistry

FULL PAPER

Hydroxy- and Methoxy-Benzene Derivatives with

Benzenediazonium Salts: Chemical Behavior and Tautomeric

Problems

Gabriele Micheletti,*^[a]Carla Boga,^[a]Luciano Forlani,^[a]Erminia Del Vecchio,^[a]Nicola Zanna,^[a]Andrea

Mazzanti,^[a]Magda Monari^[b]

Abstract:.

The

azo

coupling

reaction

between

4-

proton elimination and the re-aromatization process from the W

nitrobenzenediazonium tetrafluoroborate and a series of benzene

derivatives bearing as electron donating substituents at least one

hydroxy or methoxy group has been carried out. Depending on the

nucleophile and its relative ratio with the diazonium salt it was

possible to obtain mono-, di-, and, only in the case of phloroglucinol,

evidence of trisubstitution products. The reaction between 3,5-

diaminoanisole- or 3,5-diaminophenol- derivatives and two

equivalents of diazonium salt gave, in the first case, the product

derived from a mono attack, and a diadduct in the second case; their

X-ray diffraction analysis showed an highly symmetric structure for

the latter. The different behavior of hydroxy- with respect to the

methoxy-substituted compounds was particularly evident for

phloroglucinol and 1,3,5-trimethoxybenzene and it may be

rationalized on the basis of the different electronic effect of the

substituents. The propensity to undergo H/D exchange reaction on

the aromatic ring was investigated on a series of substrates and the

comparison of the results obtained provided new insights on this

kind of phenomenon and permitted a better explanation of the

findings reported here, by introducing a new particular interaction

which competes with the σ-complex formation between proton and

phloroglucinol.

intermediate is not the driving force of the reaction but it is the

rate-limiting process.⁶Furthermore, we obtained

a clear

evidence of the reversibility of the whole azo coupling reaction.⁷

As a consequence, the usually reported pathway of this

electrophilic reaction result is modified as reported in Scheme 1,

in which the possible π complexes⁸have been omitted.

These findings our us to focus attention towards the reactions of

benzene rings activated by electron donating substituents

bearing the oxygen atom, such as 1,3,5-trihydroxybenzene (1,

also called phloroglucinol) and 1,3,5-trimethoxybenzene (2) that,

in principle, may be expected to behave as nucleophilic reagents

with a power similar to that of the triaminobenzenes previously

studied.

Scheme 1. Reaction pathway for the azo coupling reaction; the step indicated

by B means a proton abstraction by base catalysis.

Introduction

Moreover, phloroglucinol and its derivatives are interesting

molecules from synthetic,⁹biological^10-12and pharmaceutical^13-20

point of view.

Based on the above considerations, we planned to start a study

on phloroglucinol (1), 1,3,5-trimethoxybenzene (2) and some of

their derivatives using benzenediazonium salts as electrophiles

with the aim to obtain new compounds of interest in applicative

field and to deepen their chemical behavior and their tautomeric

properties.

Aromatic rings strongly activated by powerful electron donating

groups are substrates particularly suitable for mechanistic

investigations on the electrophilic aromatic substitution. The

carbon-carbon bond forming reactions between neutral or

charged electrophilic reagents and naphthols,¹2-amino-1,3-

thiazole derivatives,²and 1,3,5-triaminobenzenes³allowed us to

isolate and investigate σ complexes, including those that are

simultaneously Wheland (W) and Meisenheimer (M)

complexes.^2a,4,5

In

particular,

the

reaction

between

triaminobenzenes and diazonium salts permitted to elucidate the

reaction mechanism of the azo coupling reaction by studying it in

separate steps, owing the stability of the W complexes.^3aThe

obtained results clearly indicated, contrarily to that usually

claimed on the rate limiting step of S_EAr reactions, that the

Results and Discussion

Scheme 2 shows the possibility to obtain mono-, di-, and tri-

substituted products by reaction of the substrates 1 and 2 with

the 4-nitrobenzenediazonium tetrafluoroborate (3), which is one

of the most powerful electrophilic aryldiazonium salts.²¹The

mono substitution on 1 and 2 (in CH₃CN, reaction A in Scheme

2) in an equimolar amount with 3 is a simple and fast reaction

affording the salts of the azo compounds 4H and 5H (R = H, CH₃,

respectively). The free bases 4 and 5 may be obtained after

flash chromatography or by simple filtration (or percolation) of

the tetrafluoroborate salt 4H (or 5H) on silica gel or basic

alumina. The reaction between 2 and an excess (more than

three times) of p-nitro benzenediazonium tetrafluoborate (3)

[a]

[b]

Department of Industrial Chemistry ‘Toso Montanari’, ALMA MATER

STUDIORUM - Università di Bologna

Viale del Risorgimento, 4 40136 Bologna, Italy

gabriele.micheletti3@unibo.it

Department of Chemistry ‘G. Ciamician’, ALMA MATER

STUDIORUM - Università di Bologna Institution

Via Selmi, 2, 40125 Bologna, Italy

Supporting information for this article is given via a link at the end of

the documen.

10.1002/ejoc.201601393

European Journal of Organic Chemistry

FULL PAPER

gave almost quantitatively 5H, which is poorly soluble in the

reaction medium (and in other usual solvents), and

spontaneously precipitates. It has to be noted that, to the best of

our knowledge, no diadducts from 2 and diazonium salts have

been reported so far.

Scheme 3. Reaction between 3 and the triaminobenzene derivative 8.

We emphasize that the solubility of 8 played an important role in

obtaining the di-substituted derivative, instead of the expected

mono substituted compound, because the reaction mixture,

initially, presents a large excess of 3 with respect to 8, which is

present mostly as solid part. Attempts to obtain the trisubstituted

products of 8 failed, probably because other processes take

place on the di-substituted derivative.²⁵Obviously, in the crude

reaction mixture, compound 9H, bearing two positive charges, is

not prone to undergo a further electrophilic attack to form the

trisubstituted derivative.

Scheme 2. Reactions of 1 or 2 with 3.

From the reaction between phloroglucinol (1) and 3, in the

relative ratio 1:2, a very complicated reaction mixture was

obtained, in which compound 4H was present, together with

some other unidentified compounds (the presence of compound

6H, in this reaction mixture, cannot be excluded). When

phloroglucinol was reacted with three equivalents of 3 in

acetonitrile, a mixture of insoluble compounds was formed from

In the case of the 1,3,5-trihydroxybenzene (1) and 1,3,5-

trimethoxybenzene (2) we were not able to obtain evidence

(neither at room temperature nor at –35 °C) of the presence of

W complexes.

which compound

chromatography on alumina, whereas the presence of 7 was

revealed by mass spectrometry.

It has to be noted that the obtaininig of the

tris(phenylazo)phloroglucinol was described by Perkin as early

as in 1897,²²and later other reports on the synthesis of similar

compounds have appeared²³whereas only fewer example of

diadducts with 6-like structure, mostly derived from

alkylphloroglucinols, have been described.²⁴

6 was separated (less than 5%) by

Clearly, the obtaining of mono-, di-, or tri-azo compounds by azo

copuling reaction depends on three main points: the relative

ratio between the reagents, the relative solubility of the reagents

and of the reaction products, and the electron releasing power of

the substituents (OH, OCH₃and NR₂) on the starting compound,

whose trend is: NR₂> OH >OCH₃, if the σ_pHammett parameter

is used in evaluating their electron donor ability (σ_pvalues are –

0.83, – 0.13, – 0.16 for NR₂, OH and OCH₃, respectively).²⁶The

σ_pvalues of the OH and OCH₃groups are very close, as well as

other parameters related to their electron donating power by

resonance mechanism, such as σ_R, but, as a matter of fact, the

OH group easily allows polysubstitution reaction, while OCH₃

does not permit it.

The obtaining of trisubstituted derivatives such as 7 from

phloroglucinol partially agrees with the electron donating

properties of the OH group in comparison with the OMe group,

as tested by the σ values of the Hammett treatment.²⁶Even if

the electron donating properties of the OH and OCH₃groups are

compared by using σ⁺parameters (σ+_OH= – 0.92, σ+_OMe= –

0.78) the electron donating power of the OH groups is not so

large to afford convincing explanation for the different chemical

behavior shown by the derivatives substituted with the two

groups. However, in our opinion, the dissociation of the –O-H

group affording the strong electron donating group (–O^–group)

may produce the polysubstitution reaction observed for 1.

Based on the above findings, we considered that azo-coupling

reactions with other benzene derivatives bearing strong

electron-donating groups might be useful to investigate the

Previously,^7,25we reported that the reaction, in CD₃CN, of some

1,3,5-triaminobenzenes with two equivalents of 3 affords the

product of the double attack. This latter was also observed when

the reaction was carried out directly in the NMR spectroscopy

tube, in CD₃CN at -30 °C with the reagents in an equimolar

amount, without waiting for the complete dissolution of the

triaminobenzene derivative, as shown in Scheme 3 for the

reaction between tris(N-piperidinyl)benzene (8) and 3. As 8

slowly dissolved, compound 9H released a diazonium moiety to

yield the mono substituted derivative, via the Wheland

intermediate (W complex, see Scheme 3).⁷

10.1002/ejoc.201601393

European Journal of Organic Chemistry

FULL PAPER

different behavior of methoxy derivatives in comparison with

hydroxy derivatives. For this purpose, we prepared the

substrates 10a, 10b, and 12 of Scheme 4, which, presumably,

have similar activation activity toward electrophilic reagents, and

we checked their reaction toward 3.

Figure 2. X-Ray structure of 11Hb.

Scheme 4. Azo coupling reaction of 1,3-diaminobenzene derivatives 10a, 10b,

and 12 with 3.

Compounds 10a and 10b are hydroxy-derivatives while

compound 12 is a methoxy-derivative, a fixed parent of 10b in its

aromatic tautomeric form. When reacted with two equivalents of

3, the compound 12 afforded as main product the mono

derivative 13H (which gave 13 after column chromatography),

while from 10a and 10b the products of di-substitution 11Ha and

11Hb (this latter is formed also in the absence of 3) were

recovered.

Compounds 11Ha, 11Hb and 13 were characterized by usual

spectroscopic methods and 11Hb and 13 also by X-ray

diffraction analysis. Different possible structures for 11Hb and

13 are represented in Figure 1, and their X-ray structures are

shown in Figures 2 and 3.

Figure 3. X-Ray structure of 13.

The X-ray crystal structure of compound 11Hb (Figure 2) (as

tetrafluoroborate salt), shows that the molecule has

a

crystallographically imposed C₂symmetry with the twofold axis

passing through C4, H4, C1, O1 and the boron atom of the

anion. Obviously, this symmetry is absent in the neutral

compound 13 (Figure 3) where all the atoms are in general

positions and water molecule is present in the asymmetric unit.

For comparison purposes of the two crystal structures the

labelling of the atoms in 11Hb and 13 has been unified following

the one in Figure 1. Table 1 collects the most relevant bond

distances (in Å). In compound 13 the C1-C6 and C3-C4 bond

lengths [1.378(2) Å in both cases] of the ring B are shorter than

the others thus indicating the presence of a quinoid structure

caused by the presence of the azo group in position 2 and of the

piperidinyl group in position 5 and explained by assuming an

internal electron charge transfer from the nitrogen atom of the

piperidinyl group to the nitrogen of the azo group, as depicted in

13-form B (Fig. 1).

Figure 1. Possible structures for 11Hb and 13.

10.1002/ejoc.201601393

European Journal of Organic Chemistry

FULL PAPER

charged oxygen which reaches a sp²configuration similar to that

of keto group, while the O-C1 bond distance of 13 is that

expected for a methoxy group bound to an aromatic ring.

All these data indicate that 11Hb in the solid state presents a

character near to a bis-hydrazone derivative as reported in

11HbB of Fig. 2, with a six-membered ‘chelate’ structure, in

agreement with a recent paper^23ereporting a phloroglucinol

derivative bearing three arylazo groups, similar to compound 7

of Scheme 2.

Moreover, in 11HbB there are two strong intramolecular

hydrogen bonding interactions between the N and O atoms,

[N…O 2.577(2) Å] with the hydrogen bound to the nitrogen

bearing the nitrophenolate group as can be inferred by the short

value of the C-O1 bond which falls into the typical range for

ketones and the lengthening of the N1-N2 bond with respect to

the same bond in 13. Therefore, in the solid state, of the two

possible tautomeric forms 11Hb and 11HbB, the latter is the

most stable being favored also by the C₂symmetry of this

molecule that might be useful in delocalizing the electronic cloud.

Also the symmetry, probably, participates in lowering the energy

of the transition state of the reaction here reported, by electronic

delocalization in conjugated bonds, involving heteroatoms too.

An X-ray diffraction study and DFT calculations carried out on 2-

tert-butyl-4-methoxy-6-(quinoline-8-ylazo)-phenol (Figure 4)

Table 1. Selected distances of both 11Hb and 13

.

Bond

C1-C2^[a]

C1-C6

11Hb

13

Bond

C1-C2^[a]

C1-C6

11Hb

1.453(2)

1.470(2)

1.394(2)

1.322(2)

1.308((2)

1.308(2)

1.422(2)

1.378(2)

1.427(2)

1.397(2)

1.378(2)

1.406(2)

1.263(2)

–

1.453(2)

1.470(2)

1.394(2)

1.322(2)

1.308((2)

C2-C3^[a]

C5-C6

C2-C3^[a]

C5-C6

C3-C4^[a]

C4-C5

C3-C4^[a]

C4-C5

N1-N2^[a]

N3-N4

N1-C2^[a]

N3-C6

N1-N2^[a]

N3-N4

N1-C2^[a]

1.385(2)

-

N3-C6

N2-C7^[a]

N4-C6

O-C1

1.308(2)

1.395(2)

1.231(3)

1.328(2)

N2-C7^[a]

N4-C6

O-C1

1.395(2)

1.231(3)

1.328(2)

1.434(2)

–

1.346(2)

1.420(2)

1.380(2)

C3-N3^[a]

C5-N4

C3-N3^[a]

C5-N4

[a] The two consecutive bonds are identical due to the presence of the

symmetry operation -x, y, 0.5-z.

Figure 4. Structureof 2-tert-butyl-4-methoxy-6-(quinoline-8-ylazo)-phenol.

also indicate that the tautomeric equilibrium in the solid state is

displaced towards the hydrazone/quinone (‘NH’) form rather

than an ‘OH’ form.²⁷The reported results suggest that the

tris(hydrazone) tautomer might be preferred to the

tris(azo)tautomer, because the former is stabilized by hydrogen

bonding assisting the resonance.

In compound 11Hb, the same electron-withdrawing effect of

both azo groups toward the piperidinyl groups produces the

shortness of C3-C4 and C4-C5 bonds [1.394(2) Å], that are

identical due to the presence of the symmetry operation -x, y,

0.5-z (see Fig. SI-1).

This internal charge transfer acts also on the N1-N2 bond

distance [1.263(2) Å for 13 and 1.322(2) Å for 11Hb]; N1-N2

reveals a slightly higher π character in 13 than in N1-N2 bonds

of 11Hb. The para-nitrophenyl moieties partecipate to the

resonance effect with the results to have quite complete co-

planarity between aromatic rings in both compounds, 11Hb and

13. Consequently, the N1-C2 bond is shorter in 11Hb [1.308(2)

Å] than in 13 [1.385(2) Å], due to the electronic effect.

In 11Hb the C3-N3 and C5-N4 bond distances [1.328(2) Å] are

shorter than the corresponding distances in 13, which are

1.420(2) Å and 1.380(2) Å, respectively. These bond distances

are an interesting indication that in 13, a part of the π electronic

cloud of aromatic ring is localized on bonds external to the so-

called aromatic ring. In other words, both piperidinyl groups in 13

are involved in a direct electron transfer towards the azo groups.

The O-C1 bond in 11Hb [1.231(2) Å] is shorter than the

analogous bond in the methoxy derivative 13 (1.346(2) Å)

indicating the high electron donating power of the negatively

The different behavior of the hydroxy-substituted compounds

10a,b, that gave the di-substitution reaction, with respect to 12,

where the hydroxy group is substituted with the methoxy group,

for which a mono-substitution occurs, may be tentatively

explained by the different activation ability of the two - hydroxy

and methoxy - groups, as discussed above.

After that, we tried the reaction between

3 and 3,5-

dimethoxyphenol (14). As shown in Scheme 5, the only

recovered products, both with 1:1 and 2:1 molar ratio between

14 and 3, were the mono azo derivatives 15 and 16, isolated in

46:54 relative molar ratio. This behavior, different from that

observed in the case of the reaction between 10a and 10b and 3

(Scheme 4), can be explained by the different electron-donor

ability of the piperidinyl group with respect to the methoxy one.

10.1002/ejoc.201601393

European Journal of Organic Chemistry

FULL PAPER

Usually, the keto/enol tautomeric process is catalysed by both,

acids and bases. As reported in the literature,^28b,33,34in the

presence of acid (63-70% HClO₄), the equilibrium in Scheme 6,

probably, occurs via a σ complex with the proton as electrophilic

reagent, as depicted in Scheme 7.

Scheme 5. Reaction between 3,5-dimethoxyphenol and 3.

Another possible explanation for the difference in reactivity of

hydroxy and methoxy derivatives may be ascribed to the

tautomerism of hydroxy derivatives such as phloroglucinol that,

obviously, is absent in trimethoxybenzene. Below we try to gain

some information on this prototropic problem.

Scheme 7. H/D exchange reaction of 1 and 2 via Wheland intermediate.

A

particular problem about the chemical properties of

phloroglucinol 1 regards the structure, since it may exist in (at

least) two tautomeric forms²⁸(1a and 1b) as depicted, in a

simplified form, by the equilibrium shown in Scheme 6.

Table 2 collects the obtained results.

Table 2. Results of H/D exchange^[a]for aromatic derivatives shown in Chart

1, at 25°C, in the mixture DMSO-d₆/CD₃OD (96/4 v/v, unless otherwise

indicated).

[b]

Entry

Compound Added

% of H/D

Time

Scheme 6. Tautomeric forms of phloroglucinol.

reagent

[c]

1

2

1

4

2

5

8

–

n.e. ^[d]

n.e.^[d]

65

3 days

30 min

3 days

5 h

Phloroglucinol is usually considered to be in aromatic form.^28b

However, the obtaining of some derivatives typical of ketones,

such as the formation of a trioxime in the reaction between 1

and hydroxylamine,²⁹or the formation of a tri-bisulfite adduct of

1b by the reaction with sodium bisulfite³⁰have been reported as

indicating the presence of the triketo form 1b. The two

tautomeric forms of phloroglucinol derivatives were investigated

by NMR spectroscopy³¹and spectral evidences on the

dependence of the prototropic equilibrium of phloroglucinol on

pH value have been reported.³²We tried to obtain some

information about the equilibrium in Scheme 6 by using the

hydrogen/deuterium exchange reaction on several substrates

including 1, 2, and some other derivatives suitable to elucidate

the tautomerism of aromatic rings bearing hydroxy groups.

Figure 5 shows the structures of the considered substrates.

[e]

DCl

Et₃N

DBU

–

3

4

90

[f]

5

98

6

–

n.e.^[d]

95

[e]

7

DCl

Et₃N

–

8

n.e.^[d]

<10^[g]

n.e.^[d]

>97

3 days

1 min

3 days

9

[e]

[h]

10

11

12

13

14

15

16

17

18

DCl

Et₃N

D₂SO₄

Et₃N

–

N₂C₆H₄p-NO₂

OH

N₂C₆H₄p-NO₂

OCH₃

NO₂

HO

OH

H₃CO

OCH₃HO

H₃CO

HO

OH

1

OCH₃

2

OH

4

OCH₃

5

OH

17

14

10b

18

19

20

NR₂

OH

n.e.^[d]

OH

HO

OH

R₂N

NR₂

R₂N

NR₂

H₃CO

OCH₃

10b

8

14

18

NR₂= Piperidinyl

N₂C₆H₄p-NO₂

OH

O

OH

CH₃

OH

O

OH

19

20

21

22

Figure 5. Compounds tested in the hydrogen/deuterium exchange reaction.

10.1002/ejoc.201601393

European Journal of Organic Chemistry

FULL PAPER

[i]

19

20

21

22

19

20

21

22

Et₃N

80

3 days

20 min

3 days

(Table 2, entry 19).

vi.

The introduction of a nitro group on phloroglucinol

(compound 17) depresses the H/D exchange in the

presence of Et₃N (entry 13 of Table 2) This can be

explained by considering that the nitro group

enhances the acidity of the hydroxy group favoring

the formation of an anionic species, but the

localization of the negative charge out of the ring (on

the oxygen of the nitro group) reduces the proton

affinity of carbon atoms thus decreasing the amount

of H/D exchange.

Base catalysed H/D exchange cannot be explained

by the mechanism of Scheme 7, even if the formation

of anionic species of the hydroxy-containing aromatic

substrate strongly enhances the nucleophilicity of the

ring carbon atom.

–

98

65

[i]

n.e.^[d]

[a] Exchange, observed in the ¹H NMR spectrum, related to hydrogen atoms

bound to aromatic carbon atoms; when CD₃OD was used OH/OD exchange

was also observed. [b] Time after which is reached the percent of exchange

indicated. [c] Reaction of 1 with O-deuterated picric acid showed about 35%

of H/D exchange both after 5 min and after 5 days. [d] No exchange

observed. [e] When DCl 35% in D₂O was used, the reaction was carried out

in DMSO-d₆. [f] The product between phloroglucinol and p-

methoxybenzenediazonium tetrafluoroborate showed 95% of H/D exchange

after 30 min. [g] This compound shows a de-methylation reaction, and very

poor H/D exchange. [h] Compound 8 in neutral or basic medium did not

showed H/D exchange also after week; in the presence of 35% DCl in D₂O

did not exchange probably because of formation of a σ complex;³⁵with

excess of D₂SO₄the exchange occurred (see SI-27-28). [i] Exchange of both

protons of the substituted cycle. [l] in the presence of Et₃N quickly 22 reacts

giving a complex mixture of unidentified compounds.

vii.

viii.

ix.

The introduction of an azo group on 1, (compound 4,

Table 2, entry 5), favors the H/D exchange without

addition of DCl.

Azo compounds 4 and 20 show H/D exchange in

“neutral” medium (Table 2, entries 5, 20, 21) because

of internal base catalysis, like that reported in

Scheme 8, which may be the first step for a catalysed

tautomeric process in the presence of base.

Obviously, the internal catalysis of Scheme 8 cannot

occur for the trimethoxy derivative 5 (Table 2, entries

9, 10), which did not give H/D exchange.

From results summarized in Table 2, some data are worthy of

consideration:

i.

In ”neutral” medium both compounds, 1 and 2, did not

exchange in DMSO-d₆/CD₃OD (Table 2, entries 1 and

6). Consequently, H/D exchange cannot be

considered a “spontaneous” reaction of the reported

substrates: probably, in the absence of catalyst, this

is a very slow process.

ii.

Phloroglucinol (1) did not show appreciable H/D

exchange in the presence of DCl, (Table 2, entry 2)

but the exchange occurs in the presence of a base

(Table 2, entries 3 and 4). An opposite behavior has

been shown by 2, which quickly undergoes H/D

exchange in acidic medium (Table 2, entry 7),

confirming previous data of Schubert and Quacchia

regarding the acid catalyzed reaction,^33bbut it does

not exchange in the presence of Et₃N (Table 2, entry

8).

Scheme 8. Internal base catalysis acting in compound 4.

x.

Compounds 19, 20, and 21 are naphthol derivatives,

and they exchange the hydrogen atoms on the

substituted cycle in neutral (20 and 21 in entries 20

and 21, respectively) or basic medium (19, entry 19),

owing to the occurrence of equilibrium.

In agreement with the above, lawsone (21) quickly

exchanges the proton in position 3 in a spontaneous

process (entry 21 of Table 2), i.e. without the

presence of a base, while 22 does not exchange.

This can be considered an indication of the

involvement, also in this case, of the quinone form.

iii.

Compound 5 shows a slow H/D exchange (less than

10% in 3 days, see Table 2, entry 10), but in this

case, de-methylation reaction takes place to

complicate the NMR spectral data. Surely, 5 is less

prone to undergo H/D exchange in the presence of

DCl, than 2, likely due to the electronic withdrawing

effect of the azo group (the σ value of the azo group

is 0.64).²⁶This can be explained by the main

protonation equilibrium on the nitrogen atoms of the

azo group, enforcing the electron withdrawing effect

of this substituent.

xi.

iv.

v.

The presence of three hydroxy groups seems to be

essential to have exchange in the presence of base:

1,3-dihydroxybenzene 18 is not reactive (Table 2,

entry 17).

If the aromatic resonance energy is lowered as in 1,3-

dihydroxynaphthalene 19, the H/D exchange, in the

presence of Et₃N, occurs almost in the same time of 1

We reported a similar situation in amino azo containing

heterocycles showing a N/N tautomerism³⁶or in the case of

hydroxy-pyridines and related compounds (in this case N/O

tautomerism).³⁷In these examples the presence of association

to form dimers such as that reported in Scheme 9, produces

the protons close to both interested centres.

Moreover, some theoretical calculations on the pathway of

10.1002/ejoc.201601393

European Journal of Organic Chemistry

FULL PAPER

tautomerism in heterocyclic series agree with prototropic

equilibrium via the dimmer formation.³⁸

Scheme 11 is a reasonable pathway to explain also other results

reported in Table 2, regarding other hydroxy-bearing substrates.

Also in the case of phloroglucinol some self-assembling may be

operative in the tautomeric process.

Finally, it is of interest to provide explanation on why, under

present experimental conditions, the proton is not able to afford

a σ-complex as indicated for phloroglucinol (even if in more

drastic experimental conditions),^33atrimethoxybenzene,^33band

triaminobenzenes.³⁵As discussed above, the electronic effect of

the OH group (as indicated by σ_pvalues of the Hammett

treatment) indicates that the phloroglucinol is slightly more prone

than 1,3,5-trimethoxybenzene in similarly accepting a positive

charge of electrophilic reagents. In other words, the lack of H/D

exchange of phloroglucinol, under our experimental conditions,

Scheme 9. Dimer formed by self-association of 2-hydroxypyridine.

In conclusion, the keto-enol tautomerism is operating in

producing H/D exchange reaction on phloroglucinol and on

related compounds.

The H/D exchange on 1 is favoured by bases and not by acids,

which are surely able to protonate the carbonyl groups of 1b,

without affording H/D exchange. Protonated 1b (1bH, see

Scheme 10), have the only possibility to return back to the 1b

specie.

needs

a

different explanation than the difference in the

further

electronic effect of –OH and OCH₃groups.

A

complication may be a possible intervention of the solvent^28a

(D₂O, for herein used DCl solutions) that might play an important

role in depressing the attack of the proton on the carbon atom of

phloroglucinol and 1,3,5-trimethoxybenzene to give the Wheland

intermediate. Actually, this latter has been found under strong

conditions, such as 65-70% HClO₄solutions.³³Recently, a study

about the complexity of hydration of phloroglucinol⁴⁰has been

reported, where hydrate phloroglucinol molecules are linked by

O−H···O hydrogen bonds through water molecules, but also

intermolecular hydrogen bonds occur in its anhydrate status.

By summarizing, some main points worthy of consideration

about the interaction of the proton with 1 are:

•

The trihydroxybenzene 1 is an electron donor, due to

the ring π electrons and the electronic pairs of the

oxygen atoms, strong enough to yield the donicity of

the whole molecule able to stabilizing the π complex in

comparison with the σ complex.

The hydroxy group is able to give intermolecular

hydrogen bonding interaction (surely not relevant in the

case of trimethoxybenzene) in assembling two or more

molecules of 1 including the proton, and in self-

assembling too.³⁹

The above point emphasizes that there is high

probability to have strongly symmetric structures which

are destroyed by the formation of a σ bond to the

Wheland complex (W-1 in Scheme 7).

The absence of sigma complex in mixtures of 1 and

DCl, (as indicated by NMR spectral data) may be

explained by considering that the proton appears to be

not able to discriminate the carbon atom to form a new

Scheme 10. Formation of protonated form of 1b in acidic medium.

Apparently, the lack of H/D exchange in the presence of acid

may be conceived as indicating the absence of the aromatic

form 1a. In other words, phloroglucinol seems to be active in

base-catalyzed H/D exchange in the non-aromatic form 1b only.

This conclusion does not agree with the NMR data in DMSO-d₆,

CD₃CN and in CD₃OD; in these solvents (see Experimental)

there is one ¹³C NMR signal in the range δ = 94–96 ppm, related

to a sp²hybridized carbon atom and proton-coupled mode

experiments indicate that this signal is responsible for the

resonance of a carbon atom bound to an hydrogen atom (C-H).

Furthermore, the reactions here reported between 1 and

diazonium salts are usually labelled in the field of aromatic

electrophilic substitution reaction which, surely, starts from the

presence of the aromatic form 1a.

•

The base catalysed H/D exchange as indicated by data as

indicated in Table 2, is drawn in Scheme 11 which shows the

usual base catalysed enol/keto tautomerism with proton

exchange.

σ

bond as in the Wheland complex W-1. This

resembles what has already been reported by us in

explaining the “proton dance” regarding the proton

interaction with tris(amino)benzene derivatives.³⁵The

interaction between proton and phloroglucinol might

involve the π-ring electrons and in minor extent the

oxygen atoms of the OH groups. The first interaction is

indicated as structure 23 in scheme 12. Probably,is

favored by the high symmetry of 23 which depresses

its energy level with respect to the less symmetric

situation of W-1, and also by formation of a sandwich

Scheme 11. Base-catalyzed enol/keto tautomerism with H/D exchange in

phloroglucinol

10.1002/ejoc.201601393

European Journal of Organic Chemistry

FULL PAPER

involving two (or more) molecules of phloroglucinol and

a proton can not be excluded

are not favored, a fortiori, when the azo group is

bearing a positive charge in the salt form.

4. On the contrary, the introduction of the first azo group

on phloroglucinol does not prevent it from further

attacks of the electrophilic reagent because it poorly

reduces the high electron donating effects of the

hydroxyl groups, until to have tri-substitution reaction.

The electronic effect of the involved groups, as

measured by σ_pvalue of the Hammett treatment, as

+

well as σ_p, showing a moderately more efficient ability

Scheme 12. Schematic representation of the interaction between proton and

phloroglucinol.

in delocalizing a positive charge of the OH group with

respect to that of OCH₃group, might explain this

conclusion.

5. Also in the case of reactions of the triaminobenzene

derivative 8, the electron-withdrawing power of the azo

group poorly contrast the strong electron-releasing

Reasonably, both complex W-1 and interactions 23,

involve phloroglucinol in the aromatic form 1a.

+

In

the

case

of

the

interaction

between

effect of the three amino groups (σ_pof dimethylamino

group is reported to be – 1.7).²⁶In this case, some

solubility characters of reagents/products are important

parameters in complicating the first reaction affording

the disubstituted derivative, while the third attack

cannot occur.

tris(amino)benzenes and 4,6-dinitrobenzofuroxan the

energy difference between the π complex and the σ

complex (the WM complex) is very low, about 15

kcal/mol.⁴⁰In that case, the electrophile/nucleophile

interaction afforded WM complexes which were

analysed and characterized by NMR spectroscopy at

low temperature^4aand showed the electrophilic moiety

(4,6-dinitrobenzofuroxan) to be enable to choose the

carbon atom in fixing the σ-bond^4ain a situation similar

to that depicted by 23.

6. The rationalization of the steps of the substitution

reactions on 1, 2, and 8 may be explained by a simple

balance between the relative electron-donating

electronic effect of hydroxy, methoxy and amino

groups and the electron-withdrawing effect of the

entering moiety, the azo group, in particular, in its

protonated form.

7. The attacks to form 7 are in three subsequent steps

passing through the mono- and di-substituted

compound. Probably, the first attack is in the field of

the aromatic electrophilic substitution, while the second

and the third attacks are in the field of the

addition/elimination reaction on alkenes (on substrates

like as 4B and 6B of Fig. 6).

Conclusions

In conclusion, the following points can summarize the main

findings of this study:

1. The azo-coupling reaction between equimolar amounts

of 4-nitrobenzenediazonium tetrafluoroborate (3) and

phloroglucinol (1) or 1,3,5-trimethoxybenzene (2), in

acetonitrile, afford in almost quantitative yields the

expected products of monosubstitution as salts of the

tetrafluoroboric acid, as already found in the case of

1,3,5-tris(N-piperidinyl)benzene (8).³

2. The H/D exchange reactions provide an indirect

indication to confirm the phloroglucinol (1) undergoes

prototropic equilibria, even if the reaction between 1

and the 4-nitrobenzenediazonium tetrafluoroborate (3)

does not appear to be affected by the presence of

tautomeric forms other than the usual aromatic form,

as shown by reaction A of Scheme 2.

Figure 6. Tautomeric forms of

diazonium salt

4 and 6 that undergo further attack of

3

.

3. Attempts to obtain a second and a third attack of the

diazonium salt, producing di- and tri-substituted azo

derivatives of 2 failed: also in the presence of excess

of 3 the only product obtained is that derived from a

mono attack. The introduction of the first azo group

reduces the nucleophilic power of trimethoxybenzene

(σ_pof -N=NPh group is evaluated to be 0.64, σ_mis

0.29),²⁶thus other attacks on 2 of the diazonium salt

Diazonium salts were indicated to react with methyl ketones or

with other methylene and methine groups activated by electron-

withdrawing groups, yielding hydrazone derivatives.⁴¹Actually,

we checked the reaction between the diketone 24 and the

diazonium salt 3, as reported in Scheme 13.

10.1002/ejoc.201601393

European Journal of Organic Chemistry

FULL PAPER

1,3,5-Tris(N-piperidinyl)benzene

8

was prepared as described

previously.³Phloroglucinol (1), 1,3,5,-trimethoxybenzene (2), 3,5-

dimethoxyphenol (12), p-nitrobenzenediazonium tetrafluoroborate (3) and

p-methoxybenzenediazonium

tetrafluoroborate

are

commercially

available, as well as compounds 17, 18, 19, 21, 22, and 24. The NMR

1

signals of phlorolucinol in different solvents are reported below: H NMR

(300 MHz, DMSO-d₆): δ = 8.93 (s, 3 H, OH), 5.65 ppm (s, 3 H, CH); ¹³C

NMR (75 MHz, DMSO-d₆): δ = 158.9, 94.1 ppm (CH); ¹H NMR (300 MHz,

CD₃CN): δ = 6.78 (s, 3 H, OH), 5.82 ppm (s, 3 H, CH); ¹³C NMR (75

MHz, , CD₃CN): δ = 159.6, 95.3 ppm (CH); ¹H NMR (300 MHz, CD₃OD):

δ = 5.79 ppm(s, 3 H, CH); ¹³C NMR (75 MHz, , CD₃OD): δ = 160.1, 95.5

ppm (CH).

Scheme 13. Reaction between acetylacetone (24) and diazonium salts.

Compounds 4,⁴²5,²¹5H,⁴³10a,^44,4510b,⁴⁶and 25,⁴⁷are known and their

chemico-physical data agree with those reported; additional data are

reported in SI.

The formation of the hydrazone 25 probably occurs via the enol

24A, by an addition /elimination reaction and it may be achieved

by a final tautomeric equilibria. We emphasize that 24 is a part

of the ring of 4B and of 6B of Figure 5.

General procedure for the synthesis of compounds 4 and 5.

In this way, the different behavior of 1 and 2 is explained by

simple tautomeric equilibria. On the other hand, there are

evidences^23,30that the tris(hydrazone) of phloroglucinol is in the

triketo form as depicted for 7 in Scheme 2.

Finally, a series of experiments on the H/D exchange, in acidic,

basic, or neutral medium, on different substrates, permitted to

deepen the role of the tautomeric equilibria involving the hydroxy

groups in the exchange reaction.

4-Nitrobenzenediazonium tetrafluoroborate (3) (0.05 g, 0.2 mmol) was

added to an equimolar amount of 1 (or 2) dissolved in 2 mL of acetonitrile.

Immediately, the color of the solution became red and after a few min a

coral-red solid precipitated. The reaction course was monitored by TLC

(eluent: diethyl ether/petroleum light 1/1) until complete disappearance of

reagents. Compound 4 and 5H were recovered as solids after filtration

then washed with little amount of acetonitrile and their data agree with

those reported.^42,43Compound 4 was obtained also by FC of the crude

reaction mixture, compound 5²¹was obtained by FC of 5H (eluent:

dichloromethane) and their data agree with those already reported.²¹

Experimental Section

Synthesis of 2,4-bis-(4-nitrophenyl)diazenylbenzene-1,3,5-triol (6)

and 2,4,6-tris(2-(4-nitrophenyl)hydrazono)cyclohexane-1,3,5-trione

(7).

General

4-Nitrobenzenediazonium tetrafluoroborate (3) (0.075 g, 0.6 mmol) was

added to 1 (0.2 mmol) dissolved in 5 mL of acetonitrile. Immediately, the

colour of the solution became red and after a few min a dark red solid

precipitated. After 30 min. the solid was collected by filtration, washed

with CH₃CN and dried; its mass data agreed with those of compound 6.

The mother liquor was concentrated under reduced pressure and the

residue (red solid, almost insoluble in usual organic solvents) was

washed with CHCl₃and dried and its analytical data agreed with those of

The ¹H and ¹³C NMR spectra were recorded at 300, 400, or 600 MHz (¹H

NMR) and 75.46, 100.56, or 150.80 MHz (¹³C NMR), respectively. J

values are given in Hz. Signal multiplicities were established by DEPT-

135 experiments. Chemical shifts were referenced to the solvent [δ =7.27

and 77.0 ppm for CDCl₃), (δ=2.0 and 0.3 ppm for CD₃CN), (δ = 2.5 and

39.5 ppm for DMSO-d₆) for ¹H and ¹³C NMR, respectively]. GC-MS

analyses were carried out with a gas chromatograph directly interfaced

with a mass selective detector (injection temperature: 250°C; oven

temperature was programmed as follows: 60°C for 2 min, increased up to

260°C at the rate of 20°/min, followed by 260°C for 20 min; the carrier

gas was helium, used at a flow rate of 1 mL; the transfer line temperature

was 280°C; the ionization was obtained by electron impact (EI);

acquisition range was 50-500 m/z). EI mass spectra were recorded using

a VG-7070E spectrometer at an ionization voltage of 70 eV. ESI-MS and

HR-ESI-MS spectra were recorded using Waters 2Q 4000 and Xevo

instrument, respectively. Elemental analyses were performed on a Carlo

Erba Model EA-1108 elemental analyser. Chromatographic purifications

were carried out on silica gel or aluminum oxide (activated, basic,

Brockmann I, standard grade ca. 150 mesh) columns at medium

pressure. In the Supporting Information, copies of the ¹H and ¹³C NMR

spectra of all new compounds are provided. In general, NMR spectra of

tetrafluoroborate salts have been carried out in DMSO-d₆, due to their

very low solubility in other solvents Their ¹⁹F NMR signal (376 MHz,

DMSO-d₆) was at δ = –143.5 ppm, referred to hexafluorobenzene (δ = –

163.0 ppm) as external standard. In that cases, the spectra showed the

same NMR signals of the neutral compound obtained after flash

chromatography likely due to the dissociation of the salt in the used

solvent

a

complex mixture of compounds, among them the presence of

compound 7 was deduced by its HR-ESI-MS spectrum. Compound 6

(less than 5%) was obtained also after chromatography on alumina of the

crude reaction mixture.

2,4-Bis-(4-nitrophenyl)diazenylbenzene-1,3,5-triol (6). ¹H NMR (400

MHz, DMSO-d6, 25 °C): δ = 8.24 (d, 2 H, J = 7.7 Hz), 7.50 (d, 2 H, J =

7.7 Hz), 5.10 ppm (s, 1 H). ESI-MS (m/z): ES^–= 423 (M – H)^–; HRMS

(ES^–) m/z: (M – H)^–calcd for C₁₈H₁₁N₆O₇^–423.0695 found 423.0689.

2,4,6-Tris(2-(4-nitrophenyl)hydrazono)cyclohexane-1,3,5-trione (7).

MS (m/z): ES^–= 572 (M – H)^–. HRMS (ES^–) m/z: (M – H)^–calcd for

C₂₄H₁₄N₉O₉^–572,0920 found 572.0914.

General solvent-free procedure for the synthesis of compounds 10a

and 10b.

1,3,5-Trihydroxybenzene (0.25 g, 2 mmol) was dissolved in 1 mL of

pyrrolidine (12 mmol) or piperidine (10 mmol) and the reaction progress

was monitored by GC-MS analysis. The formation of compound 10a

resulted completed after 5 h at room temperature and 10b was obtained

10.1002/ejoc.201601393

European Journal of Organic Chemistry

FULL PAPER

after 40 h at reflux. Flash chromatography of the crude reaction mixture

(eluent: diethyl ether) gave the product. It has to be noted that reactions

and product purification were carried out in the dark, in order to minimize

the decomposition of the reaction product, that appears to be light and

moisture sensitive, giving a green oxidation by-product.⁴⁴Chemico-

physical data of 10a⁴⁵and 10b⁴⁶agree with those reported in the

literature (see SI).

Synthesis of compounds 13, 15, 16, and 20.

4-Nitrobenzenediazonium tetrafluoroborate (3) (0.05 g, 0.2 mmol) was

added to an equimolar amount of 12 (or 14, or 19) dissolved in 5 mL of

acetonitrile. Immediately, the color of the solution became red and after a

few min a solid precipitated. The reaction course was monitored by TLC

until complete disappearance of reagents. Chromatographic purification

on silica gel of the crude reaction mixture gave compounds 13, 15, 16,

and 20.

General procedure for the synthesis of compounds 11Ha and 11Hb.

A solution of compound 10 (0.2 mmol) in acetonitrile (6.0 mL) was added

to a solution of 3 (0.095 g, 0.4 mmol) in acetonitrile (2.0 mL). Immediately,

the color of the mixture became red, and a solid precipitated. After 5 min

the TLC analysis (eluent: diethyl ether) revealed absence of 10. After

about 20 min the solid was recovered by filtration and characterized.

(E)-1,1'-(5-Methoxy-4-((4-nitrophenyl)diazenyl)-1,3-

phenylene)dipiperidine (13). Red solid 0.077 g (91%), m.p.: >125 °C

1

(dec.). H NMR (400 MHz, CDCl₃, 25 °C): δ = 8.28 (d, J = 9.1 Hz, 2 H),

7.85 (d, J = 9.1 Hz, 2 H), 6.10 (d, J = 2.0 Hz, 1 H), 6.06 (d, J = 2.0 Hz, 1

H), 3.94 (s, 3 H, OCH₃), 3.50-3.41 (m, 4 H, NCH₂), 3.19-3.10 (m, 4 H,

NCH₂), 1.85-1.44 ppm (m, 12 H, NCH₂CH₂and NCH₂CH₂CH₂). ¹³C NMR

(100 MHz, CDCl₃, 25 °C) δ = 157.6, 155.4, 153.4, 146.0, 127.0, 124.7,

121.3, 113.2, 96.1, 91.6, 56.4, 54.2, 48.9, 26.2, 25.6, 24.3, 24.2 ppm.

ESI-MS (m/z): ES⁺= 424 (M⁺+1), 446 (M⁺+Na). Elemental analysis calcd

(%) for C₂₃H₂₉N₅O₃: C 65.23, H 6.90, N 16.54; found: C 65.34, H 6.92, N

16.51. Crystal Data and Structure Refinement for 13 are shown in Table

3. CCDC 1482311 contains the supplementary crystallographic data for

compound 13. These data can be obtained free of charge from The

2,6-Bis((E)-1-(4-nitrophenyl)diazen-1-ium-2-yl)-3,5-di(pyrrolidin-1-

yl)phenolate tetrafluoroborate (11Ha). 0.044 g (35%), m.p.>260 °C

(dec). ¹H NMR (400 MHz, CD₃CN, 25 °C): δ = 8.36 (d, H, J = 9.2 Hz, CH),

7.68 (d, 4 H, J = 9.2 Hz, CH), 5.66 (s, 1 H, CH), 4.22-4.16 (m, 4 H, CH₂N),

3.80-3.70 (m, 4 H, CH₂N), 2.13-2.07 ppm (m, 8 H, CH₂CH₂N). ¹³C NMR

(100 MHz, DMSO-d₆, 25 °C) δ = 176.6, 152.8, 146.6, 144.2, 127.6, 125.8

(CH), 117.1 (CH), 93.4 (CH), 55.0 (CH₂), 52.4 (CH₂), 26.4 (CH₂), 23.4

ppm (CH₂). HRMS (ES⁺) m/z: (M⁺+1) calcd for C₂₆H₂₇N₈O₅531.2099

found 531.2097; ESI MS (ES⁺) m/z: 531 (M⁺+1); ESI MS (ES^-) m/z: 87

(M-H)^–.

Cambridge

Crystallographic

Data

Centre

via

www.ccdc.cam.ac.uk/data_request/cif.

3,5-Dimethoxy-2-((4-nitrophenyl)diazenyl)phenol (15). orange solid

0.022 g (36%) m.p.: 223-240 °C (dec.). ¹H NMR: (300 MHz, DMSO-d₆,

25°C) δ = 8.36 (d, J = 9.1 Hz, 2 H), 7.90 (d, J = 9.1 Hz, 2 H), 6.12 (d, J =

2.3, 1 H), 6.03 (d, J = 2.3, 1 H), 3.91 (s, 3 H, OCH₃), 3.87 ppm (s, 3H,

OCH₃). ¹³C NMR: (100 MHz, DMSO-d₆) δ = 169.1, 165.8, 159.9, 151.5,

145.9, 126.2, 125.5, 120.2, 94.6, 93.2, 56.44 (OCH₃), 56.40 ppm (OCH₃).

ESI MS (ES^–) m/z: 302 (M – H)^–. Elemental analysis calcd (%) for

C₁₄H₁₃N₃O₅: C 55.45, H 4.32, N 13.86; found: C 55.53, H 4.33, N 13.82.

2,6-bis((E)-1-(4-nitrophenyl)diazen-1-ium-2-yl)-3,5-di(piperidin-1-

yl)phenolate tetrafluoroborate (11Hb). 0.057 g (28%), m.p.>237 °C

(dec). ¹H NMR (400 MHz, DMSO-d₆, 25 °C): δ = 14.1 (s, OH), 8.36 (d, H,

J = 9.5 Hz, CH), 7.77 (d, 4 H, J = 9.5 Hz, CH), 6.21 (s, 1 H, CH), 4.00-

3.86 (m, 8 H, CH₂N), 3.60-3.33 (br.s., 1 H), 1.91-1.70 ppm (m, 12 H,

CH₂CH₂N and CH₂CH₂CH₂N). ¹³C NMR (100 MHz, DMSO-d₆, 25 °C) δ =

176.3, 158.1, 146.6, 144.1, 127.4, 125.8 (CH), 117.0 (CH), 97.0 (CH),

52.7 (CH₂), 26.3 (CH₂), 23.6 ppm (CH₂). HRMS (ES⁺) m/z: (M⁺+1) calcd

for C₂₈H₃₁N₈O₅559.2412 found 559.2410; ESI MS (ES⁺) m/z: 559 (M⁺

+1); ESI MS (ES^-) m/z: 87 (M-H)^–. Crystal Data and Structure refinement

for 11b are shown in Table 3. CCDC 1482444 contains the

supplementary crystallographic data for compound 11Hb. These data

can be obtained free of charge from The Cambridge Crystallographic

Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

3,5-Dimethoxy-4-[(4-nitrophenyl)diazenyl]phenol (16). orange solid

0.026 g (43%) m.p.: 220-228 °C (dec.). ¹H NMR: (400 MHz, DMSO-d₆,

25°C) δ = 8.27 (d, J = 9.2 Hz, 2 H), 7.67 (d, J = 9.2 Hz, 2 H), 5.78 (br.s, 2

H), 3.84 ppm (br.s, 6 H, OCH₃). ¹³C NMR: (100 MHz, DMSO-d₆) δ =

184.9, 158.9, 148.9, 142.8, 125.5, 125.2 115.7, 102.0, 56.4 ppm (OCH₃).

ESI MS (ES^–) m/z: 302 (M – H)^–. Elemental analysis calcd (%) for

C₁₄H₁₃N₃O₅: C 55.45, H 4.32, N 13.86; found: C 55.55, H 4.33, N 13.81.

Synthesis of 1,1'-(5-methoxy-1,3-phenylene)dipiperidine (12).

2-((4-Nitrophenyl)diazenyl)naphthalene-1,3-diol (20). Orange solid,

0.044 g (71%) m.p.: >260 °C (dec.). ¹H NMR (400 MHz, DMSO-d₆,

25 °C): δ = 12.31 (br.s, OH), 8.31 (dd, J₁= 7.9 Hz, J₂= 1,1 Hz, 1 H), 8.23

(d, J = 9.3 Hz, 2 H), 7.90 (dd, J₁= 7.3 Hz, J₂= 1,3 Hz, 1 H), 7.73 (d, J =

9.3 Hz, 2 H), 7.63 (dt, J₁= 7.3 Hz, J₂= 1,3 Hz, 1 H), 7.50 (dt, J₁= 7.3 Hz,

J₂= 1,1 Hz, 1H), 5.98 ppm (s, 1H). ¹³C NMR (100 MHz, DMSO-d₆, 25 °C)

δ = 181.0, 167.2, 148.0, 142.6, 133.0, 130.6, 127.7, 125.7, 125.3, 123.8,

122.5, 115.5, 104.5 ppm. ESI MS (ES^–) m/z: 308 (M – H)^–. Elemental

analysis calcd (%) for C₁₆H₁₁N₃O₄: C 62.14, H 3.59, N 13.59; found: C

62.27, H 3.60, N 13.54.

1,3-Dichloro-5-methoxybenzene (0.45 g, 2.54 mmol), piperidine (1.5 mL,

15 mmol), potassium t-butylate (1.2g, 10mmol) and toluene (2.5 mL)

were introduced in an autoclave that was sealed and the system was

introduced in an oil bath and warmed at ~155 °C. After 24 h the system

was allowed to stand then toluene (10 mL) and water (30 mL) was added.

After extraction with dichloromethane (3 x 30 mL) the combined organic

layers were dried over anhydrous MgSO₄, and the filtrate was

concentrated. Compound 12 (0.44 g, 63%) was recovered as pale red

liquid after purification by FC (eluent: n-hexane/diethyl ether 7/3) of the

1

residue. H NMR (400 MHz, CDCl₃, 25 °C): δ = 6.16 (t, J = 2.1 Hz, 1 H),

6.04 (d, J = 2.1 Hz, 2 H), 3.77 (s, 3 H, OCH₃), 3.13 (t, J = 5.6 Hz, 8 H,

H/D exchange experiments.

NCH₂), 1.74-1.66 (m,

8 H, NCH₂CH₂), 1.61-1.53 ppm (m, 4 H,

NCH₂CH₂CH₂). ¹³C NMR (100 MHz, CDCl₃, 25 °C) δ = 161.0, 154.1, 98.8

(CH), 94.7 (CH), 55.0 (OCH₃), 51.0 (CH₂), 25.9 (CH₂), 24.4 ppm (CH₂).

MS (EI) m/z: 274 (M⁺, 100), 259 (30), 245 (27), 231 (10), 217 (14), 203

(6), 190 (17), 176 (9). Elemental analysis calcd (%) for C₁₇H₂₆N₂O: C

74.41, H 9.55, N 10.21; found: C 74.53, H 9.58, N 10.24.

A solution of the considered compound (see Chart 1 and Table 2)

dissolved in a mixture DMSO-d₆/CD₃OD 96/4 v/v (in cases in which DCl

or D₂SO₄was used, the solvent was CD₃OD) was introduced into a NMR

spectroscopy tube and the ¹H NMR spectrum was recorded. The spectra

were recorded after different times from the addition, or not, of acid (DCl

35% in D₂O or D₂SO₄98% in D₂O, ≥ 5 eq.), or bases (~ 1 eq.), as

reported in Table 2. p-Dioxane added as internal standard or solvent

10.1002/ejoc.201601393

European Journal of Organic Chemistry

FULL PAPER

peak were used as reference signals to determine the amount of the

CH/CD exchange. In the case of compound 19 (Table 2, entry 19), both

CH signals of the hydroxylated ring exchanged, and in cases of

compounds 20 and 21 (Table 2, entries 20 and 21, respectively) the

signal of the hydroxylated ring exchanged.

largest diff. peak 0.612 and -0.379

and hole, e Å^-3

0.450 and -0.391

[a] R₁= ∑||F_o| - |F_c|/∑|F_o|. [b] wR₂= [∑w(F_o²- F_c²)²/∑w(F_o²)²]^1/2, where w =

1/[σ²(F_o²) + (aP)²+ bP] where P = (F_o²+ 2F_c²)/3.

Crystallographic Data Collection and Structure Determination.

The X-ray intensity data of compounds 11Hb and 13 were measured on

a Bruker Apex II CCD diffractometer. Cell dimensions and the orientation

matrix were initially determined from a least-squares refinement on

reflections measured in three sets of 20 exposures, collected in three

different ω regions, and eventually refined against all data. A full sphere

of reciprocal space was scanned by 0.3° ω steps. The software SMART⁴⁸

was used for collecting frames of data, indexing reflections and

determination of lattice parameters. The collected frames were then

processed for integration by the SAINT program,⁴⁸and an empirical

absorption correction was applied using SADABS.⁴⁹The structure was

solved by direct methods (SIR 2004)⁵⁰and subsequent Fourier

syntheses and refined by full-matrix least-squares on F²(SHELXTL)⁵¹

using anisotropic thermal parameters for all non-hydrogen atoms. All the

hydrogen atoms were added in calculated positions, included in the final

stage of refinement and refined with U(H)=1.2U_eq(C) and allowed to ride

on their carrier atoms. In 12Hb the molecule lies on a crystallographic

Acknowledgements

Work supported by Alma Mater Studiorum – Università di

Bologna (RFO funds). Authors thank Mr. L. Zuppiroli for mass

spectra

Keywords: Phloroglucinol • tautomerism • trimetoxybenzene •

diazonium salts • H/D exchange

[1].

[2].

C. Boga, J. Degani, E. Del Vecchio, R. Fochi, L. Forlani, P. E.

Todesco, Eur. J. Org. Chem., 2002, 3837.

a) C. Boga, E. Del Vecchio, L. Forlani, R. Goumont, F. Terrier, S.

Tozzi, Chem. Eur. J., 2007, 13, 9600; b) L. Forlani, A.-L. Tocke

Dite Ngobo, E. Del Vecchio, S. Lakhdar, R. Goumont, F. Terrier, J.

Org. Chem., 2006, 71, 5527; c) C. Boga, S. Cino, G. Micheletti, D.

Padovan, L. Prati, A. Mazzanti, N. Zanna, Org. Biomol. Chem.

2016, 14, 7061.

–

twofold axis passing H4, C4, C1, O1 and the boron atom of the BF₄

counterion. Molecular graphics were generated by using Mercury 3.3.⁵²

Color codes for all molecular graphics: orange (Cu), blue (N), red (O),

grey (C), white (H). Crystal data and details of data collections for

compounds 11Hb and 13 are reported in Table 3.

[3].

[4].

G. Micheletti, C. Boga, M. Pafundi, S. Pollicino, N. Zanna Org.

Biomol. Chem. 2016, 14, 768.

a) C. Boga, E. Del Vecchio, L. Forlani, A. Mazzanti, P. E. Todesco,

Angew. Chem. Int. Ed., 2005, 44, 328; b) C. Boga, E. Del Vecchio,

L. Forlani, A. Mazzanti, C. Menchen Lario, P. E. Todesco, S. Tozzi,

J. Org. Chem., 2009, 74, 5568.

[5].

a) L. Forlani, C. Boga, A. Mazzanti, N. Zanna, Eur. J. Org. Chem.,

2012, 1123; b) C. Boga, G. Micheletti, S. Cino, S. Fazzini, L.

Forlani, N. Zanna, D. Spinelli Org. Biomol. Chem. 2016, 14, 4267.

L. Forlani, C. Boga, E. Del Vecchio, A.-L. Tocke Dite Ngobo, S.

Tozzi, J. Phys. Org. Chem., 2007, 20, 201.

Table 3. Crystal Data and Structure Refinement for 12Hb and 14.

Compound

Formula

FW

11Hb

13

[6].

[7].

[8].

C₂₈H₃₁BF₄N₈O₅

645.41

C₂₃H₃₁N₅O₄

441.53

C. Boga, E. Del Vecchio, L. Forlani, S. Tozzi, J. Org. Chem., 2007,

72, 8741–8747.

Crystal

Monoclinic

a) S. M. Hubig, J. K. Kochi, J. Org. Chem., 2000, 65, 6807; b) S. M.

Hubig, J. K. Kochi, J. Am. Chem. Soc., 2000, 122, 8279; c) T. M.

Bockman, D. Kosynkin, J. K. Kochi, J. Org. Chem., 1997, 62,

5811; d) S. V. Rosokha, J. K. Kochi, J. Org. Chem., 2002, 67,1727.

P. Singh, J. Sidana, S. B. Bharate, W. J. Foley, Nat. Prod. Rep.,

2010, 27, 393.

symmetry

Space group

a, Å

C2/c

P-1

19.0729(16)

11.3920(7)

12.9852(8)

90

10.236(4)

10.372(4)

12.130(4)

100.260(4)

112.741(4)

99.401(4)

1129.85

2

[9].

b, Å

c, Å

[10].

[11].

P. Singh, S. B. Bharate, Nat. Prod. Rep., 2006, 23, 558.

K.W. Glombitza, H.U. Rosener, H. Vilter, W. Rauwald, Planta Med.,

1973, 24, 301.

α, °

β, °

98.511(4)

90

γ, °

cell volume, Å³

[12].

[13].

M. A. Ragan, J. S. Craigie, Can. J. Biochem., 1976, 54, 66.

R. Cahen, E. Assous, M. Sautai, A. Pessonnier, Therapie, 1962,

17, 1349.

2790.3(3)

4

Z

[14].

[15].

R. Cahen, Arch. Int. Pharmacodyn. Ther., 1962, 138, 311.

B. Queguineur, L. Goya, S.; Ramos, M. A. Martin, R. Mateos, L.

Bravo, Food Chem. Toxicol., 2012, 50, 2886.

D_c, Mg m^-3

µ(Mo Kα), mm^-1

F(000)

1.536

1.298

0.125

0.091

1340

472

[16].

[17].

G. Cargill, B. Salin, S. Lubin, F. Kohler, T. Coste, J. Rautureau,

Presse Med., 1992, 21, 19.

crystal size, mm

T, K

0.30×0.25×0.20

153

0.50×0.50×0.30

298

M.-C. Chang, H.-H. Chang, C.-P. Chan, H.-Y. Chou, B.-E. Chang,

S.-Y. Yeung, T.-M. Wang, J.-H. Jeng, Toxicol. Appl. Pharmacol.,

2012, 263, 287.

θ limits, °

Refl. Collected

2.09 - 30.10

18251

1.89 – 27.50

12544

[18].

[19].

P. Mainguet, Bruxelles Med., 1968, 48, 383.

unique refl. (R_int) 4086 [R(int) = 0.0734]

GooF on F²

1.043

R₁(F)^[a], wR₂(F²)^[b]0.0597, 0.1528

5098 (0.0460)

1.023

P. Delinotte, J. Michon, L. Delouche, J. Urol. Nephrol., 1963, 69,

505.

[20].

P. Morin, R. Hamelin, J. Grepinet, Presse Med., 1964, 72, 3121.

0.0756, 0.2185

10.1002/ejoc.201601393

European Journal of Organic Chemistry

FULL PAPER

[21].

[22].

[23].

H. Mayr, M. Hartnagel, K. Grimm, Liebigs Ann., 1997, 1, 55.

G. Perkin, J. Chem. Soc., Trans., 1897, 71, 1154.

[47].

[48].

H. V. Patel, K. A. Vyas, S. P. Pandey, P. S. Fernandes, Org. Prep.

Proc. Int., 1994, 26, 118.

a) B. F. Abrahams, S. J. Egan, R. Robson J. Am. Chem. Soc.,

1999, 121, 3535; b) M. Van der Auweraer, C. Catry, L. F. Chi, O.

Karthaus, W. Knoll, H. Ringsdorf, M. Sawodny, C. Urban, Thin

Solid Films, 1992, 210-211, 39; c) M. Ghisletta, H.-P. Jalett, T.

Gerfin, V. Gramlich, K. Hegetschweiler, Helv. Chim. Acta, 1992, 75,

2233; d) J. Yariv, M. M. Rapport, L. Graf, Biochem. J., 1962, 85,

383; e) H. Y. Lee, X. Song, H. Park, M.-H. Baik, D.Lee, J. Am.

Chem Soc., 2010, 132, 12133.

SMART & SAINT Software Reference Manuals, version 5.051

(Windows NT Version), Bruker Analytical X-ray Instruments Inc.:

Madison, WI, 1998.

[49].

[50].

G. M. Sheldrick, SADABS, program for empirical absorption

correction, University of Göttingen, Germany, 1996.

M. C. Burla, R. Caliandro, M. Camalli, B. Carrozzini, G. L.

Cascarano, L. De Caro, C. Giacovazzo, G. Polidori, R. Spagna, J.

Appl. Crystallogr., 2005, 38, 381.

[24].

a) V. I. Ushkarov, K. I. Kobrakov, A. I. Alafinov, S. A. Shevelev, A.

Shakhnes, Kh. Theor. Found. Chem. Engin., 2007, 41, 671; b) V. I.

Ushkarov, K. I. Kobrakov, A. I. Alafinov, G. S. Stankevich, S. A.

Shevelev, A. Shakhnes, Kh. Fibre Chem., 2006, 38, 188; c) R.

Hirata, Jpn. J. Exp. Med., 1957, 27, 99; d) R. Koshiura, R. Shimizu,

Kanazawa Daigaku Kekkaku Kenkyusho Nempo, 1961, 19, 225.

E. Del Vecchio, C. Boga, L. Forlani, S. Tozzi, G. Micheletti, S. Cino,

J. Org. Chem., 2015, 80, 2216.

[51].

[52].

G. M. Sheldrick, SHELXTLplus (Windows NT Version) Structure

Determination Package, Version 5.1. Bruker Analytical X-ray

Instruments Inc.: Madison, WI, USA, 1998.

C. F. Macrae, I. J. Bruno, J. A. Chisholm, P. R. Edgington, P.

McCabe, E. Pidcock, L. Rodriguez-Monge, R. Taylor, J. van de

Streek, P. A. Wood, J. Appl. Crystallogr., 2008, 41, 466.

[25].

[26].

a) O. Exner, Advances in Linear Free Energy Relationship, N. B.

Chapman and J. Shorter, Eds.; Plenum Press: London, 1972; b) C.

Hansch, A. Leo, R. W. Taft Chem. Rev., 1991, 91, 165-195.

Kochem, M. Orio, C. Philouze, H. Jamet, A. du Moulinet

d'Hardemare, F. Thomas, Eur. J. Inorg. Chem., 2011, 45.

a) R. J. Highet, I. V. Ekhato, J. Org. Chem., 1988, 53, 2843; b) M.

Lohrie, W. Knoche, J. Am. Chem. Soc., 1993, 115, 919.

a) A. Baeyer, Ber. 1886, 19, 159; b) H. Freund, Angew. Chem.,

1961, 73, 433.

[27].

[28].

[29].

[30].

W. Fuchs, Deutsch. Tech. Hochschule Brunn. Ber., 1921, 54B,

245.

[31].

[32].

R. J. Highet, T. J. Batterham, J. Org. Chem., 1964, 29, 475.

D. Wang, K. Hildebrand, J. Leitich, H.-P. Schuchmann, C. von

Sonntag, Z. Naturforsch. 1993, 48, 478.

[33].

a) A. J. Kresge, G. W. Barry, K. R. Charles, Y. Chiang, J. Am.

Chem. Soc., 1962, 84, 4343; b) W. M. Schubert, R. H. Quacchia, J.

Am. Chem. Soc., 1963, 85, 1278.

[34].

[35].

[36].

[37].

[38].

S. H. M. Mehr, K. Fukuyama, S. Bishop, F. Lelj, M. J. MacLachlan,

J. Org. Chem., 2015, 80, 5144.

C. Boga, L. Forlani, S. Tozzi, E. Del Vecchio, A. Mazzanti, M.

Monari, N. Zanna, Curr. Org. Chem. 2014, 18, 512.

L. Forlani, E. Mezzina, C. Boga, M. Forconi, Eur. J. Org. Chem.,

2001, 2779.

a) C. Boga, A. C. Bonamartini, L. Forlani, V. Modarelli, L. Righi, P.

Sgarabotto, P. E. Todesco, Eur. J. Org. Chem., 2001, 1175.

a) A. A. Mohamed, A. W. El-Harby, J. Mol. Struct. Theochem.,

2008, 849, 52; b) S. Angelova, V. Enchev, N. Markova, P.

Denkova, K. Kostova, J. Mol. Struct. Theochem., 2004, 711, 201.

c) Y. Zeng, Y. Ren, Int. J. Quantum Chem., 2007, 107, 247.

D. E. Braun, D. A. Tocher, S. L. Price, U. J. Griesser, J. Phys.

Chem. B, 2012, 116, 3961.

[39].

[40].

[41].

P. Jin, F. Li, K. Riley, D. Lenoir, P. v. R. Schleyer, Z. Chen, J. Org.

Chem., 2010, 75, 3761.

a) H. Zollinger, Diazo chemistry I, VCH, Weinheim, 1994, 332; b) N.

K. Masoud, A. B. Sakla, Z. Sawiris, N. A. Yassa, J. Chem. Soc.

Perkin 2, 1974, 1312; c) V. Machàček, O. Machàčkova, V. Štĕrba,

Coll. Czech. Chem. Commun., 1970, 35, 2954; d) V. Machàček, O.

Machàčkova, V. Štĕrba, Coll. Czech. Chem. Commun., 1971, 36,

3187.

[42].

[43].

a) K. G. Liphard, A. Jost, Ber. Bunsenges. Phys. Chem., 1978, 82,

707; b) R. Rastogi, V. K. Gupta, J. Ind. Chem., 1998, 75, 267.

L. M. Anderson, A. R. Butler, A. S. McIntosh, J. Chem. Soc. Perkin

Trans 2, 1987, 1239.

[44].

[45].

[46].

R. J. Highet, J. Org. Chem., 1986, 51, 3231.

F. Effenberger, R. Niess, Chem. Ber., 1968, 101, 3787.

a) F. Effenberger, R. Niess, Chem. Ber., 1966, 101, 3787; b) F.

Effenberger, R. Niess, Angew. Chem., 1967, 1100.

10.1002/ejoc.201601393

European Journal of Organic Chemistry

FULL PAPER

Entry for the Table of Contents

FULL PAPER

Phloroglucinol tautomerism

Gabriele Micheletti,*^[a]Carla Boga,^[a]

Luciano Forlani,^[a]Erminia Del

Vecchio,^[a]Nicola Zanna,^[a]Andrea

Mazzanti,^[a]Magda Monari^[b]

Page No. – Page No.

The H/D exchange on phenol derivatives can explain the tautomeric equilibrium of

the phloroglucinol and its particular reactivity respect to the electrophilic

substitution.

Hydroxy- and Methoxy-Benzene

Derivatives with Benzenediazonium

Salts: Chemical Behavior and

Tautomeric Problems

Article Doi

Hydroxy- and Methoxybenzene Derivatives with Benzenediazonium Salts ― Chemical Behavior and Tautomeric Problems

DOI: 10.1002/ejoc.201601393

Source and publish data:

Authors:

Article abstract of DOI:10.1002/ejoc.201601393

Full text of DOI:10.1002/ejoc.201601393

Products guided by the article

R&D Labs maybe for 16857-94-6

Relevant to this article

Hot Product