Sigmatropic rearrangements in 5-allyloxytetrazoles

View Article Online / Journal Homepage / Table of Contents for this issue

Organic &

Biomolecular

Chemistry

Dynamic Article Links

Cite this: Org. Biomol. Chem., 2011, 9, 6040

www.rsc.org/obc

PAPER

Sigmatropic rearrangements in 5-allyloxytetrazoles†

Lu´ıs M. T. Frija,‡^a,bIgor Reva,*^bAmin Ismael,^aDaniela V. Coelho,^aRui Fausto^band M. Lurdes S. Cristiano*^a

Received 22nd March 2011, Accepted 23rd May 2011

DOI: 10.1039/c1ob05460k

Mechanisms of thermal isomerization of allyl tetrazolyl ethers derived from the carbocyclic allylic

alcohols cyclohex-2-enol and 3-methylcyclohex-2-enol and from the natural terpene alcohol nerol were

investigated. In the process of the syntheses of the three 1-aryl-5-allyloxytetrazoles, their rapid

isomerization to the corresponding 1-aryl-4-allyltetrazol-5-ones occurred. The experiments showed that

the imidates rearrange exclusively through a [3,3¢]-sigmatropic migration of the allylic system from O to

N, with inversion. Mechanistic proposals are based on product analysis and extensive quantum

chemical calculations at the DFT(B3LYP) and MP2 levels, on O-allyl and N-allyl isomers and on

putative transition state structures for [1,3¢]- and [3,3¢]-sigmatropic migrations. The experimental

observations could be only explained on the basis of the MP2/6-31G(d,p) calculations that favoured

the [3,3¢]-sigmatropic migrations, yielding lower energies both for the transition states and for the ﬁnal

isomerization products.

1. Introduction

Tetrazoles are applied in many areas, and these applications are

often related to the acid/base properties and metabolic stability

of the tetrazolic ring. Tetrazole¹and its derivatives have important

applications in medicinal chemistry, mainly as surrogates for

carboxylic acids,^2–7in agriculture, as herbicides, fungicides and

plant-growth regulators,⁸in photography and photo-imaging,

as stabilizers⁹and in the car manufacturing industry, as gas-

generating agents for airbags.¹⁰Tetrazoles are also of use as multi-

dentate nitrogen ligands¹¹and are widely applied in synthesis.^12–19

Tetrazolyl ethers are used as intermediate compounds for reductive

cleavage of the C–O bond in phenols and alcohols. The strongly

electron-withdrawing tetrazolyl system, together with oxygen

from the original alcohol, represents an efﬁcient nucleofuge in

heterogeneous transfer hydrogenolysis catalyzed by transition

metals.^16–19Aryl-, allyl-, benzyl-, and naphthyl-tetrazolyl ethers,

used in this synthetic strategy, are easily obtained from reaction

of the corresponding hydroxylic compound with commercially

available 5-chloro-1-phenyl-(1H)-tetrazole.²⁰

Scheme 1

linkage (HAR = heteroaromatic ring and A = allyl), caused by the

powerful electron-withdrawing effect of the saccharyl or tetrazolyl

ring system.^21,22Upon etheriﬁcation, the originally strong C_A–O

bond in the allyl alcohol becomes weak, and the bond between

the oxygen and the carbon of the heteroaromatic ring (C_HAR–O)

becomes very strong. These electronic changes provide a molecular

structure that lies close to a transition state structure in which the

C_A–O bond in the ether becomes easily cleavable. Thus, ethers 3a,b

are readily converted into the corresponding N-allyl-isomers 4 or

5 when heated (Scheme 1).

An earlier investigation of the thermal rearrangement in 3-

allyloxysaccharins 3a (Scheme 1) in solution, revealed that migra-

tion of the allyl group from O to N may occur through both [3,3¢]-

and [1,3¢]-processes,^22,23the relative proportion of products (4a,

5a) depending on structural features of the starting ether such as

electron density and steric hindrance on the allylic system, polarity

of the reaction medium and temperature. It was demonstrated that,

for compounds 3a, the [3,3¢]-products undergo inversion to the

thermochemically more favourable [1,3¢]-isomers upon extended

The reactivity of benzisothiazolyl (saccharyl) and tetrazolyl

derivatives of allyl alcohols (ethers 3a,b; Scheme 1) was shown

to be related to bond lengths around the central C_HAR–O–C_Aether

^aDepartment of Chemistry and Pharmacy, F.C.T. and CCMAR, Uni-

versity of Algarve, Campus de Gambelas, 8005-039 Faro, Portugal.

E-mail: mcristi@ualg.pt; Fax: +351 289 800 066; Tel: +351 289 800 100 x

7642

^bDepartment of Chemistry, University of Coimbra, 3004-535 Coimbra,

Portugal. E-mail: reva@qui.uc.pt; Fax: +351 239 827 703; Tel: +351 239

854 489

† Electronic supplementary information (ESI) available. See DOI:

10.1039/c1ob05460k

‡ Current address: iMed.UL, Faculdade de Farma´cia da Universidade de

Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal

6040 | Org. Biomol. Chem., 2011, 9, 6040–6054

This journal is

The Royal Society of Chemistry 2011

©

View Article Online

heating.²³It was also observed that the saccharyl derivative of the

cyclic allyl alcohol myrtenol isomerises at ambient temperature

with exclusive formation of the [1,3¢]-product. This behaviour

was interpreted on the basis of steric constraints imposed by

the cyclic myrtenyl system, which destabilize the transition state

required for concerted [3,3¢]-migration, preventing its formation.

For this derivative, the enthalpy of activation for the [3,3¢]-shift

was calculated to be 67 kJ mol^-1higher than that for the [1,3¢]-

shift, thus explaining the observed selectivity.²²It is not clear

whether the [1,3¢]-rearrangement in these ethers occurs through

a fragmentation–recombination process or through a pseudo-

pericyclic mechanism. Recently, the thermal isomerization of neat

3-allyloxysaccharin was investigated in the liquid phase, com-

bining matrix-isolation FTIR spectroscopy, differential scanning

calorimetry and quantum chemical calculations. From the results,

a [3,3¢]-sigmatropic shift mechanism for the isomerization in the

liquid phase was proposed.²⁴

Contrasting with the non-selective isomerization of 3-

allyloxybenzisothiazoles 3a, kinetic studies have demonstrated

that the thermal O to N migration of the allylic system in a range

of 5-allyloxytetrazoles 3b proceeds through a [3,3¢]-sigmatropic

Claisen-type mechanism, with formation of isomers 4b.^22,25,26The

observed selectivity in the thermal isomerization of allyl tetrazolyl

ethers has been advantageously used in the design of synthetic

routes to other heterocycles. For instance, N-allyltetrazolones 4b

are quantitatively converted into 3,4-dihydro-pyrimidinones^12,13,15

Therefore, due to the importance of this rearrangement reaction

in synthesis, the structural effect of steric constraints imposed by

bulky allylic moieties on selectivity should be properly explored.

In particular, according to the best of our knowledge, there are no

detailed studies of the isomerization of ethers 3b using quantum

chemical methods.

sigmatropic shift of the allylic system (Scheme 2 and Fig. 1–4), for

the corresponding N-allyl isomers 16–18 resulting from a [1,3¢]-

sigmatropic shift of the allylic system (Scheme 2 and Fig. 1–4) and

also for putative transition state structures TS1a–TS3a and TS1b–

TS3b. Product analysis shows that the thermal isomerization

of ethers 9, 10 and 14 proceeds through an exclusive [3,3¢]-

sigmatropic mechanism. Considering the results obtained from

theoretical studies, the observed selectivity was ascribed to kinetic

control.

2. Results and discussion

2.1 Synthesis and characterisation of tetrazolyl derivatives 9–12

and 14, 15

Allylic derivatives of tetrazole 9–12 and 14, 15 were synthesised as

depicted in Scheme 2. The carbocyclic allylic alcohols cyclohex-2-

enol (7) and 3-methylcyclohex-2-enol (8) and the natural product

nerol (13), were initially converted into the more nucleophilic al-

lylic alkoxides, through reaction with sodium hydride in anhydrous

conditions. Subsequent addition of 5-chloro-1-phenyltetrazole

resulted in nucleophilic displacement of chloride, with formation

of the required ethers 9, 10 and 14. Ether 9 could be isolated and

characterised. However, putative ether 10 could not be isolated, as

it readily isomerised to the corresponding tetrazolone 12, under

the conditions used for etheriﬁcation. It was also observed that

isomerization of ether 14 occurs very easily at room temperature.

This ether was isolated as a solid (m.p. 43–45 ^◦C), and the infrared

spectrum registered immediately after isolation reveals the absence

of bands corresponding to the carbonyl stretching vibration,

indicating that no tetrazolone is detected. However the ¹H-NMR

spectrum of the solid, obtained some days after isolation, clearly

shows that ether 14 is already “contaminated” with its N-allyl

isomer 15. In ethers 10 and 14, the allylic double bond is more

substituted than in ether 9. Assuming that the thermal sigmatropic

isomerization occurs with development of a positive charge on the

allylic moiety, the transition state structures obtained from 10 and

14 will be further stabilised, lowering the activation energy for

isomerization. Thus, it is expected that the activation energy for

thermal isomerization of ether 9 will be higher than that for ethers

10, 14. In fact, as stated, only ether 9 could be isolated. This ether

was then heated to afford its neat N-allyl isomer 11.

We now describe the results of our investigation on the

sigmatropic isomerization of tetrazolyl ethers derived from the

cyclic allyl alcohols cyclohex-2-enol (7) and 3-methylcyclohex-2-

enol (8) and from the natural product nerol (13) (see Scheme 2). In

the present investigation, ethers 9, 10 and 14 were synthesised and

thermally isomerised to the corresponding N-allyl isomers 11, 12,

15, which were subsequently characterised. Extensive theoretical

calculations (using the DFT(B3LYP)/6-31G(d,p) and MP2/6-

31G(d,p) levels) were performed for ethers 9, 10 and 14, for the

corresponding N-allyl isomers 11, 12, 15 resulting from a [3,3¢]-

Scheme 2

This journal is

The Royal Society of Chemistry 2011

Org. Biomol. Chem., 2011, 9, 6040–6054 | 6041

©

View Article Online

Fig. 2 Relative energies of the most stable stationary points for the ther-

mal isomerization of 5-(cyclohex-2-enyloxy)-1-phenyl-1H-tetrazole (9)

into 1-(cyclohex-2-enyl)-4-phenyl-1H-tetrazol-5(4H)-one (11) calculated

at the DFT(B3LYP)/6-31G(d,p) (DE_G) and MP2/6-31G(d,p) (DE_el) levels.

Fig.

1 Top: Structure of allyl tetrazolyl ethers derived from

the carbocyclic allylic alcohols: cyclohex-2-enol [5-(Cyclohex-2-

enyloxy)-1-phenyl-1H-tetrazole (9) X = H] and 3-methylcyclohex-2-enol

[5-(3-Methylcyclohex-2-enyloxy)-1-phenyl-1H-tetrazole (10) X = CH₃].

Middle: Structure of the rearrangement products resulting from

[3,3¢]-sigmatropic migration of the allylic system: 1-(cyclohex-2-enyl)-4-

phenyltetrazol-5-one (11) (X = H) and 1-(cyclohex-2-enyl)-1-methyl-

4-phenyltetrazol-5-one (12) (X = CH₃). Bottom: Structure of the rear-

rangement products resulting from [1,3¢]-sigmatropic migration of the

allylic system: 1-(cyclohex-2-enyl)-4-phenyltetrazol-5-one (16) (X = H)

and 1-(3-methylcyclohex-2-enyl)-4-phenyltetrazol-5-one (17) (X = CH₃).

Note that the X substituent remains attached to the same carbon atom

during both sigmatropic migrations (though the formal atom numbering

changes). The adopted atom numbering of the cyclohex-2-enyl ring is

shown explicitly. Carbon atom C(1) of the cyclohex-2-enyl ring is chiral

for all compounds. Arrows accompanied with letters A, B, C, D show

intramolecular conformationally relevant degrees of freedom.

of isomerization of 10 exhibits a prominent signal at d 5.97–

6.04 (Table 1 and Fig. 1S, ESI†), corresponding to the two vinyl

protons, in agreement with the predicted spectra for compound 12,

resulting from a [3,3¢]-shift mechanism, and no other signals that

could correspond to compound 17 were detected, thus establishing

compound 12 as the sole product of isomerization. (¹H-NMR

spectra, ESI†).

1

Concerning the isomerization of ether 14, predicted H-NMR

spectra of the putative rearranged products reveal characteristic

signals for the [1,3¢]- and [3,3¢]-migration products, compounds 18

and 15, respectively (Fig. 4). In particular, signals at d 3.83 (CH₂)

and 5.33 (CH) are expected for the product of [1,3¢]-migration,

(18) and at d 5.22–5.19 (CH₂) and 5.83 (CH) for the product of

[3,3¢]-migration (15) (Table 2 and Fig. 4S, ESI†). The experimental

¹H-NMR spectrum of the product of isomerization of 14 shows

prominent and well resolved signals corresponding to two doublets

between d 5.16–5.25 (CH₂), resulting from resonances of the two

vinyl protons at one extreme of the double bond (cis and trans).

These protons are coupled with the vinyl proton at the other

extreme of the double bond, which corresponds to a doublet

of doublets at 6.23–6.30 (CH) (Table 2 and Fig. 3S, ESI†).

This pattern is clearly in agreement with the predicted spectra

for compound 15, resulting from a [3,3¢]-shift mechanism, and

no other signals that could correspond to compound 18 were

detected. Thus, compound 15 appears to be the sole product of

isomerization (¹H-NMR spectra, ESI†).

Analysis of the isomerization products by ¹H-NMR enables the

differentiation between putative [1,3¢]- and [3,3¢]-products through

analysis of the signals corresponding to resonances of protons of

the allylic system, since resonances for these protons are predicted

to be substantially different in inverted and non-inverted N-allyl

isomers.

1

Concerning the isomerization of ether 10, the predicted H-

NMR spectra for putative rearranged products reveal, for the

product of [1,3¢]-migration, compound 17, a characteristic signal

at d 4.06 (CH) for the allylic proton connected to the carbon

that is linked to the tetrazolone ring and another characteristic

signal at 5.37 (CH) for the sole vinyl proton (Table 1 and Fig. 2S,

ESI†). However, for the product of [3,3¢]-migration, compound

12, an overlapping signal is predicted for the two vinyl protons, at

d 5.59 (CH). The experimental ¹H-NMR spectrum of the product

1

In conclusion, analysis of the H-NMR spectra of the com-

pounds obtained shows that tetrazolones 12 and 15 are the

6042 | Org. Biomol. Chem., 2011, 9, 6040–6054

This journal is

The Royal Society of Chemistry 2011

©

View Article Online

Table 1 Experimental ¹H-NMR chemical shifts d (ppm) of protons of the allylic system corresponding to the rearranged product of ether 10 (tetrazolone

12), and predicted signals for putative [1,3]- and [3,3]-migration products (tetrazolones 17 and 12)^a,b

Experimental d (ppm)

(multiplicity; integration)

Predicted d (ppm) for [1,3¢]

(multiplicity; integration) (17)

Predicted d (ppm) for [3,3¢]

(multiplicity; integration) (12)

Atom Number

H4

H9

CH

5.97–6.04 (m,2)^c

4.06 (m,1)

5.37 (d,1)

5.59 (m,2)^c

^aExperimental data (¹H-NMR spectrum) is included as supplementary material. ^bPredicted ¹H-NMR shifts were acquired using the ChemDraw software.

^cIntegration with value 2 due to overlapping of signals for H4 and H9, as predicted for the [3,3]-migration products.

Table 2 Experimental ¹H-NMR chemical shifts d (ppm) of vinyl protons for the rearranged product of ether 14 (tetrazolone 15) and predicted signals

for putative products resulting from [1,3]- and [3,3]-migration (compounds 18 and 15)^a,b

Experimental d (ppm)

(multiplicity; integration)

Predicted d (ppm) for [1,3¢]

(multiplicity; integration) (18)

Predicted d (ppm) for [3,3¢]

(multiplicity; integration) (15)

Atom Number

H4

H5

CH₂

CH

5.16–5.25 (m,2)

6.23–6.30 (m,1)

3.83 (d,2)

5.33 (t,1)

5.22/5.19 (m,2)

5.83 (m,1)

^aExperimental data (¹H-NMR spectra) is included as supplementary material. ^bPredicted ¹H-NMR shifts acquired with ChemDraw software.

Fig. 4 Top: Structure of allyl tetrazolyl ether derived from the allylic

alcohol nerol: (E)-5-(3,7-dimethylocta-2,6-dienyloxy)-1-phenyl-1H-tetra-

zole (14). Middle: Structure of the rearrangement product

resulting from [3,3¢]-sigmatropic migration of the allylic system:

1-(3,7-dimethylocta-1,6-dien-3-yl)-4-phenyl-1H-tetrazol-5(4H)-one (15).

Fig. 3 Relative energies of the most stable stationary points for

the thermal isomerization of 5-(3-methylcyclohex-2-enyloxy)-1-phenyl-

1H-tetrazole (10) into 1-(cyclohex-2-enyl)-1-methyl-4-phenyltetrazol-5-one

Bottom: Structure of the rearrangement product resulting

(12) and 1-(3-Methylcyclohex-2-enyl)-4-phenyltetrazol-5-one (17)

from

[1,3¢]-sigmatropic

migration

of

the

allylic

system:

calculated at the DFT(B3LYP)/6-31G(d,p) (DE_G) and MP2/6-31G(d,p)

(DE_el) levels.

(E)-1-(3,7-dimethylocta-2,6-dienyl)-4-phenyl-1H -tetrazol-5(4H)-one

(18). Arrows, accompanied with letters A, B, C, show intramolecular

conformational degrees of freedom similar to the ethers derived from the

carbocyclic allylic alcohols 9 and 10. Carbon atoms of the side chain are

numbered, so that in all three systems (14, 15, 18) the same carbon atom

retains the same number.

sole products of thermal rearrangement and arise from [3,3¢]-

isomerization of ethers 10 and 14, respectively.

In order to gather further information on the observed selec-

tivity, the isomerizations were simulated theoretically by means of

extensive DFT(B3LYP)/6-31G(d,p) and MP2/6-31G(d,p) calcu-

lations performed on O-allyl and N-allyl isomers and on putative

transition state structures. Two possibilities were explored: [1,3¢]-

and [3,3¢]-sigmatropic migrations of the allylic system. The results

obtained are presented and discussed below, and clearly conﬁrm

This journal is

The Royal Society of Chemistry 2011

Org. Biomol. Chem., 2011, 9, 6040–6054 | 6043

©

View Article Online

Table 3 Conformationally relevant geometric parameters and relative energies of conformers of 5-(3-methylcyclohex-2-enyloxy)-1-phenyl-1H-tetrazole

10 [in brief: Ether 10 (R)] and corresponding isomeric 1-(3-methylcyclohex-2-enyl)-4-phenyltetrazol-5-one 17 [in brief: Tetrazolone 17 (R)] and isomeric

1-(cyclohex-2-enyl)-1-methyl-4-phenyltetrazol-5-one 12 [in brief: Tetrazolone 12 (S)] calculated at the DFT(B3LYP)/6-31G(d,p) level of theory

Compound / Conformer

Dihedral angle/^◦

Relative energy/kJ mol^-1

No.

1

2

3

4

5

6

7

8

Ether 10 (R)

A

B

C

D

DE_el

DE_ZPE

0.00

0.06

0.12

0.28

1.23

1.67

2.45

2.96

11.45

11.86

15.91

17.01

DE_G

0.00

0.82

0.03

0.51

2.14

0.20

3.15

3.56

13.17

12.46

16.33

17.26

Ph⁺TTG^-

Ph⁺TG^-G^-

Ph^-TTG^-

28.3

23.7

-27.6

-19.1

-23.8

22.0

27.0

-26.4

28.7

-28.1

29.3

-28.5

176.7

178.3

-175.6

-176.6

178.5

177.2

-178.2

170.1

177.9

159.4

172.2

-158.1

-83.0

-162.3

-82.0

-80.8

-81.1

-155.2

-158.2

68.7

-58.8

-59.6

-59.3

-59.1

60.6

60.8

0.00

-0.28

0.13

0.15

1.12

1.74

2.30

2.83

11.31

11.97

16.08

17.21

Ph^-TG^-G^-

Ph^-TG^-G⁺

Ph⁺TG^-G⁺

Ph⁺TTG⁺

Ph^-TTG⁺

Ph⁺TG⁺G⁺

Ph^-TG⁺G⁺

Ph⁺TG⁺G^-

Ph^-TG⁺G^-

9

10

11

12

65.9

79.9

73.8

-53.1

-52.4

No.

1

2

3

4

Tetrazolone 17 (R)

A

C

3.1

10.6

179.1

-170.2

D

DE_el

DE_ZPE

DE_G

CG⁺

CG^-

TG⁺

TG^-

-0.5

0.0

3.8

0.1

60.6

-59.0

60.9

-57.4

-68.58

-67.67

-65.06

-62.56

-67.16

-66.03

-63.62

-60.75

-66.80

-65.93

-62.47

-59.03

No.

1

2

3

4

5

6

Tetrazolone 12 (S)

A

C

61.4

-177.9

-176.5

61.7

-59.9

-78.6

D

DE_el

DE_ZPE

DE_G

G⁺G⁺

TG⁺

-0.5

-1.8

2.3

1.0

-1.7

-0.7

61.0

59.0

-61.5

-60.1

-59.9

58.5

-49.46

-48.57

-46.13

-45.90

-45.06

-41.10

-48.16

-47.21

-44.70

-44.64

-43.85

-40.31

-44.67

-43.67

-41.46

-41.61

-40.40

-38.59

TG^-

G⁺G^-

G^-G^-

G^-G⁺

Distance/pm

OC(1)

276.3

271.4

245.9

No.

1

2

3

4

TS type

OC(3)

339.0

404.9

343.3

341.2

NC(1)

275.0

270.1

338.9

335.0

NC(3)

399.1

335.1

242.7

240.9

DE_el

DE_ZPE

133.22

131.97

98.12

DE_G

1,3¢-shift

3,3¢-shift

144.65

143.44

106.21

98.93

131.05

129.76

103.00

93.75

239.8

90.58

Deﬁnition of the geometric parameters (see also Fig. 1 for the graphical representation). Compound “Ether 10” (R-enantiomer): A is deﬁned as CCNC

dihedral angle; B is deﬁned as N–COC dihedral angle; C is deﬁned as COC(1)C(6); D is deﬁned as C(1)C(6)C(5)C(4). Compound “Tetrazolone 17”

resulting from 1,3¢-shift (R-enantiomer): A is deﬁned as CCNC dihedral angle; dihedral angle “B” (analogous of ether) is not applicable; C is deﬁned

as C–NC(1)H dihedral angle; D is deﬁned as C(1)C(6)C(5)C(4) dihedral angle. Compound “Tetrazolone 12” resulting from 3,3¢-shift (S-enantiomer): A

is deﬁned as CCNC dihedral angle; dihedral angle “B” (analogous of ether) is not applicable; C is deﬁned as C–NC(1)C(6) dihedral angle; D is deﬁned

as C(1)C(6)C(5)C(4) dihedral angle. “TS” stands for transition state. Numbering of the carbon atoms corresponds to that of the starting compound.

Nitrogen atom is N(5) of the ether. All relative energies are calculated with respect to Ph⁺TTG^-conformer (No. 1) of Ether 10. DE_el, DE_ZPE, DE_Gstate

for the relative electronic, zero-point-corrected and Gibbs free energy (at 298.15 K), respectively. The absolute values calculated for Ph⁺TTG^-at the

DFT(B3LYP)/6-31G(d,p) level are: E_el= -837.319052; E_ZPE= -837.031930, E_G= -837.077882 hartree.

that the [3,3¢]-shift is kinetically favoured over the [1,3¢]-shift for

the three allylic ethers of tetrazole investigated.

and the phenyl ring (dihedral angle B). For this dihedral, only the

starting trans orientation was considered since only in this case the

allylic fragment is aligned properly for intramolecular migration;

(iii) relative orientation of the cyclohex-2-enol and tetrazole rings

(dihedral angle C). It is important to note that the carbon atom

C(1) is chiral. In the present study all calculations were carried out

for the R-enantiomer of the starting compound; (iv) conformation

of the cyclohex-2-enol ring (dihedral angle D).

The calculated energetic and geometric parameters of the

equilibrium structures are collected in Tables 1S (DFT) and 2S

(MP2), ESI,† for compounds 9 and 16 (X = H) and in Tables

3 (DFT) and 4 (MP2) for compounds 10 and 17 (X = CH₃).

As mentioned in the introduction, allyl tetrazolyl ethers may

undergo thermal isomerization to the corresponding tetrazolones.

Such isomerizations were simulated theoretically in the present

2.2. Isomerization of 5-(cyclohex-2-enyloxy)-1-phenyl-1H-tetra-

zole (9) and 5-(3-methylcyclohex-2-enyloxy)-1-phenyl-1H-tetra-

zole (10)

2.2.1. Molecular geometry. Fig. 1 shows the structure of

allyl tetrazolyl ethers derived from the carbocyclic allylic alcohols

cyclohex-2-enol (7, X = H) and 3-methylcyclohex-2-enol (8, X =

CH₃). The starting compounds (ethers 9 and 10) have four

intramolecular rotational degrees of freedom (designated in Fig. 1

by arrows) that may result in different conformers. These include:

(i) relative orientation of the phenyl and tetrazolyl rings (dihedral

angle A); (ii) relative orientation of the allylic ether substituent

6044 | Org. Biomol. Chem., 2011, 9, 6040–6054

This journal is

The Royal Society of Chemistry 2011

©

View Article Online

Table 4 Conformationally relevant geometric parameters and relative energies of conformers of 5-(3-methylcyclohex-2-enyloxy)-1-phenyl-1H-tetrazole

10 [in brief: Ether 10 (R)] and corresponding isomeric 1-(3-methylcyclohex-2-enyl)-4-phenyltetrazol-5-one 17 [in brief: Tetrazolone 17 (R)] and isomeric

1-(cyclohex-2-enyl)-1-methyl-4-phenyltetrazol-5-one 12 [in brief: Tetrazolone 12 (S)] calculated at the MP2/6-31G(d,p) level of theory

Compound / Conformer

Dihedral angle/^◦

Relative Energy/kJ mol^-1

No.

1

2

3

4

5

6

7

8

Ether 10 (R)

A

B

C

D

DE_el

0.00

0.03

1.15

1.58

4.69

4.85

5.07

5.16

10.57

10.61

11.40

16.99

Ph^-TTG^-

-34.9

36.4

33.3

-33.8

-34.4

35.4

34.6

-34.9

38.6

36.6

-37.0

-40.4

-172.8

-179.2

174.9

-176.8

-176.7

177.9

176.2

-177.4

89.7

-168.9

-165.3

-78.9

-79.8

-78.1

-161.5

-76.8

-163.2

105.8

72.0

-62.2

-61.8

-62.4

-62.2

63.3

63.5

63.3

63.5

-59.6

62.8

Ph⁺TTG^-

Ph⁺TG^-G^-

Ph^-TG^-G^-

Ph^-TG^-G⁺

Ph⁺TTG⁺

Ph⁺TG^-G⁺

Ph^-TTG⁺

9

Ph⁺A⁺G⁺G^-

Ph⁺TG⁺G⁺

Ph^-TG⁺G⁺

Ph^-A⁺G⁺G^-

10

11

12

165.6

175.8

131.4

68.4

102.7

62.9

-57.9

No.

1

2

3

4

5

6

7

8

Tetrazolone 17 (R)

Ph⁺CG^-

A

C

27.2

28.2

9.1

D

DE_el

22.0

-22.1

22.7

-23.0

23.6

-23.4

25.5

-25.4

-62.3

-62.4

63.3

63.4

-60.3

-67.29

-67.28

-64.92

-63.11

-62.99

-62.58

-62.41

Ph^-CG^-

Ph⁺CG⁺

Ph^-CG⁺

10.0

Ph⁺TG⁺

179.9

-179.8

-163.1

-162.8

Ph^-TG⁺

Ph⁺TG^-

Ph^-TG^-

No.

1

2

3

4

5

6

7

8

Tetrazolone 12 (S)

Ph⁺G⁺G⁺

Ph^-G⁺G⁺

Ph⁺TG⁺

A

C

61.5

61.8

-175.2

-175.3

-176.9

-177.0

60.5

D

64.4

62.5

DE_el

24.5

-24.1

24.6

-23.7

-24.4

24.8

24.6

-23.9

-24.0

23.9

-26.5

25.3

-64.73

-64.68

-63.43

-63.28

-58.90

-58.88

-58.56

-58.52

-57.78

-57.62

-56.22

-56.05

Ph^-TG⁺

62.5

Ph^-TG^-

-64.1

-62.5

-62.4

-62.3

62.3

Ph⁺TG^-

Ph⁺G⁺G^-

Ph^-G⁺G^-

Ph^-G^-G^-

Ph⁺G^-G^-

Ph^-G^-G⁺

Ph⁺G^-G⁺

60.7

9

-60.8

-61.0

-84.5

-85.1

10

11

12

62.4

Distance/pm

No.

1

2

3

4

TS type

OC(1)

266.7

267.0

210.6

220.9

OC(3)

284.7

416.6

317.8

324.7

NC(1)

285.9

316.6

321.0

327.2

NC(3)

368.8

303.1

218.2

223.5

DE_el

1,3¢-shift

3,3¢-shift

188.21

169.24

117.96

109.31

For the deﬁnition of the geometric parameters see caption of Table 3 and also Fig. 1 for the graphical representation. All relative electronic energies

(DE_el, in kJ mol^-1) are calculated with respect to Ph^-TTG^-conformer (No. 1) of Ether 10. The absolute value calculated for Ph^-TTG^-conformer at the

MP2/6-31G(d,p) level is E_el= -834.810723 hartree.

study. Two possibilities were explored: [1,3¢]- and [3,3¢]-sigmatropic

migrations of the allylic system. The products resulting from such

migrations (tetrazolones 11, 12, 16 and 17) are shown in Fig. 1

(along with ethers) and their parameters are included in Tables

3, 4, 1S and 2S, ESI,† also. In the course of theoretical studies,

it was found that the [1,3¢]-sigmatropic shift does not change the

stereochemistry of the chiral carbon atom C(1). However, during

the [3,3¢]-sigmatropic shift, the stereochemistry around the C(1)

carbon atom of the tetrazolone product changes from R to S.

The X group (X = H or X = CH₃) remains the lowest-priority

substituent around the C(1) atom in the course of the [3,3¢]-shift,

while the heteroatom (O in ether; N in tetrazolone) remains the

highest priority substituent. The change of chirality is related

to the switch of positions of the second (–CH C) and third

(–CH₂–C) priority groups around C(1). The additional difference

between the [1,3¢]- and [3,3¢]-shift is the nature of the lowest-

priority substituent around the C(1) atom. In the case of [1,3¢]-

shift, it is always H. In the case of [3,3¢]-shift, it is the X functional

group. If X = H, the molecule resulting from the [3,3¢]-sigmatropic

shift is the mirror image of the molecule produced in the [1,3¢]-

sigmatropic shift. If X = CH₃, the two sigmatropic shifts, [1,3¢] and

[3,3¢], produce two distinct isomers.

Due to the difference in chirality, the two tetrazolones resulting

from [1,3¢]- and [3,3¢]-sigmatropic shift are named, for brevity, in

Tables 3, 4, 1S and 2S, ESI,† as tetrazolone (R) and tetrazolone (S),

respectively. However, it should be noted here that this difference

This journal is

The Royal Society of Chemistry 2011

Org. Biomol. Chem., 2011, 9, 6040–6054 | 6045

©

View Article Online

in chirality is not the only difference between them. The most

important difference is the change in the position of the substituent

X relatively to the tetrazolone ring.

higher relative energies, exceeding the T and G^-conformers by

more than 10 (DFT) or 5 (MP2) kJ mol^-1.

Upon the [1,3¢]-sigmatropic shift, the dihedral angle C in the

tetrazolone product corresponds to the rotation around the newly

formed N–C(1) bond. Unlike for the case of the ether, only two

minima were found per 360^◦rotation in the tetrazolone, being

grouped around the cis and trans orientation of the CNCH

dihedral angle. All the cis conformers around the dihedral angle C

are systematically more stable than the trans conformers in these

products. For the methylated compound 12, resulting from the

[3,3¢]-sigmatropic shift, substitution of H by CH₃at C(1) changes

remarkably the energy proﬁle for the rotation around N–C(1)

bond: for one 360^◦turn, compound 11 has only two minima,

while the methylated compound 12 exhibits three minima. For

the tetrazolone of S-chirality, the corresponding optimized values

(both DFT and MP2) of the CO_◦C(1)C(6) _◦dihedral angle form_◦two

dense groups, trans (from -175 to -178 ) and G⁺(from 60 to

62^◦), as well as one loose group around G^-orientation (from -60^◦

to -85^◦).

Now that all the conformationally important degrees of freedom

have been brieﬂy introduced, it is important to comment on

the consistent patterns and on the exceptions. In the starting

compounds 9 and 10, at all levels of theory, there is a group

of four conformers that have relative energies of 10 or more kJ

mol^-1, compared to the most stable form. All these conformers

have one common geometric parameter: the dihedral angle C

[or more precisely, COC(1)C(6)] adopts a G⁺orientation. This

is equivalent to saying that the dihedral angle COC(1)C(2) should

adopt a cis orientation. Such an orientation results in a crowded

geometry which brings the cyclohex-2-enol and tetrazole rings

into a very close vicinity. These crowded geometries become

even more strained when the cyclohex-2-enol units assume a

G^-conformation. In order to compensate for such unfavourable

orientation, the internal twist of the cyclohex-2-enol ring (dihedral

angle D) reduces to about -53^◦(while the strain-free value is ca.

-59^◦). At the DFT level of theory, such geometric changes of

the Ph( )TG⁺G^-conformers (No. 11 and 12, Tables 3 and 1S,

ESI†) are accompanied by an additional destabilization of 5 kJ

mol^-1compared to the Ph( )TG⁺G⁺conformers (No. 9 and 10).

Additionally, dihedral angle B (normally “trans”) strongly deviates

from the geometry characteristic of the unstrained conformers,

reaching in the crowded conformers distorted values down to 160^◦

(see Tables 3 and 1S, ESI†).

Comparative analysis of Tables 3, 4, 1S and 2S, ESI,† shows

some interesting trends. First of them is the relative orientation

of the phenyl ring with respect to the ring to which it is attached

(tetrazole (ether) or tetrazolone), i.e. values of dihedral angle A.

The exchange of the substituent X (H or CH₃) does not have

inﬂuence on this parameter. However, the theory levels and the

nature of the tetrazolic ring do have inﬂuence. In the ether, the

phenyl ring is not co-planar with the tetrazole ring. The calculated

inter-ring angles lie in a narrow interval equal to 26 4^◦(DFT)

or 36 3^◦(MP2). In tetrazolones, calculations at the DFT level

predict the two rings to be essentially co-planar, while the MP2

calculations show a well-deﬁned deviation from co-planarity: 24

2^◦. In the latter case, the inter-ring angle is deﬁnitely not cis, since

it has two non-equivalent orientations, but still this dihedral is not

large enough to be designated as gauche. Therefore, we adopted,

in the names of conformers in Tables 3, 4, 1S and 2S, ESI,† a non-

traditional designation Ph⁺or Ph^-, which unequivocally describes

the orientation of the dihedral angle A. Variations from Ph⁺to

Ph^-(if the dihedral angle A is different from cis), produce pairs of

conformers of approximately equal energy, i.e. the conformational

preference is deﬁned by other conformational degrees of freedom.

It is important to note here that the MP2 calculated values of

dihedral angle A always show a higher degree of non-co-planarity

comparing to the calculations of the same structures at the DFT

level. This is due to the fact that MP2 calculations better describe

the non-covalent interactions (between the tetrazole and phenyl

rings) existing in the studied molecules.

Dihedral angle B occurs only in the two ether (starting)

compounds (9 and 10). As it was mentioned, the initial value of this

dihedral angle selected for optimizations was chosen around the

trans orientation, which permits the occurrence of the sigmatropic

shifts. Upon optimizations, most of conformers retained the trans

orientation for the dihedral angle B and stayed around 179 5^◦

(DFT) or 180 5^◦(MP2). A few exceptions will be discussed

below.

A very regular pattern of values was also found for dihedral

angle D, describing the conformation of the partially saturated

cyclohex-2-enol ring. With two possible directions of the internal

rotation, dihedral angle D assumed in all conformers only two

values, G⁺and G^-. For both ether derivatives and for the

tetrazolones, the calculated absolute values of the dihedral angle

D were found to fall in a very narrow range and amount to 60

1^◦(DFT) and 63 1^◦(MP2). A very high reproducibility of the

numeric values of the dihedral angle D indicates the rigidity of the

cyclohex-2-enol ring. In a few conformers, larger deviations from

these values were found. These cases will be commented on below

as well.

The MP2 calculations “deal with the situation” in a slightly

different way. Instead of the distortion of the dihedral angle D

(i.e. forcing twist of the rigid cyclohex-2-enol ring), a stronger

deviation of dihedral angle B from the trans orientation has

occurred during the optimization of geometries. Such deviation

reached the dihedral angles B as low as 90^◦(see Tables 4 and

2S, ESI†, conformers Ph⁺A⁺G⁺G^-, “A” stands for “anticlinal”).

This geometry change not only avoids the crowded orientation of

the two rings, but also apparently creates a stabilizing interaction

between them. Such stabilization is even capable of compensating

partially for the distortion of the dihedral angle B: the relative

energy of the corresponding conformers decreases from 16.3 kJ

mol^-1(DFT level, Ph⁺TG⁺G^-form, No. 11, Table 3) to 10.6 kJ

mol^-1(MP2 level, Ph⁺A⁺G⁺G^-form, No 9, Table 4).

Dihedral angle C is the most ﬂexible conformational degree of

freedom. In the ether compounds, three groups of minima per

360^◦rotation of the cyclohex-2-enol fragment around the O–C(1)

bond were found. In the ethers of R-chirality, the corresponding

optimized values of the COC(1)C(6) dihedral ang_◦le densely group

around the trans (-159 4^◦, DFT and -165 4 , MP2) and G^-

(-82 2^◦, DFT and -78 2^◦, MP2) conformations, while they

are loosely scattered around the G⁺orientation (72 8^◦, DFT and

87 20^◦, MP2). Note that G⁺conformers consistently have much

Now let us discuss the calculated energies in more detail.

Unfortunately, the vibrational characterization of the entire set

6046 | Org. Biomol. Chem., 2011, 9, 6040–6054

This journal is

The Royal Society of Chemistry 2011

©

View Article Online

of the optimized structures at the MP2 level is beyond practical

limitations. For a few selected optimized structures, the vibra-

tional MP2 calculations were carried out numerically. This was

extremely time-consuming but conﬁrmed the expected nature of

the optimized stationary points. Under these circumstances, the

DFT vibrational calculations (Tables 3 and 1S, ESI†) provide some

useful information. Comparison of DE_elwith DE_ZPEand with DE_G

shows that accounting for the zero-point vibrational energy, as

well as accounting for the thermochemistry at room temperature

does not signiﬁcantly change the position of conformers on the

relative energy scale: the most stable forms remain most stable,

the order of stability is mostly preserved, the differences in relative

energies do not exceed a few kJ mol^-1upon moving from DE_elto

DE_ZPEand to DE_G. This is true for all studied compounds. We

extrapolated this trend to the MP2 calculations, assuming that the

order of the calculated electronic energies should describe, fairly

enough, the stabilities of the studied compounds under standard

conditions (at 298.15 K).

17 “R”). However, the MP2 calculations carried out for the same

compounds (see Table 4), show only a marginal difference (ca.

2.6 kJ mol^-1) between the two products, i.e. they can be considered

essentially isoenergetic (Fig. 3). Therefore, the control over the

outcome of the isomerization reaction should be kinetic and the

expected product should be that corresponding to the [3,3¢]-shift,

compound 12. As discussed above, the experimental data are

in agreement with this conclusion, showing that the tetrazolone

adopts the structure consistent with the [3,3¢]-shift mechanism

(¹H-NMR spectra, ESI†).

2.3. Isomerization of (E)-5-(3,7-dimethylocta-2,6-dienyloxy)-1-

phenyl-1H-tetrazole (14)

2.3.1. Molecular geometry. Fig. 4 shows the structure of

tetrazolyl ether (14) derived from the allylic alcohol nerol. Ether

14 is not chiral and has eight intramolecular rotational degrees

of freedom. Three of them (A, B, C, designated in Fig. 4 by

arrows) are similar to ethers 9 and 10. The remaining ﬁve dihedral

angles correspond to the internal rotations of the carbon atom

side-chain (around the C(1)–C(2), C(2) C(3), C(3)–C(4), C(4)–

C(5), C(5)–C(6) bonds). The products of the intramolecular shifts,

tetrazolones 15 and 18, are also shown in Fig. 4. In product 15

of the [3,3¢]-shift, carbon atom C(3) becomes chiral, while no

chirality is acquired in product 18 of the [1,3¢]-shift. The resulting

tetrazolones have six (15) and seven (18) conformational degrees

of freedom.

The large ﬂexibility of species 14, 15 and 18 may result in

over a hundred possible conformers which makes the complete

characterization of their conformational space impractical. De-

spite the large number of intramolecular degrees of freedom,

several trends were revealed in the course of optimizations. These

trends helped to localize the set of most stable conformers.

The calculated energetic and geometric parameters for the most

relevant equilibrium structures of ether (E)-5-(3,7-dimethylocta-

2,6-dienyloxy)-1-phenyl-1H-tetrazole (14) and of its isomerization

products, tetrazolones 15 [1-(3,7-dimethylocta-1,6-dien-3-yl)-4-

phenyl-1H-tetrazol-5(4H)-one] and 18 [(E)-1-(3,7-dimethylocta-

2,6-dienyl)-4-phenyl-1H-tetrazol-5(4H)-one], are collected in Ta-

bles 3S (DFT) and 4S (MP2), ESI.†

For dihedral angle A, describing the relative orientation of the

phenyl and tetrazole rings, the trends for compounds 14, 15, 18

were found to be the same as for 9, 10, 11, 12, 16 and 17. The

absolute value of the inter-ring angle in ether 14 amounts to ca.

25 2^◦(DFT) or 34 2^◦(MP2). In tetrazolones 15 and 18, the

DFT method predicts the two rings to be co-planar, while the MP2

calculations result in the twist of 23 2^◦. For dihedral angle B, as

in the case of ethers 9 and 10, out of the two possibilities (cis and

trans), only the starting trans orientation was considered in ether

14. Only in this case is the allylic fragment aligned properly for

intramolecular migration.

For the allylic fragments, the atoms directly linked to the car-

bons forming the C C double bonds are located approximately

in one plane. There are two such groups in compounds 14 and 18:

one group is composed by carbon atoms 1, 2, 3, 4, 9 and the other

group consists of atoms 5, 6, 7, 8, 10 (Fig. 4). Moreover, in the most

stable conformers found, the planes formed by these two groups

of atoms tend to be parallel to each other. The orientation of the

bonds O–C(1) (14) or N–C(1) (18) and C(4)–C(5) (14 and 18) is

2.2.2. Mechanism of isomerization. In all calculations, the

relative zero level of energy was chosen to be the energy of the

most stable ether conformer. The calculated relative energies for

the sigmatropic shifts are shown in the last section of each of the

Tables (3, 4, 1S and 2S, ESI†) and in Fig. 2 and 3 (energy proﬁles

for isomerizations) for derivatives 9 and 10. The structures of

transition states are most important in this study, as they dictate

the barriers to the two different isomerization pathways. The

optimized Cartesian coordinates of all the transition states found

in this study are collected in the ESI,† along with their calculated

electronic energies and net dipole moments. It should be noted as

well that, for each of the studied isomerizations, two alternative

parallel pathways were found.§ The energies and dipole moments

of these parallel transition states are qualitatively similar.

The calculations show that the [1,3¢]-sigmatropic shifts are

energetically more demanding as compared with the [3,3¢]-shifts.

At the DFT level of theory, the transition states for the [1,3¢]-

shifts are above 148 kJ mol^-1(X = H, TS1a) or 130 kJ mol^-1

(X = CH₃, TS2a), while at the MP2 level these values increase

up to at least 209 and 169 kJ mol^-1respectively. The calculated

barriers for the [3,3¢]-shifts were found to be much lower: 103

and 94 kJ mol^-1(DFT); 121 and 109 kJ mol^-1(MP2) (see TS1b

and TS2b in Fig. 2 and 3). This means that kinetically the [3,3¢]-

shifts should dominate over the [1,3¢]-shifts. According to all

calculations, tetrazolones formed in the processes of sigmatropic

shifts are far more stable than the starting ethers. For the [1,3¢]-

shifts, in ethers 9 and 10, the gain in stability constitutes about

67–68 kJ mol^-1(for the most stable tetrazolone conformer), both

at the DFT and MP2 levels. For the [3,3¢]-shifts and X = H, the ﬁnal

tetrazolone product (11) is identical with that of the [1,3¢]-shifts,

so the process of isomerization should occur via the [3,3¢]-shift,

since it requires much lower activation energy (see Fig. 2). For

the methylated compound (10, X = CH₃), the structure of the

tetrazolone formed (12 or 17) is unique to the mechanism. The

DFT calculations (see Table 3) predict the product of the [3,3¢]-

shift (tetrazolone 12 “S”) to be higher in energy by as much as 22 kJ

mol^-1as compared to the product of the [1,3¢]-shift (tetrazolone

§ The conformational ﬂexibility of the migrating fragment in the nerol

derivative may increase this number.

This journal is

The Royal Society of Chemistry 2011

Org. Biomol. Chem., 2011, 9, 6040–6054 | 6047

©

View Article Online

not parallel to the above-mentioned “ﬁve-atom-planes” and the

intramolecular rotations around these bonds represent the main

conformational variable.

At the DFT level (Table 3S, ESI†), ether 14 adopts many

conformational structures that are very close in energy to each

other: at least 18 structures fall into a 0–5 kJ mol^-1energy interval.

It is interesting to note that correction for the calculated Gibbs

free energies (at 298.15 K) retains these 18 structures in the same

energy gap. However, the order of their relative energy changes: it

is sensitive to the presence of a large number of the low-frequency

vibrational modes that contribute most to the thermal corrections.

Regarding the equilibrium geometries of these 18 structures, the

nerol residue assumes an extended conformation with the two

5-atom mini-planes being essentially co-planar. The entire nerol

residue then adopts a multitude of different orientations with

respect to the tetrazole ring, depending on the values of dihedral

angle C, which assumes all of the T, G⁺and G^-positions.

The calculated DFT energies of the product of [3,3¢]-shift,

tetrazolone 15, show a stabilization in energy by about 44 kJ

mol^-1, with respect to ether 14, comparing the two most stable

respective conformers. For the product of [1,3¢]-shift, tetrazolone

18, the DFT-calculated stabilization is much more pronounced

and amounts to about 79 kJ mol^-1. In all cases, the most

stable conformations of 15 and 18 correspond to a distended

conﬁguration of the nerol residue, which is oriented approximately

perpendicularly to (“away from”) the tetrazolone ring. The

theoretical ﬁnding obtained on the basis of the DFT calculations

(Table 3S, ESI†), should imply that the isomerization of ether 14,

if thermochemically controlled, should proceed via the [1,3¢]-shift

mechanism, which contradicts the experimental ﬁnding showing

that the resulting product is formed via the [3,3¢]-shift. The

theoretical explanation of this discrepancy represented one of the

main challenges of this study and could be successfully solved with

recourse to ab initio calculations.

The ab initio calculations were carried out at the MP2/6-

31G(d,p) level of theory. The geometry optimizations were

started from the equilibrium geometries obtained previously at

the DFT(B3LYP)/6-31G(d,p) level. Adopting such an approach,

optimization of a single structure at the MP2/6-31G(d,p) level

took between 2 and 10 days of the processor time which is about

one order of magnitude higher than was required to complete

the DFT calculations. The MP2 calculations took several months

overall. The conformationally relevant dihedral angles, for the

MP2 optimized geometries, of compounds 14, 18 and 15 are

presented in Table 4S, ESI.† Anticipating the discussion of the

equilibrium MP2 geometries, it should be stated here that the

main result of the MP2 calculations is in agreement with the

experimental observation: tetrazolone 15 resulting from the [3,3¢]-

shift was predicted energetically more stable than tetrazolone 18

resulting from the [1,3¢]-shift!

Fig. 5 Equilibrium geometries of the most stable structures of tetrazolone

15 (product of the [3,3¢]-shift) resulting from the optimizations at the DFT

and MP2 levels of theory. For reference, the orientation of the tetrazolone

moiety in the ﬁgure was kept the same.

moiety, as much as the anchor N atom allows it. The latter (MP2)

geometry suggests the importance of the p–p stacking interaction

in tetrazolones derived from nerol.

It is known that the SCF based methods, like DFT(B3LYP)

are unable to predict local minima on the potential energy

surfaces for p–p stacked systems.²⁷Only calculations at the MP2

theory level were successful in ﬁnding local minima for stacked

dimers of quinine–pyrimidine,²⁸uracil–thymine²⁹and other N-

heteroaromatic systems.³⁰In such calculations, the stabilization

energies of the stacking interaction ranged from 12 to 25 kJ

-1

˚

mol , while an equilibrium interplane distance of about 3.2 A

was found.³⁰

It is interesting to note that the most stable tetrazolone structure,

found at the MP2 level in this study, corresponds to product 15 of

the [3,3¢]-isomerization (tetrazolone 15, conformer 1, Table S4†).

In this conformer, the interatomic distances between the carbon

atom of the tetrazole ring C(T) and the two carbon atoms forming

˚

a double bond, C(6) and C(7), were found to be 2.99 and 3.49 A,

respectively. Such distances, as well as the pronounced stabilization

of tetrazolone 15, suggest existence of a p–p interaction in this

structure. Indeed, the natural bond orbital (NBO) analysis reveals

a strong overlap between the p-electron systems of tetrazole ring

and the terminal C C bond (see Fig. 6).

The most stable structures found at the MP2 level of theory

for compounds 14, 15 and 18 were used as the initial guess

geometries for the recurrent optimizations at the DFT level. The

most stable MP2 form of 15, after re-optimization at the DFT

level, distanced the side chain away from the tetrazole fragment.

The C(T)–C(6) and C(T)–C(7) distances increased to 3.23 and

The different order of the relative stabilities (with respect to ether

14) of tetrazolones 15 and 18 at the MP2 and DFT levels of theory

was achieved at the expense of the strikingly different equilibrium

geometries obtained with these two methods. Fig. 5 compares

the geometries of the most stable forms of the two tetrazolones.

In the DFT calculations the nerol residue adopts a distended

conformation, which is oriented approximately perpendicularly to

the plane of the tetrazole moiety. In the MP2 calculations, the nerol

residue tends to assume an orientation parallel to the tetrazole

˚

3.84 A, respectively. The relative change of geometry after such

6048 | Org. Biomol. Chem., 2011, 9, 6040–6054

This journal is The Royal Society of Chemistry 2011

©

View Article Online

the MP2 level, and to the distended structures at the DFT level of

optimization. The same situation was also found for ether 14 where

the two most stable respective geometries (DFT and MP2) do not

have even a slight geometrical resemblance (see Fig. 8). An even

more striking result was obtained when the most stable (in the MP2

energy scale) geometry of 14 was subjected to DFT optimization.

The resulting structure, while a local minimum, turned to be the

least stable among all DFT-optimized structures (Tables 3S and

4S, ESI†).

Fig. 6 Selected p-orbitals of the tetrazolone moiety and p-orbital of the

terminal C C bond of the nerol residue in the most stable conformer

of tetrazolone 15. Note co-planarity of the two p-electron systems and

substantial orbital overlap.

re-optimization was not very signiﬁcant: the TA⁺TG⁺A^-orienta-

tion of the conformationally sensitive dihedral angles remained

the same. However, in terms of the relative energy, the TA⁺TG⁺A^-

conformer moved from position 1 (MP2) up to position 5 (DFT).

The most stable DFT conformer changed to TA⁺T TA⁺which

corresponds to the unfolded nerol residue (see Fig. 5).

Similar trends were also found for tetrazolone 18 (see Fig. 7):

the most stable geometries correspond to the folded structures at

Fig. 8 Equilibrium geometries of the most stable structures of ether 14

resulting from optimizations at the DFT and MP2 levels of theory. For

reference, the orientation of the tetrazolone moiety in ﬁgure was kept the

same (viewed along the OC axis).

A question arises: “if the stabilization in tetrazolone 15 due

to the non-bonded interactions is important, could a similar

stabilization take place in 18?” In order to answer this question

it is interesting to analyze the topology of 15 and 18. In 15, the

side chain anchored to the nitrogen atom could be represented as

N–C–C–C–C C(CH₃)₂(omitting methyl and vinyl groups linked

to the carbon atom next to the nitrogen, which were not important

in this case). The terminal C C bond in 15 is placed topologically

at the ideal distance to make an intramolecular loop and establish

the p–p stacking interaction with the tetrazole moiety: C C is

separated from the nitrogen by three tetrahedral carbon atoms.

In 18, the side chain anchored to the nitrogen atom could be

represented as N–C–C C–C–C–C C(CH₃)₂. In 18, the carbon

chain is longer, but it is more rigid than in 15. The carbon

chain separating the terminal double bond C(6) C(7) from the

anchor nitrogen atom is by two carbon atoms longer, but has

only two tetrahedral carbon atoms: as it was discussed above, the

atoms adjacent to C(2) C(3) constitute a rigid mini-plane and

render lack of ﬂexibility in the nerol residue of 18. This imposes

restrictions on the spatial position of the remaining fragment.

Indeed, the reference distances C(T)–C(6) and C(T)–C(7) in the

Fig. 7 Equilibrium geometries of the second most stable structures of

tetrazolone 18 (product of the [1,3¢]-shift) resulting from the optimizations

at the DFT and MP2 levels of theory. For reference, the orientation of the

tetrazolone moiety in the ﬁgure was kept the same.

˚

second most stable conformer of 18 amount to 3.64 and 4.84 A,

This journal is

The Royal Society of Chemistry 2011

Org. Biomol. Chem., 2011, 9, 6040–6054 | 6049

©

View Article Online

clearly indicating the remoteness of the tetrazole from the C

C

2.3.2. Mechanism of isomerization. In all calculations, the

relative zero level of energy was chosen to be the energy of the

most stable ether conformer. The calculated relative energies for

the sigmatropic shifts in nerol derivative 14 are shown in the last

section of each of Tables 3S and 4S, ESI,† and in Fig. 11 (energy

proﬁles for isomerization). The calculations show that the [1,3¢]-

sigmatropic shift is energetically more demanding as compared

with the [3,3¢]-shift. At the DFT level of theory, the transition

state for the [1,3¢]-shift is above 134 kJ mol^-1(TS3a), while at

the MP2 level this value increases up to above 197 kJ mol^-1. As

observed for the sigmatropic migration of ethers 9 and 10, the

calculated barriers for the [3,3¢]-shifts were found to be much

lower: 101 kJ mol^-1(DFT) and 125 kJ mol^-1(MP2) (see TS3b

in Fig. 11). Therefore, the [3,3¢]-shift should dominate kinetically

over the [1,3¢]-shift, as observed for ethers 9 and 10.

bond. Under such circumstances, the stabilizing p–p stacking

interaction cannot be established. This is demonstrated in Fig.

9. To reinforce this conclusion, it should be stated that the most

stable conformer of 18 does not have the tetrazolone moiety and

nerol residue in a close proximity to each other. Instead there is a

“coiled” geometry having a relative proximity of C(2) C(3) and

C(6) C(7) bonds (Fig. 10), but the stabilizing interaction of these

p-systems is weaker, than that existing in 15.

Fig. 9 Selected p-orbitals of the tetrazolone moiety and p-orbital of

the terminal C C bond of the nerol residue in the second most stable

conformer of tetrazolone 18. Note the lack of co-planarity of the two

p-electron systems and the lack of orbital overlap.

Fig. 11 Relative energies of the most stable stationary points for

the thermal isomerization of (E)-5-(3,7-dimethylocta-2,6-dienyl-

oxy)-1-phenyl-1H-tetrazole (14) into 1-(3,7-dimethylocta-1,6-dien-

3-yl)-4-phenyl-1H-tetrazol-5(4H)-one (15) and (E)-1-(3,7-dimethylocta-

2,6-dienyl)-4-phenyl-1H-tetrazol-5(4H)-one (18) calculated at the

DFT(B3LYP)/6-31G(d,p) (DE_G) and MP2/6-31G(d,p) (DE_el) levels.

Fig. 10 Optimized MP2 geometry of the most stable conformer of

tetrazolone 18.

The above ﬁndings show clearly the importance of accounting

for the non-covalent interactions in the interpretation of the

conformational picture of the studied compounds. The DFT

calculations failed to ﬁnd minima for the structures predicted as

the most stable structures at the MP2 level. This also explains why

the full conformational search at the cheaper and faster theory

levels, as for example semi-empirical or DFT calculations, could

not be sufﬁcient to rationalize the observations of the present

study.

According to all calculations, tetrazolones formed in both

processes of sigmatropic shift are more stable than the starting

ether 14. For the [1,3¢]-shift, the gain in stability for the most stable

conformer of tetrazolone 18 is 79 kJ mol^-1, at the DFT level, but

only 63 kJ mol^-1at the MP2 level. For the [3,3¢]-shift, the most

stable conformer of the ﬁnal tetrazolone product (15) presents a

gain in stability of 44 kJ mol^-1, at the DFT level, and of 70 kJ mol^-1

at the MP2 level. Thus, the DFT calculations (see Table 3S, ESI†)

predict the product of the [3,3¢]-shift to be higher in energy by as

6050 | Org. Biomol. Chem., 2011, 9, 6040–6054

This journal is

The Royal Society of Chemistry 2011

©

View Article Online

Table 5 Selected structural data obtained from X-ray crystallographic analysis and molecular orbital calculations for 1-aryl-5-allyloxytetrazoles 9, 10,

14 and I and 1-aryl-4-allyltetrazol-5-ones (11, 12, and 15–18)

Structure

Bond distances/pm

Angles/^◦

Method

9

132.7 133.5

—

132.4 133.4

—

132.6 133.4

—

131.6

148.5 147.9

—

149.1 148.2

—

147.1 146.5

—

148.9

—

116.3 113.9

—

116.0 113.9

—

116.6 113.4

—

115.5

DFT MP2

X-ray

11

16

10

12

17

14

15

18

I

146.6 146.6

—

149.8 148.3

—

148.4 146.9

—

146.6 146.6

—

146.8 146.8

—

146.5 145.6

—

much as 35 kJ mol^-1as compared to the product of the [1,3¢]-shift

but the MP2 calculations carried out for the same compounds (see

Table 4S, ESI†), predict the [3,3¢]-shift to be lower in energy by

7 kJ mol^-1as compared to the product of the [1,3¢]-shift (Fig. 11).

As explained above, the DFT methods revealed to be inadequate

for this system, due to their incapacity for accounting for the

stabilizing effect of non-covalent interactions such as p–p stacking

between the heteroaromatic tetrazolyl system and the overlapping

terminal double bond of the N-terpenyl substituent in compound

15. On the contrary, the results obtained by MP2 methods are in

keeping with the experimental data, predicting that the control

over the outcome of the isomerization reaction of 14 is both

kinetic (lower barriers) and thermodynamic (lower energies of

the products) and that the expected product should be that

corresponding to the [3,3¢]-shift, compound 15. The experimental

data are in agreement with this conclusion, showing that the

tetrazolone adopts the structure consistent with the [3,3¢]-shift

mechanism (¹H-NMR spectra, ESI†).

to 117^◦, which is very close to the value experimentally obtained

for ether I in the condensed phase (116^◦) and implies a signiﬁcant

degree of sp²character on oxygen. Thus, in the ground state, the

structures of ethers 9, 10, and 14 are already advanced along the

reaction coordinate for isomerisation, thus explaining the ease of

isomerisation in these ethers.

C–N bond lengths c, in tetrazolones 11, 12, and 15, range from

147 to 150 pm, the difference reﬂecting the relative bulkiness of the

substituents connected to carbon. For tetrazolones 16–18, bond

lengths d for the less crowded C–N bonds are around 147 pm.

The values for bond lengths c and d are unexceptional, indicating

that the electron-withdrawing power of the tetrazole is much less

effective towards the allyl group attached to nitrogen than it is

when the group is attached to oxygen. This is in keeping with

what has been observed from the X-ray structure of N-myrtenyl

benzisothiazole (saccharin).²²

3. Conclusions

The electron-withdrawing effect of the heteroaromatic system

on the ground state structures of some allylic derivatives of

tetrazole has been discussed and related to observed reactivity.²²

Table 5 shows selected geometric parameters for the most stable

conformers of ethers 9, 10, and 14 and tetrazolones 11, 12,

and 15–18, obtained from theoretical calculations (DFT and

MP2). For comparative purposes, the corresponding parameters

for 5-cinnamyloxy-1-phenyl tetrazole (I) obtained by X-Ray

crystallography, are also included. For ethers 9, 10, and 14, the

calculated length for C–O bond a is around 133 pm, and for C–O

bond b is around 148 pm. These theoretical values are very close

to those experimentally obtained for the cinnamyloxy derivative

I (132 pm for bond a and 149 pm for bond b). Thus, due to the

electron-withdrawing effect of the tetrazole ring, bond a exhibits

a considerable degree of double bond character whereas bond b is

longer, and weaker, than a common C–O bond in an aliphatic ether

(typically 143 pm). Also, the C–O–C bond angles range from 113

Mechanisms of thermal isomerization of allyl tetrazolyl ethers

derived from the carbocyclic allylic alcohols cyclohex-2-enol and

3-methylcyclohex-2-enol and from the natural terpene alcohol

nerol were investigated. These 1-aryl-5-allyloxytetrazoles undergo

rapid isomerization to the corresponding 1-aryl-4-allyltetrazol-5-

ones and the results of our investigation showed that the imidates

rearrange exclusively through a [3,3¢]-sigmatropic migration of

the allylic system from O to N, with inversion. Mechanistic

proposals are based on the product analysis and extensive

quantum chemical calculations at the DFT(B3LYP) and MP2

levels, on O-allyl and N-allyl isomers and on putative transition

state structures for [1,3¢]- and [3,3¢]-sigmatropic migrations. The

experimental observations could be only explained on the basis

of the MP2/6-31G(d,p) calculations that favoured the [3,3¢]-

sigmatropic migrations, yielding lower energies both for the

transition states and for the ﬁnal isomerization products. DFT

This journal is

The Royal Society of Chemistry 2011

Org. Biomol. Chem., 2011, 9, 6040–6054 | 6051

©

View Article Online

methods proved to be inadequate for these compounds, due

to their poor performance on predicting and accounting for

non-covalent interactions. In fact, the stabilizing effect of p–p

stacking interactions established between the tetrazolyl system

and the double bond of the allylic substituent appears to be

instrumental in dictating the reaction pathway, accounting for the

exclusive formation of the [3,3¢]-isomer. The observed selectivity in

the synthesis of allyl tetrazolones is of great interest because these

compounds may be used as starting materials in the preparation

of other heterocycles, namely pyrimidinones.

–CH₂–), 4.88–4.91 (1H, m, CH–N), 5.71–5.74 (1H, d, –CH ),

6.08–6.10 (1H, m CH–), 7.39–7.42 (1H, t, ArH), 7.50–7.54 (2H,

t, ArH), 7.87–7.89 (2H, d, ArH); ¹³C NMR (100 MHz, CDCl₃):

d_C20.14, 24.78, 28.70, 52.03, 77.14, 77.45, 77.77, 119.71, 124.31,

127.98, 129.73, 133.45, 135.19; MS (EI), m/z 243 [M+H]⁺.

4.2.3. 5-(3-Methylcyclohex-2-enyloxy)-1-phenyl-1H-tetrazole

(10). The synthesis of tetrazolyl ether 10 was attempted using

several sets of experimental conditions. However, the desired ether

could never be recovered. Instead, the product of its isomerization,

4-allyltetrazol-5-one (12) was isolated in all cases. A general

procedure for the synthesis of this compound is described.

4. Experimental section

4.2.4. 4-(3-Methylcyclohex-2-enyl)-1-phenyl-1H-tetrazol-5-

(4H)-one (12). 3-Methyl-cyclohex-2-enol (0.62 g; 5.54 mmol) in

dry THF (30 mL) was added to slurry of sodium hydride (55%

in mineral oil; 0.32 g; 7.4 mmol) in dry THF (5 mL). When

effervescence of hydrogen had ceased (20 min), 5-chloro-1-phenyl-

1H-tetrazole (1.0 g; 5.54 mmol) in dry THF (10 mL) was added

and the mixture was stirred at ª10 ^◦C for 4 h until analysis

by TLC (AcOEt/hexane 1 : 1) indicated the absence of starting

material. The solvent was removed under reduced pressure at RT

to give a residue. This residue was extracted with ethyl acetate

(3 ¥ 50 mL) and the organic extract was washed with ice water

(3 ¥ 50 mL). The organic extract was dried (Na₂SO₄) and the

ﬁltrate evaporated to dryness to give the 4-(3-methylcyclohex-2-

enyl)-1-phenyl-1H-tetrazol-5(4H)-one as light yellow oil (1.1 g;

71% yield). IR n_max: 2927, 1721, 1596, 1504, 1460, 1367, 1095, 904

4.1. Equipment and experimental conditions

All chemicals were used as purchased from Aldrich. Solvents for

extraction and chromatography were of technical grade. When

required, solvents were freshly distilled from appropriate drying

agents before use. Analytical TLC was performed with Merck

silica gel 60 F₂₅₄plates. Melting points were recorded on a Stuart

Scientiﬁc SMP3 melting point apparatus and are uncorrected.

Mass spectra were obtained on a VG 7070E mass spectrometer

by electron ionization (EI) or chemical ionization (CI, NH₃) at

70 eV. NMR (400 MHz) spectra were obtained on a Bruker

AM-400 spectrometer using TMS as the internal reference (d =

0.0 ppm). Elemental analyses were performed on an EA1108-

Elemental Analyzer (Carlo Erba Instruments). Infrared spectra

were obtained on a Bruker FTIR-TENSOR 27 spectrometer.

1

cm^-1; H NMR (400 MHz, CD₃OD): d 1.69 (3H, s, CH₃), 1.79–

1.86 (4H, m, –CH₂CH₂–), 2.09–2.11 (2H, m, CH₂), 5.97–6.03 (2H,

m, CH CH), 7.38–7.42 (1H, t, ArH), 7.50–7,54 (2H, t, ArH),

7.85–7.87 (2H, d, ArH); ¹³C NMR (100 MHz, CD₃OD): d_C18.34,

24.21, 25.29, 32.78, 60.16, 119.63, 127.59, 128.15, 129.05, 130.50,

134.59, 148.71; MS (EI), m/z 257 [M]⁺.

4.2. Synthesis of 5-allyloxytetrazoles and 4-allyltetrazol-4-ones

4.2.1. 5-(Cyclohex-2-enyloxy)-1-phenyl-1H-tetrazole

(9).

Cyclohex-2-enol (1.36 g; 13.9 mmol) in dry THF (30 mL) was

added to a slurry of sodium hydride (55% in mineral oil; 0.65 g;

14.9 mmol) in dry THF (5 mL). When effervescence of hydrogen

had ceased (30 min), 5-chloro-1-phenyl-1H-tetrazole (2.5 g;

13.9 mmol) in dry THF (20 mL) was added and the ﬁnal mixture

was stirred at room temperature for 3 h, when TLC analysis

(EtOAc/hexane 1 : 1) indicated the absence of starting material.

The solvent was removed under reduced pressure at RT to give a

residue. This residue was extracted with ethyl acetate (3 ¥ 50 mL)

and the organic extract was washed with ice water (3 ¥ 50 mL).

The organic phase was dried (Na₂SO₄) and the ﬁltrate evaporated

to dryness to give colourless oil. Recrystallization with ethanol

gave the 5-(cyclohex-2-enyloxy)-1-phenyl-1H-tetrazole as white

crystals (2.1 g; 61% yield), mp 60–62 ^◦C. IR n_max: 2927, 1591, 1549,

1504, 1457, 910 cm^-1; ¹H NMR (400 MHz, CD₃OD): d 1.66–1.83

(2H, m, –CH₂–), 2.04–2.18 (4H, m, –CH₂–), 5.47–5.48 (1H, m,

CH–O-), 5.98,6.00 (1H, d, –CH ), 6.09–6.13 (1H, m, CH–),

7.47–7.51 (1H, t, ArH), 7.54–7.58 (2H, t, ArH), 7.70–7.72 (2H,

d, ArH); ¹³C NMR (100 MHz, CD₃OD): d_C18.06, 24.64, 27.87,

78.52, 121.85, 123.44, 128.98, 129.44, 133.47, 134.91, 159.85 MS

(EI), m/z 242 [M]⁺.

4.2.5. (E)-5-(3,7-Dimethylocta-2,6-dienyloxy)-1-phenyl-1H-

tetrazole (14). The synthesis of tetrazolyl ether 14 was attempted

using several sets of experimental conditions. However, due to

an easy and fast isomerisation of ether 14 only a mixture of this

ether and its N-allyl isomer 15 could be characterized. ¹H-NMR

signals are easily distinguishable by their integration ratio. The

signal chosen for the integration ratio of these two compounds

was at 7.70–7.72 (two protons from ether 14). The integral value

0.4 was assigned as one hydrogen is present in the N-allyl isomer. A

general procedure for the synthesis of this compound is described.

(E)-3,7-Dimethylocta-2,6-dien-1-ol (Nerol; 2.15 g; 13.9 mmol)

in dry THF (20 mL) was added to a slurry of sodium hydride

(60% in mineral oil; 0.60 g; 14.6 mmol) in dry THF (20 mL).

When effervescence of hydrogen had ceased (30 min.), 5-chloro-1-

phenyl-1H-tetrazole (2.5 g; 13.9 mmol) in dry THF (20 mL) was

added and the reaction was stirred at ª10 ^◦C for 12 h. The reaction

was monitored by TLC using a mixture of toluene/acetone (5 : 1)

as eluent. The solvent was removed under reduced pressure at RT

to give a residue. This residue was extracted with ethyl acetate (3 ¥

50 mL) and the organic extract was washed with ice water (3 ¥

50 mL). The organic phase was dried (Na₂SO₄) and evaporated

to dryness to give a yellow solid. Recrystallization with ethanol

gave the required product as white crystals (1.0 g; 24% yield), mp

43–45 ^◦C. IR n_max: 2967, 2912, 2858, 1592, 1570, 1506, 1460, 1443,

939; ¹H NMR (400 MHz, CD₃OD): d 1.56 (3H, s, CH₃), 1.60 (3H,

4.2.2. 4-(Cyclohex-2-enyl)-1-phenyl-1H-tetrazol-5(4H)-one

(11). A neat sample of 5-(cyclohex-2-enyloxy)-1-phenyl-1H-

tetrazole (1.0 g; 4,1 mmol) was heated at 40 ^◦C for 2 h to give

1-(cyclohex-2-enyl)-4-phenyl-1H-tetrazol-5(4H)-one as yellow oil

(quantitative yield). IR n_max: 2927, 1724, 1595, 1552, 1504, 1459,

1

904 cm^-1; H NMR (400 MHz, CD₃OD): d 1.71–2.23 (6H, m,

6052 | Org. Biomol. Chem., 2011, 9, 6040–6054

This journal is

The Royal Society of Chemistry 2011

©

View Article Online

s, CH₃), 1.81 (3H, s, CH₃), 2.09–214 (2H, q, CH₂), 2.21–2.25 (2H,

t, CH₂), 5.09,5.10 (3H, d, CH–, CH₂), 5.58–5.61 (1H, t, CH–),

7.48–7.52 (1H, m, ArH), 7.55-7.58 (2H, t, ArH), 7.70,7.72 (2H, d,

ArH);

Acknowledgements

The authors acknowledge Fundac¸a˜o para a Cieˆncia e Tecnologia

(FCT) and FEDER [Project PTDC/QUI/67674/2006 and grants

BD/17945/2004 and BPD/43853/2008], for ﬁnancial support.

4.2.6. 1-(3,7-Dimethylocta-1,6-dien-3-yl)-4-phenyl-1H-tetra-

zol-5(4H)-one (15). The solution remaining from the recrystal-

lization of ether 14 was evaporated under reduced pressure, to

afford the required product as yellow oil (1.6 g, 36% yield).

A neat sample of (E)-5-(3,7-dimethylocta-2,6-dienyloxy)-1-

References

1 S. C. S. Bugalho, E. M. S. Mac¸oˆas, M. L. S. Cristiano and R. Fausto,

Phys. Chem. Chem. Phys., 2001, 3, 3541.

2 T. Mavromoustakos, A. Kolocouris, M. Zervou, P. Roumelioti, J.

Matsoukas and R. Weisemann, J. Med. Chem., 1999, 42, 1714.

3 J. H. Toney, P. M. D. Fitzgerald, N. Grover-Sharma, S. H. Olson, W.

J. May, J. G. Sundelof, D. E. Vanderwall, K. A. Cleary, S. K. Grant, J.

K. Wu, J. W. Kozarich, D. L. Pompliano and G. G. Hammond, Chem.

Biol., 1998, 5, 185.

4 Y. Hashimoto, R. Ohashi, Y. Kurosawa, K. Minami, H. Kaji, K.

Hayashida, H. Narita and S. Murata, J. Cardiovasc. Pharmacol., 1998,

31, 568.

◦

phenyl-1H-tetrazole (0.8 g; 2.7 mmol) was heated at 40 C for 1

h to give 1-(cyclohex-2-enyl)-4-phenyl-1H-tetrazol-5(4H)-one as

yellow oil (quantitative yield). IR n_max: 1725, 1598, 1560, 1502,

1376, 757 cm^-1; ¹H NMR (400 MHz, CDCl₃): d 1.54 (3H, s, CH₃),

1.57 (3H, s, CH₃), 1.77 (3H, s, CH₃), 1.98–2.37 (4H, m, –CH₂CH₂–

), 5.01–5.07 (1H, t, CH–), 5.16–5.25 (2H, m, CH₂), 623–6.30

(1H, m, CH–), 7.36–7.40 (1H, t, ArH), 7.48–7.52 (2H, t, ArH),

7.85,7.87 (2H, d, ArH); ¹³C NMR (100 MHz, CD₃OD): d_C16.37,

21.69, 22.19, 24.54, 36.97, 64.95, 113.63, 119.38, 122.75, 127.53,

129.03, 131.75, 134.55, 139.51, 148.76;MS (EI), m/z 299 [M+H]⁺;

Anal. Calcd for C₁₇H₂₂N₄O: C, 68.43; H, 7.43; N, 18.78%. Found:

C, 68.22; H, 7.75; N, 18.30%.

5 A. Desarro, D. Ammendola, M. Zappala, S. Grasso and G. B. Desarro,

Antimicrob. Agents Chemother., 1995, 39, 232.

6 A. D. Abell and G. J. Foulds, J. Chem. Soc., Perkin Trans. 1, 1997, 2475.

7 Y. Tamura, F. Watanabe, T. Nakatani, K. Yasui, M. Fuji, T.

Komurasaki, H. Tsuzuki, R. Maekawa, T. Yoshioka, K. Kawada, K.

Sugita and M. Ohtani, J. Med. Chem., 1998, 41, 640.

8 G. Sandmann, C. Schneider and P. Boger, Z. Naturforsch. C, 1996, 51,

534.

9 G. I. Koldobskii, V. A. Ostrovskii and V. S. Poplavskii, Khim.

Geterotsikl. Soedin., 1981, 10, 1299.

4.3. Computational details

10 R. A. Abramovitch, C. I. Azogu, I. T. McMaster and D. P. Vanderpool,

J. Org. Chem., 1978, 43, 1218.

11 L. M. T. Frija, R. Fausto, R. M. S. Loureiro and M. L. S. Cristiano, J.

Mol. Catal. A: Chem., 2009, 305, 142.

12 L. M. T. Frija, I. V. Khmelinskii and M. L. S. Cristiano, Tetrahedron

Lett., 2005, 46, 6757.

13 L. M. T. Frija, I. V. Khmelinskii and M. L. S. Cristiano, J. Org. Chem.,

2006, 71, 3583.

14 L. M. T. Frija, I. V. Khmelinskii, C. Serpa, I. D. Reva, R. Fausto and

M. L. S. Cristiano, Org. Biomol. Chem., 2008, 6, 1046.

15 L. M. T. Frija, A. Ismael and M. L. S. Cristiano, Molecules, 2010, 15,

3757.

For all considered systems, all the calculations were carried out

using the Gaussian 03 program package.³¹At the DFT(B3LYP)

level of theory^32,33with the standard 6-31G(d,p) basis set,³⁴the

geometries of the investigated molecules were fully optimized

and the harmonic vibrational frequencies were calculated. The

nature of the obtained stationary points was checked through

the analysis of the corresponding Hessian matrices. Absence of

imaginary frequencies indicated that they correspond to true

minima. This also enabled the determination of thermodynamic

quantities such as zero-point-corrected vibrational energy and

free energy at 298.15 K. All relevant barriers to intramolecular

rearrangements were calculated using either the QST2 or QST3

variety of the synchronous transit-guided quasi-Newton (STQN)

method.^35,36All transition states were characterized as ﬁrst-order

saddle points by the presence of one imaginary frequency, as

revealed by analysis of the corresponding Hessian matrices and

visualization of the corresponding vibrational mode graphically.

Natural bond orbital (NBO) analysis was performed using NBO

3, as implemented in Gaussian 03.

The full geometry optimizations were also carried out at the

MP2 level of theory^37–39with the same 6-31G(d,p) basis set as used

in the DFT calculations. The large size of the studied molecules

did not allow analytical calculation of the MP2 vibrational

frequencies, due to the limitations of the 32-bit version of Gaussian

03 for Windows. Their characterization as minima or saddle

points was concluded on the basis of geometrical resemblance

with the similar structures obtained at the DFT level of theory

and also based on the absence of the lower-energy structures

after applying optimization with the “tight” criteria and without

symmetry restriction. For a few most important geometries (the

most stable conformers of 10, 12, 17, TS2a and TS2b), the

vibrational MP2 characterization was carried out numerically,

at a very high computational cost, and conﬁrmed the general

conclusions.

16 R. A. W. Johnstone, A. H. Wilby and I. D. Entwistle, Chem. Rev., 1985,

85, 129.

17 M. L. S. Cristiano, R. A. W. Johnstone and P. J. Price, J. Chem. Soc.,

Perkin Trans. 1, 1996, 1453.

18 N. C. P. Arau´jo, A. F. Brigas, M. L. S. Cristiano, L. M. T. Frija, E. M.

O. Guimara˜es and R. M. S. Loureiro, J. Mol. Catal. A: Chem., 2004,

215, 113.

19 L. M. T. Frija, M. L. S. Cristiano, E. M. O. Guimara˜es, N. C. Martins,

R. M. S. Loureiro and J. Bikley, J. Mol. Catal. A: Chem., 2005, 242,

241.

20 S. C. S. Bugalho, L. Lapinski, M. L. S. Cristiano, L. M. T. Frija and R.

Fausto, Vibrat. Spectrosc., 2002, 3541.

21 J. V. Barkley, M. L. S. Cristiano, R. A. W. Johnstone and R. M. S.

Loureiro, Acta Crystallogr., Sect. C: Cryst. Struct. Commun., 1997, 53,

383.

22 N. C. P. Arau´jo, P. M. M. Barroca, J. F. Bickley, A. F. Brigas, M. L. S.

Cristiano, R. A. W. Johnstone, R. M. S. Loureiro and P. C. A. Pena, J.

Chem. Soc., Perkin Trans. 1, 2002, 1213.

23 M. L. S. Cristiano, A. F. Brigas, R. A. W. Johnstone, R. M. S. Loureiro

and P. C. A. Pena, J. Chem. Res. (S), 1999, 704.

24 A. Go´mez-Zavaglia, A. Kaczor, R. Almeida, M. L. S. Cristiano, M. E.

S. Euse´bio, T. M. R. Maria, P. Mobili and R. Fausto, J. Phys. Chem.

A, 2009, 113, 3517.

25 M. L. S. Cristiano and R. A. W. Johnstone, J. Chem. Soc., Perkin Trans.

2, 1997, 489.

26 M. L. S. Cristiano and R. A. W. Johnstone, J. Chem. Res. (S), 1997,

164.

27 I. Da˛bkowska, P. Jurecˇka and P. Hobza, J. Chem. Phys., 2005, 122,

204322.

28 W. McCarthy, A. M. Plokhotnichenko, E. D. Radchenko, J. Smets, D.

M. A. Smith, S. G. Stepanian and L. Adamowicz, J. Phys. Chem. A,

1997, 101, 7208.

This journal is

The Royal Society of Chemistry 2011

Org. Biomol. Chem., 2011, 9, 6040–6054 | 6053

©

View Article Online

29 J. Gu, J. Wang, J. Leszczynski, Y. Xie and H. F. Schaefer III, Chem.

Phys. Lett., 2008, 459, 164.

30 Brijesh Kumar Mishra, J. Samuel Arey and N. Sathyamurthy, J. Phys.

Chem. A, 2010, 114, 9606.

Clifford, J. Cioslowski, B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz,

I. Komaromi, R. L. Martin, D. J. Fox, T. Keith, M. A. Al-Laham, C. Y.

Peng, A. Nanayakkara, M. Challacombe, P. M. W. Gill, B. G. Johnson,

W. Chen, M. W. Wong, C. Gonzalez and J. A. Pople, GAUSSIAN 03

(Revision C.02), Gaussian, Inc., Wallingford, CT, 2004.

32 A. D. Becke, Phys. Rev. A: At., Mol., Opt. Phys., 1988, 38, 3098.

33 C. T. Lee, W. T. Yang and R. G. Parr, Phys. Rev. B, 1988, 37, 785.

34 M. Frisch, M. Head-Gordon and J. Pople, Chem. Phys. Lett., 1990,

166, 281.

35 C. Peng, C. Y. Peng, P. Y. Ayala, H. B. Schlegel and M. J. Frisch, J.

Comput. Chem., 1996, 17, 49.

36 C. Peng and H. B. Schlegel, Isr. J. Chem., 1994, 33, 449.

37 H. Basch and W. J. Stevens, Chem. Phys. Lett., 1990, 169, 275.

38 L. F. Pacios, Chem. Phys. Lett., 1990, 169, 281.

31 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb,

J. R. Cheeseman, J. A. Montgomery, Jr., T. Vreven, K. N. Kudin, J. C.

Burant, J. M. Millam, S. S. Iyengar, J. Tomasi, V. Barone, B. Mennucci,

M. Cossi, G. Scalmani, N. Rega, G. A. Petersson, H. Nakatsuji, M.

Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T.

Nakajima, Y. Honda, O. Kitao, H. Nakai, M. Klene, X. Li, J. E.

Knox, H. P. Hratchian, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo,

R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi,

C. Pomelli, J. Ochterski, P. Y. Ayala, K. Morokuma, G. A. Voth, P.

Salvador, J. J. Dannenberg, V. G. Zakrzewski, S. Dapprich, A. D.

Daniels, M. C. Strain, O. Farkas, D. K. Malick, A. D. Rabuck, K.

Raghavachari, J. B. Foresman, J. V. Ortiz, Q. Cui, A. G. Baboul, S.

39 M. Head-Gordon and T. Head-Gordon, Chem. Phys. Lett., 1994, 220,

122.

6054 | Org. Biomol. Chem., 2011, 9, 6040–6054

This journal is

The Royal Society of Chemistry 2011

©

Article Doi

Sigmatropic rearrangements in 5-allyloxytetrazoles

DOI: 10.1039/c1ob05460k

Source and publish data:

Authors:

Article abstract of DOI:10.1039/c1ob05460k

Full text of DOI:10.1039/c1ob05460k

Products guided by the article

R&D Labs maybe for 1330067-99-6

Relevant to this article

Hot Product