&quot;Shadow&quot; Synthesis, Structure, and Electronic Properties of [2.2](1,6)(1,8)Pyrenophane-1-monoene

Article

“

Shadow” Synthesis, Structure, and Electronic Properties of

2.2](1,6)(1,8)Pyrenophane-1-monoene

Kiran Sagar Unikela, Zahra A. Tabasi, Louise N. Dawe, Yuming Zhao, and Graham J. Bodwell*

Cite This: J. Org. Chem. 2021, 86, 4405 −4412

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sı Supporting Information

ABSTRACT: An unexpected side product of a McMurry reaction

was found to be a new [2.2]pyrenophane consisting of two pyrene

units with diﬀerent substitution patterns as well as diﬀerent types

and degrees of distortion from planarity. The new pyrenophane

exhibits both monomer and intramolecular excimer ﬂuorescence.

Natural bond orbital (NBO) analysis revealed that there is an

intramolecular charge-transfer interaction from the more distorted

pyrene system to the less distorted one. The origin of the new

pyrenophane was traced back to an impurity that was present a full

ﬁve steps prior to the McMurry reaction from which it was

isolated. The pathway to the pyrenophane shadowed that of the

main synthetic route.

INTRODUCTION

Organic reactions seldom aﬀord the desired product(s)

without the formation of byproducts or side products.

close to one another in a speciﬁc orientation. This enables the

study of how the two aromatic systems interact with one

another.

■

For any given pair of aromatic compounds, the relative

orientation of the two aromatic systems can be varied by

changing their respective bridging motifs. Starting with

benzene, only the (1,3) and (1,4) bridging motifs are possible,

which means that there are just three constitutionally isomeric

[2.2]benzenophanes, 1−3 (Chart 1). (The total of three

excludes ortho substituted benzene rings. The inclusion of

Consequently, the separation of the various reaction products

is normally required and it is often the most time-consuming

part of completing a reaction. Isolating and identifying side

products requires eﬀort, but it can provide valuable

information about the chemistry at hand and this, in turn,

can be used to identify superior reaction conditions, to

underpin the development of new reactions or even to spark

the pursuit of new research directions.

There are three main sources of side products in an organic

reaction: the starting material, the product, and impurities in

the starting material. With regard to the starting material, side

products originate from unanticipated competing reaction

pathways. “Follow-on” side products can form if the intended

product is reactive under the conditions of its formation.

Finally, the presence of one or more impurities in the starting

material can result in the formation of side products that, on

ﬁrst inspection, are very surprising. The formation of side

products in this fashion is hardly remarkable, but it is quite

uncommon for an impurity to be carried through several steps

of a synthetic sequence, while not only undergoing appropriate

reactions at every step but also evading separation and/or

detection. Rarer still is when such a “shadow” synthesis delivers

a compound that is interesting in its own right. We report here

the isolation of a product of such a synthesis, a new

ortho substituted benzene rings brings the total to six. ) As

the arenes become larger, more bridging motifs become

available and this translates into more ways of orienting the

two arenes with respect to one another.

In the case of pyrene, which is of broad interest due to its

applications in ﬂuorescent molecules/materials and ﬂuores-

cence-based sensing, there are 12 possible bridging motifs,

which means that there are 78 possible constitutionally

isomeric [2.2]pyrenophanes. (For an arene with n available

bridging motifs, the number of possible combinations in a

[2.2]cyclophane is described by the triangular number T_n,

which is the sum of the integers from 1 to n.) In fact, only ﬁve

of them have been realized: (1,3)(1,3), (1,6)(1,6), (1,6)(2,7),

(

1,8)(1,8), and (2,7)(2,7). From three of the systems that

Received: October 29, 2020

Published: March 3, 2021

[2.2]pyrenophane.

The [2.2]cyclophanes, which consist of two aromatic

systems and two 2-carbon bridges, are one of the most

populous classes of cyclophanes. They have attracted broad

attention because the two aromatic systems are normally held

2021 American Chemical Society

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Article

Chart 1. Some Benzene and Pyrene-Based

Scheme 1. Compounds Isolated from the Intramolecular

McMurry Reaction of [10.2]Pyrenophanedialdehyde 7

[2.2]Cyclophanes (1−6) with Diﬀerent Bridging Motifs

have been synthesized (4−6), it has been learned that excimer

formation (a very important characteristic of pyrene, upon

which much of its sensing behavior is based) is sensitive to

how the two pyrene systems are oriented with respect to one

another. The best planes of the two pyrene units in these

systems are more or less parallel, but twisted to varying

amounts with respect to an orthogonal axis. The 0° twist in

pyrenophane 4 appears to be best for excimer emission. This

compound exhibits a strong emission band centered at 540

nm. Pyrenophane 5, which has a 35° twist, also exhibits

excimer emission, but it is weaker and at higher energy (500

nm). Moving to pyrenophane 6 (60° twist), the emission is

again more intense, but is now observed at 440−450 nm,

which is typical of monomer emission. Although the

pyrenophanes 4−6 have revealed how the relative positioning

of two pyrene systems can have a strong inﬂuence on the

emission behavior, a deeper understanding of this phenomen-

on will require access to more than just three compounds.

Dihydroteropyrenophane 11 arises from closure of the central

C−C bond in 8 under the conditions of its formation, and

teropyrenophane 12 is the product of dehydrogenation of 11.

The formation of both of these follow-on side products is

noteworthy in that they did not occur for the lower

homologues in the series (where the long bridge is 7−9

atoms in length) and that formal oxidation reactions

(dehydrogenations) took place under reductive conditions.

Identiﬁcation of the ﬁnal side product was less straightfor-

ward. APCI(+)-LC-MS analysis showed a strong peak at m/z =

455, which corresponds to [M + H]⁺of a [2.2]pyreno-

phanemonoene (C H ) without a long bridge. The absence

RESULTS AND DISCUSSION

We recently reported the synthesis of 1,1,10,10-tetramethyl-

10](2,11)teropyrenophane (12) as part of a study aimed at

■

[

the development of a general gram-scale synthesis of the

,1,n,n-tetramethyl[n](2,11)teropyrenophanes. One of the

key C−C bond-forming steps was the intramolecular McMurry

reaction of [10.2](7,1)pyrenophanedialdehyde 7 to aﬀord

triply bridged [10.2.2](7,1,3)pyrenophane 8 (Scheme 1). In

contrast to the analogous reactions of the next three lower

homologues, the reaction of dialdehyde 7 gave a cluster of

products with very similar R values. The desired pyrenophane

of high-ﬁeld aliphatic signals in the H and C NMR spectra

was isolated in pure form only after extensive chromatog-

supported this conclusion. In the C NMR spectrum, 34

signals in the range δ 119−136 ppm were observed, which is

consistent with the presence of two pyrene systems with

diﬀerent substitution patterns (2 × 16C) and an alkene (2C).

The aliphatic region showed just two signals for a saturated 2C

(ethano) bridge. This ruled out dealkylation of 8. Dealkylation

of 10 was also ruled out by the absence of any ABC spin

raphy (at least 15 columns) to separate it from ﬁve closely

eluting side products. (The large-scale synthesis of teropyr-

enophane 12, which was the most problematic one of the

series, was performed on only one occasion.) Interestingly,

the set of side products exempliﬁes the diﬀerent ways in which

side products can arise. Dimethylpyrenophane 9 comes from a

competing reaction pathway (reduction of the formyl groups in

systems in the aromatic region of the H NMR spectrum,

instead of reductive coupling). Cyclophane-monoene 10 is

which spanned a very broad chemical shift range (δ 8.3−4.6)

the product of an intramolecular McMurry reaction of a

(see below). Further analysis of the H NMR spectrum

regioisomer of 7, which must have been present as an impurity.

pointed toward (1,6) and (1,8) substitution patterns for the

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is discussed in detail below.

Article

two pyrene systems, which left [2.2](1,6)(1.8)pyrenophane-1-

monoene 13 as the only possible structure (Supporting

Information). COSY and NOESY experiments were then

used to assign most of the protons, which were very close to

calculated values (GIAO/B3LYP/6-311+G(2d,p) level of

theory, Supporting Information). The structure was then

unambiguously determined using X-ray single crystal diﬀrac-

tion (XRD) analysis (Figure 1). The origin of this side product

have opposite conﬁgurations (Figure S3), and close supra-

molecular C−H···π interactions between neighboring mole-

cules lead to a chain-like arrangement (Figures S5, S6 ) with H-

to-centroid distances ranging from 2.74 to 3.04 Å (Table S1).

The degree of twist can be quantiﬁed by examining the

dihedral angles along the benzylic-to-benzylic pathway through

the center of the pyrene system (Table S2). Increasing

deviation of these angles from 180° is a reﬂection of increasing

twist in the pyrene system. For 13, the dihedral angles along

the [C20, C21, C34, C35, C36, C27, C28, C1] pathway are

−

153.0°, 159.0°, −158.9°, 159.7°, and −150.7°. The deviation

from 180° ranges from 20.3° to 29.3°, and the average value is

3.8°. By comparison, the deviation from 180° in [10](1,6)-

pyrenophane (14) spans a range of 9.5° to 20.1° and has an

average value of 14.1°. In 15, the range is 5.9° to 20.0° and the

average is 10.8°. Alternatively, two twisted naphthalene units

(

rings AB and rings CD) can be identiﬁed within the 1,6-

distubstituted pyrene system and their twist angles can be

considered. The twist angles for the AB and CD naphthalene

systems are 16.9° and 18.2°, respectively. Thus, the degree of

twist is signiﬁcant. The naphthalene twist angles for 14 and 15

were not reported, but have now been determined using the

original data to be substantially lower than those in 13 (9.7°

and 9.5° for 14; 7.5° and 4.3° for 15). On the other hand, the

values for 13 are well short of those observed in more highly

Figure 1. Two views of pyrenophane 13 from the crystal structure,

represented with 50% probability ellipsoids. Crystallographic

numbering is shown. CCDC 2034879.

In the crystal, the 1,8-disubstituted ring of 13 is bent out of

strained systems such as 1,7-dioxa[7](2,7)pyrenophane (16,

planarity, but only marginally (Figure 1). The bend angle θ

7°) and [2](6,1)naphthaleno[1]paracyclophane (17,

(

the smallest angle formed between the planes deﬁned by

5.1°) both of which required powerful aromatization-

atoms [C3, C4, C16] and atoms [C11, C12, C13]) is just 9.7°.

This value is substantially smaller than that of the pyrene unit

in 1,12-dioxa[12](2,7)pyrenophane (θ = 34.6°), which

houses the least bent pyrene system of any reported

based methods for their synthesis.

The slipped stacking arrangement of the two pyrene systems

in 13 means that one edge of each of the pyrene systems lies

over the face of the other (Figure 1, right). Consequently,

[

n](2,7)pyrenophane. More substantial distortion from

these protons are observed at unusually high ﬁeld in the H

planarity is present in the 1,6-disubstituted pyrene system. In

this case, the (1,6) bridging motif causes a longitudinal twist

and a diagonal bend. The diagonal bend can be quantiﬁed

using an angle analogous to θ. Like θ, each plane is deﬁned by

a set of three atoms, which includes the bridgehead carbon

atom and the two ﬂanking atoms in the pyrene system to

which it is bonded. To diﬀerentiate these angles, they can be

referred to as θ₂_,₇and θ . Thus, the angle θ in 13 is the

NMR spectrum (Figure 2 ). The highest ﬁeld signals are

1,6

smallest angle formed between the planes containing atoms

C21, C22, C34] and atoms [C27, C28, C29] and its value is

4.0°. This is substantially larger than the corresponding values

[

in [10](1,6)pyrenophane (14) (27.3°) and the more

elaborate (1,6)pyrenophane 15 (17.4°) (Chart 2).

Pyrenophane 13 is chiral by virtue of the (1,6) bridging

motif in one of the pyrene systems. The space group (C2/c) is

centrosymmetric. Adjacent molecules in the packed unit cell

Figure 2. Aromatic and aliphatic regions of the 300 MHz H NMR

spectrum of pyrenophane 13 in CDCl₃.

Chart 2. Comparison Compounds 14−17

observed for the protons attached to the K-region located

between the two bridgeheads of the 1,8-disubstituted pyrene

system, which appear as an AX system at δ 5.22 and 4.64 ppm

(

J = 9.5 Hz). The shielded edge of the 1,6-disubstituted pyrene

appears as an AX system at δ 7.03 and 6.17 ppm (J = 9.0 Hz)

for the K-region and another AB system δ 6.26 and 6.16 ppm

(

J = 7.7 Hz). The alkene protons are observed as an AB system

at δ 7.45 and 7.18 ppm with an unusually large coupling

constant for a Z-conﬁgured alkene (J = 13.2 Hz). This large

value may be related to some combination of the rather low

dihedral angles between the alkene and the two pyrene systems

A twisted naphthalene unit in each molecule is colored red.

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nm (Figure 3 ). According to TD-DFT calculations (Table S4),

Article

to which it is attached (deviation from 90° = 37.9°−49.0°), or

the very large C−CC bond angles of the alkene bridge

(

134.2° and 128.7°). Four signals are observed for the aliphatic

bridge protons, which indicates that there is no interconversion

between enantiomers via ring ﬂipping at room temperature.

Simple inspection of molecular models suggests that this would

be an exceedingly high energy process. The bridge proton H₁_b

(Figure 1, right) resonates at much lower ﬁeld (δ 4.32 ppm)

than the other three (H₁_aat δ 2.97 ppm, H₂_aat δ 3.12 ppm,

H₂_bat δ 3.18 ppm). The low ﬁeld shift is presumably due to

steric deshielding arising from its close contact (2.12(2) Å) to

the peri- proton C29(H) (NOE cross peak). The proton H₂_b

has a similar peri- contact to C15(H) (2.18(2) Å), but the

steric deshielding here appears to be counteracted by shielding

from the opposite pyrene system. Examination of the gauche

coupling constants within the aliphatic bridge (J(H −H ) =

.3 Hz, J (H −H ) = 2.3 Hz, J(H −H ) = 4.7 Hz,

Supporting Information ) suggests that the solution structure

of 13 is close to the crystal structure. In the crystal structure,

the C28−C1−C2−C3 dihedral angle (51.5°) reveals a small

deviation from perfect staggering, which means that the H −

Figure 4. (A) Contours (isovalue = 0.03 au) and eigenvalues (in eV)

of the frontier molecular orbitals for pyrenophane 13. TD-DFT

calculated absorption wavelengths are indicated. (B) TD-DFT

simulated UV−vis absorption spectrum of 13. (C) Molecular

electrostatic potential map of 13 with maximum and minimum

potential points (kcal/mol) indicated. All calculations performed at

the CAM-B3LYP/6-311+G(2d,p)//B3LYP/6-31G(d) level of theory.

C−C−H dihedral angle should be closer to 90° than the

other gauche relationships and J(H −H ) should therefore be

the smallest.

The absorption spectrum of 13 in chloroform shows a long-

wavelength absorption tail ranging from 390 to 550 nm, along

with three signiﬁcant absorption bands at 358, 343, and 278

long-wavelength UV−vis absorption tail and the ﬁrst emission

band in the ﬂuorescence spectrum suggests a small Stokes shift

and hence a high degree of structural similarity between the

ﬁrst excited state (S ) and the ground state (S ). This outcome

is consistent with the apparent structural rigidity of cyclophane

3. The long-wavelength emission band at 559 nm appears to

be broader and weaker than the ﬁrst emission band at 439 nm.

This band can be reasonably attributed to the characteristic

emission of the pyrene excimer. Since lowering the

−

−6

concentration of 13 (from 10 to 10 M) did not result in

signiﬁcant attenuation of this band, the pyrene excimer is likely

formed intramolecularly given the close distance and partial

ring overlap between the two pyrene units in the structure of

3. The relative ﬂuorescence quantum yield (Φ ) of 13 was

determined to be 4.4% in chloroform. It is possible that the

signiﬁcant intramolecular interactions between the two pyrene

units in 13 (see below) facilitate nonradiative decay, which in

turn result in a low degree of emission eﬃciency. The

excitation spectra monitored at 470 and 550 nm (Figure S10)

support the notion that both emission bands are intrinsic to

the molecule, but also point toward more complex behavior in

the excitation manifold. More detailed study of this behavior is

warranted.

The electrostatic potential map of 13 reveals that both of the

pyrene systems bear a greater accumulation of π-electron

density on the outer surface than on the inner surface (Figures

4C, S7). This is presumably due to electronic repulsions

between the inner surfaces of the two π systems where they are

held close to one another. The largest negative potential point

on the outer face of the 1,8-disubstituted pyrene unit has a

larger value (−17.2 kcal/mol) than that of the outer face of the

1,6-disubstituted pyrene unit (−16.8 kcal/mol). The two

pyrene systems also feature outer edges with larger positive

potentials than their inner edges, but it is now the 1,6-

disubstituted pyrene unit that has the greater largest positive

potential point (+18.9 kcal/mol vs +16.8 kcal/mol). The

combination of negatively charged outer surfaces and positively

Figure 3. UV−vis absorption (blue trace) and ﬂuorescence (red trace,

exc

= 345 nm) spectra of pyrenophane 13 measured in chloroform.

the low-energy absorption bands in the UV−vis spectrum of

3 are mainly due to the electronic transitions among the

frontier molecular orbitals of 13. The experimentally observed

long-wavelength absorption tail matches the calculated

HOMO to LUMO transition at 420 nm, while the intense

absorption bands at 358 and 343 nm in the UV−vis spectrum

agree well with the TD-DFT calculated HOMO−1 to LUMO

and HOMO to LUMO+1 transitions, respectively (Figure 4).

The ﬂuorescence spectrum of pyrenophane 13 shows two

emission bands at 439 and 559 nm. The ﬁrst emission band

(

439 nm) can be assigned as the S to S transition. Due to the

1 0

diﬃculty in determining the exact λ_m_a_xvalue for the long-

wavelength absorption tail in the UV−vis absorption spectrum,

the Stokes shift of 13 cannot be precisely calculated.

Nevertheless, the signiﬁcant spectral overlap between the

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identiﬁed (Figure 5 ). The total delocalization energy (E (2))

Article

charged outer edges likely promotes the prominent edge-to-

face interactions observed in the crystal structure (Figure S5).

Interestingly, in the crystal, the outer edges of each type of

pyrene unit interact only with outer surfaces of the same type,

i.e. (1,6) with (1,6), and (1,8) with (1,8).

Using NBO analysis, three distinct through-space inter-

actions between a π bonding orbital located on the more

distorted 1,6-disubstituted pyrene unit with a π* antibonding

orbital on the less distorted 1,8-disubstituted pyrene were

Figure 6. Dipole moments contributed from the entire molecule

green arrow), 1,6-disubstituted pyrene (yellow arrow), and 1,8-

(

disubstituted pyrene (red arrow). Left: viewed from the side, and

right: viewed from the top. Calculated at the M06-2X/Def2SVP//

B3LYP/6-31G(d) level of theory.

perpendicular to the nodal direction (2,7-positions). The

molecular dipole includes contributions from the two bridges

in addition to those from the two pyrene systems.

With regard to the origin of [2.2]pyrenophane 13, it can be

traced back to the synthesis of dipyren-2-ylalkane 20, which

was accomplished via a Friedel−Crafts alkylation reaction of

pyrene (18) using dichloride 19 (Scheme 2). The reaction was

performed using dichloride 19 and a 10-fold excess of pyrene

(

18, 219 g) to suppress the formation of linear oligomers. The

Figure 5. Plots of natural bond orbitals (isovalue = 0.03 au) showing

three donor−acceptor orbital interactions between the two pyrene

units in pyrenophane 13. Top: viewed from the side, and bottom:

viewed from the top. Calculated at the M06-2X/Def2SVP//B3LYP/

desired product 20 (54%) was separated from roughly 196 g of

unreacted pyrene using column chromatography. A small

amount of pyrene in the sample of 20 is what appears to have

served as a starting material for the synthesis of 13 via a route

that shadowed the ﬁve-step sequence of reactions leading from

6-31G(d) level of theory.

0 to cyclophane-monoene 8 (via dialdehyde 21, [10.2]-

arising from these donor−acceptor orbital interactions was

calculated to be 2.29 kcal/mol. In addition to the through-

space orbital interactions between the two pyrene units, the

cyclophane 22 and dialdehyde 7).

In the “shadow” synthesis, (Although the concept is surely

not new, we suggest the name “shadow synthesis” and the

following deﬁnition: a shadow synthesis is one in which an

impurity in a starting material or synthetic intermediate in a

synthetic sequence is carried through more than one step of

that sequence while undergoing appropriate chemistry at every

stage and evading separation until it is isolated.) Rieche

formylation of pyrene (18) presumably aﬀorded pyrene-1-

carboxaldehyde 23. Reduction would then have led to 1-

(hydroxymethyl)pyrene, self-reaction of which in the sub-

sequent iodination / Wurtz coupling protocol would have

furnished 1,2-dipyren-1-ylethane (24). Considering that this

compound is the homocoupling product of a minor

component of a mixture, it is counterintuitive that any of

this compound should form. The implied success of the Wurtz

coupling leading to 24 may be a consequence of it being an

intermolecular reaction, while the one leading to 22 is

intramolecular. If the rate of the intramolecular reaction was

substantially faster than any competing intermolecular

reactions (including crossed Wurtz couplings), then the

major component of the reaction mixture would have been

quickly depleted, thereby providing a more favourable

environment for the homocoupling of the minor component

leading to 24. Rieche formylation of 24 could conceivably give

several dialdehydes arising from reaction at the 3, 6 and 8

positions of the two pyrene systems. 1-Substituted pyrenes are

known to undergo electrophilic aromatic substitution reactions

preferentially at the 6 and 8 positions, with a slight preference

,6-disubstituted pyrene was found to contribute a π orbital

interacting with the π_C₌_C* antibonding orbital of the alkene

bridge (E(2) = 8.32 kcal/mol), while a π orbital of the 1,8-

disubstituted pyrene shows hyperconjugative interaction with

the σ_C₋_C* of the ethano bridge (E(2) = 3.14 kcal/mol) (Figure

S8 ). Overall, the orbital interactions suggest the occurrence of

charge transfer from the 1,6-disubstituted pyrene system to the

,8-disubstituted pyrene system, which may explain the

diﬀerences in electrostatic potential between the outer surfaces

and outer edges of the two pyrene systems.

To further examine the charge transfer properties in

pyrenophane 13, natural population analysis (NPA) was

carried out. The 1,6-disbustituted pyrene unit possesses a

total NBO charge of +0.07, while the 1,8-disbustituted pyrene

unit shows a total NBO charge of −0.037. The diﬀerent

amounts of charge distributed on the two pyrenyl groups also

point to a mild degree of charge transfer from the bent and

twisted 1,6-disbustituted pyrene system to the relatively ﬂat

,8-disbustituted one.

Dipole moment analysis also supported the existence of

intramolecular charge transfer. The net molecular dipole

moment of 13 was calculated to be 1.094 D, and its direction

coincides with the alignment of donor-to-acceptor bonds

shown in the NBO analysis (Figure 6). The 1,6-disbustituted

pyrene contributes a dipole moment of 0.263 D, which is

roughly perpendicular to its best plane and points toward the

,8-disbustituted pyrene system beneath it. The 1,8-disub-

for the 6 position. Thus, at any point up to a 2:1 preference

for the 6 position, the most abundant dialdehyde arising from

24 would be 25. (If the relative rates of reaction of the 6 and 8

stituted pyrene unit contributes a dipole moment of 1.001 D.

The vector of this dipole is on the pyrene surface and

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Article

Scheme 2. A Portion of the Planned Synthetic Pathway En

Route to Teropyrenophane 12 and the Shadow Route from

Pyrene (18) to Pyrenophane 13

(Small peaks corresponding to pyrene (18), pyrene-1-

carbaldehyde (23), and 1-(hydroxymethyl)pyrene (not

shown) were observed in the LCMS and HRMS spectra of

0, 21 and its reduction product (not shown), respectively.

These signals are most likely due to the presumed impurities,

but could also arise from retro-Friedel−Crafts t-alkylation of

the main compounds in the instrument.) To date, we have not

found any other example of a shadow synthesis of this length.

The success of the McMurry reaction in generating 13 is also

interesting because this methodology has a long track record of

performing poorly in the synthesis of [2.2]cyclophanes that

18,19

have even a moderate amount of strain.

In this regard, it is

noteworthy that the orbital interactions discussed above oﬀer a

signiﬁcant degree of stabilization to the structure of

pyrenophane 13 and this stabilization may have contributed

to the success of this particular McMurry reaction. The

calculated (M06-2X/Def2SVP//B3LYP/6-31G(d)) strain en-

ergy of 13 is 14.4 kcal/mol (Supporting Information). (The

value calculated at the B3LYP/6-31g(d) level of theory (21.1

kcal/mol) is 47% higher. The use of the M06-2X functional

includes dispersion, so it gives more reliable values for strain

energies. ) The clear implication is that analogous reactions

leading to [2.2]pyrenophanes with other new bridging motifs

may also fare well. Furthermore, the synthetic strategy of using

a Wurtz coupling to form the ﬁrst bridge and then an

intramolecular McMurry reaction to form the second might

prove to be generally applicable to [2.2]cyclophanes with

aromatic systems larger than benzene. To test this, the ﬁrst

action would be to intentionally synthesize 13 using the

shadow pathway. This could be followed by work aimed at the

synthesis of other [2.2]pyrenophanes and/or PAH-based

[2.2]cyclophanes.

CONCLUSION

■

The isolation of pyrenophane 13 from the McMurry reaction

of dialdehyde 7 was surprising because it could not possibly

have originated from the starting material or any of the

possible side products arising from the previous reaction. Its

genesis was eventually traced back to an impurity that was

present at a much earlier stage in the synthetic sequence. This

impurity (pyrene) must have been carried through ﬁve

synthetic steps and not only have undergone appropriate

chemistry that shadowed the chemistry of the major

compound but also evaded separation. The success of the

shadow synthesis suggests that the Wurtz coupling/intra-

molecular McMurry strategy may be more widely applicable to

the synthesis of PAH-based [2.2]cyclophanes. The two

diﬀerently substituted pyrene systems in 13 are distorted in

diﬀerent ways and to quite diﬀerent extents. The 1,8-

disubstituted pyrene is very gently bent out of planarity,

while the 1,6-disubstituted pyrene is bent and twisted to a

greater extent than in all previously reported (1,6)-

pyrenophanes. Pyrenophane 13 was found to exhibit dual

monomer/excimer emission, albeit relatively weak. More

signiﬁcantly, NBO analysis, NPA, and dipole moment analysis

all pointed toward the presence of intramolecular charge-

transfer interactions between the bent and twisted 1,6-

disubstituted pyrene unit and the nearly planar 1,8-

disubstituted pyrene unit. This raises the intriguing possibility

that distortion from planarity might prove to be a means to

induce charge transfer between two otherwise electronically

similar π systems. Further investigation of this issue is

warranted. Finally, the diﬀerences in electron density between

position are 1:1, the distribution of the (1,6)(1,6), (1,6)(1,8)

and (1,8)(1,8) products is 1:2:1. If the relative rates of reaction

of the 6 and 8 position are 2:1, the distribution of the

(

1,6)(1,6), (1,6)(1,8) and (1,8)(1,8) products is

4.4:44.4:11.1.) Intramolecular McMurry reaction of 25

leads directly to 13.

Perhaps the most noteworthy features of the shadow

synthesis of 13 is the number of steps (ﬁve) through which

synthetic intermediates were not detected or separated

(

including chromatographic puriﬁcations of 21, 22, and 7).

410

J. Org. Chem. 2021, 86, 4405−4412

The Journal of Organic Chemistry

Complete contact information is available at:

Article

the two edges of each pyrene system suggests that 13 may

exhibit unusual regioselectivity in its electrophilic aromatic

substitution chemistry.

bridge Crystallographic Data Centre, 12 Union Road,

Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

AUTHOR INFORMATION

Corresponding Author

■

EXPERIMENTAL SECTION

General. H, C, and 2-D NMR spectra were recorded using

CDCl₃solutions at 300 MHz (75 MHz for C) on a Bruker

AVANCE III multinuclear spectrometer with a BBFO probe. All

■

Graham J. Bodwell − Department of Chemistry, Memorial

University of Newfoundland, St. John ’s, NL, Canada A1B

X7; orcid.org/0000-0002-9476-2078; Phone: +1-709-

NMR spectra are referenced to Me Si (δ_H= 0.00 ppm) and CDCl₃

864-8406; Email: gbodwell@mun.ca

(δ_H= 7.26 ppm). Structural assignments were made with additional

information from gCOSY and gNOESY experiments. LCMS data

were obtained using an Agilent 1100 series LC/MSD instrument, and

high resolution mass spectroscopic data were obtained using an

Aglient 6200 series Accurate-Mass-Time-of-Flight instrument. UV−

vis absorption analysis was conducted on a Cary 6000i spectropho-

tometer. A sample of 13 was dissolved in chloroform and measured

with a 1 cm quartz cuvette at room temperature. Fluorescence spectra

were measured on a Photon Technology International (PTI)

QuantaMaster spectroﬂuorometer. The relative ﬂuorescence quantum

Authors

Kiran Sagar Unikela − Department of Chemistry, Memorial

University of Newfoundland, St. John’s, NL, Canada A1B

3X7

Zahra A. Tabasi − Department of Chemistry, Memorial

University of Newfoundland, St. John’s, NL, Canada A1B

3X7

Louise N. Dawe − Department of Chemistry and

Biochemistry, Wilfrid Laurier University, Waterloo, ON,

Canada N2L 3C5; orcid.org/0000-0003-3630-990X

Yuming Zhao − Department of Chemistry, Memorial

University of Newfoundland, St. John ’s, NL, Canada A1B

3X7; orcid.org/0000-0002-1300-9309

yield (Φ ) was measured following reported procedures, with

quinine sulfate (Φ = 0.546) as the standard. Single crystal X-ray data

were collected on a Bruker Apex II Diﬀractometer equipped with an

Apex II CCD detector, using Mo X-ray radiation. Crystals of 13 were

obtained from slow evaporation of a dichloromethane/hexanes

solution.

Cyclophane 13 (5 mg) was obtained as a brown solid: R = 0.36

https://pubs.acs.org/10.1021/acs.joc.0c02579

(

10% dichloromethane/hexanes); H NMR (300 MHz, CDCl ) δ

.29 (d, J = 9.2 Hz, 1H), 8.26 (d, J = 7.9 Hz, 1H), 8.20 (d, J = 9.1 Hz,

H), 8.02 (dd, J = 7.9, 0.6 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.96 (d,

Notes

J = 7.9 Hz, 1H), 7.86 (s, 2H), 7.84 (dd, J = 8.0, 0.6 Hz, 1H), 7.63 (d, J

7.9 Hz, 1H), 7.47 (d, J = 13.2 Hz, 1H), 7.20 (d, J = 13.2 Hz, 1H),

The authors declare no competing ﬁnancial interest.

.03 (d, J = 9.0 Hz, 1H), 6.26 (d, J = 7.7 Hz, 1H), 6.17 (d, J = 9.2 Hz,

H), 6.16 (d, J = 7.3 Hz, 1H), 5.22 (d, J = 9.5 Hz, 1H), 4.64 (d, J =

.5 Hz, 1H), 4.32 (ddd, J = 12.7, 4.6, 2.3 Hz, 1H), 3.18 (ddd, J = 12.4,

2.4, 4.7 Hz, 1H), 3.12 (ddd, J = 12.7, 5.2, 2.2 Hz, 1H), 2.98 (ddd, J =

ACKNOWLEDGMENTS

■

Financial support of this work from the Natural Sciences and

Engineering Research Council (NSERC) of Canada is

gratefully acknowledged (G.J.B., Y.Z, L.N.D.).

2.3, 12.3, 5.3 Hz, 1H); C{ H} NMR (75 MHz, CDCl ) δ 135.0,

34.2, 133.0, 132.1, 130.8, 130.1, 129.3, 129.1, 128.9, 128.8, 128.5,

28.3, 128.2, 128.0, 127.7, 127.2, 127.0, 126.8, 126.6, 126.2, 126.2,

25.9, 125.2, 125.0, 124.9, 124.5, 124.2, 124.2, 124.0, 123.6, 122.0,

21.7, 119.6, 37.6, 31.6; LCMS (CI-(+)) m/z (rel. int.) 457 (6), 456

REFERENCES

■

(

1) Watson, W. On Byproducts and Side Products. Org. Process Res.

Dev. 2012, 16, 1877.

(2) (a) For the most recent collection of reviews on cyclophanes,

see: Special Issue on Cyclophanes, Isr. J. Chem. 2012, 52(1−2), 1−

92.. (b) Hassan, Z.; Spuling, E.; Knoll, D. M.; Lahann, J.; Bräse, S.

Planar Chiral [2.2]paracyclophanes: From Synthetic Curiosity to

Applications in Asymmetric Synthesis and Materials. Chem. Soc. Rev.

018, 47, 6947−6963. See also: (c) Hassan, Z.; Spuling, E.; Knoll, D.

M.; Bräse, S. Regioselective Functionalization of [2.2]-

paracyclophanes: Recent Synthetic Progress and Perspectives.

Angew. Chem., Int. Ed. 2020, 59, 2156−2170. (d) For the most

recent book on cyclophanes, see: Gleiter, R.; Hopf, H. Modern

Cyclophane Chemistry; Wiley: New York, 2004. See also: Keehn, P.

M.; Rosenfeld, S. M. Cyclophanes; Academic Press: New York, 1983;

Vols. 1 and 2. (f) Diederich, F. Cyclophanes; The Royal Society of

Chemistry: London, 1991. (g) Vögtle, F. Cyclophane Chemistry;

Wiley: New York, 1983.

3) Ghasemabadi, P. G.; Yao, T.; Bodwell, G. J. Cyclophanes

Containing Large Polycyclic Aromatic Hydrocarbons. Chem. Soc. Rev.

015, 44, 6494−6518.

4) (a) Figueira-Duarte, T. M.; Mu

for Organic Electronics. Chem. Rev. 2011, 111, 7260 −7314.

(b) Casas-Solvas, J. M.; Howgego, J. G.; Davis, A. P. Synthesis of

Substituted Pyrenes by Indirect Methods. Org. Biomol. Chem. 2014,

(

42), 455 ([M + H] , 100); HRMS (APPI) m/z [M + H] calcd for

C H 455.1782; found 455.1851.

A yield for 13 (and the other side product 10) could not be

calculated because the mass of its presumed direct synthetic precursor

5 in the sample of 7 was not determined. For context, 3.01 g of

dialdehyde 7 were used in the McMurry reaction from which 13 was

isolated. Following extensive chromatography, 320 mg (12%) of the

desired product 8 were obtained along with 80 mg (3%) of the

reduced product 9, 74 mg of the side product 10, 55 mg (2%) of the

follow-on product 11, and 3 mg of the follow-on product 12 (0.1%).

Thus, the amount of 13 (5 mg) obtained most closely resembles that

of 12.

ASSOCIATED CONTENT

■

sı Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.joc.0c02579.

Characterization data, 1-D and 2-D NMR spectra and

explanation of proton assignments for 13, and additional

crystallographic information for 13; details of UV−vis

spectroscopy, ﬂuorescence spectroscopy, and computa-

tional work; excitation spectra (PDF)

llen, K. Pyrene-Based Materials

(

2, 212−232.

Accession Codes

5) Vullev, V. I.; Jiang, H.; Jones, G. In Advanced Concepts in

CCDC 2034879 contains the supplementary crystallographic

data for this paper. These data can be obtained free of charge

via www.ccdc.cam.ac.uk/data_request/cif, or by emailing

data_request@ccdc.cam.ac.uk, or by contacting The Cam-

Fluorescence Sensing. Topics in Fluorescence Spectroscopy; Geddes, C. D.,

Lakowicz, J. R., Eds.; Springer: Boston, MA, 2005; Vol. 10.

(6) (a) Irngartinger, H.; Kirrstetter, R. G. H.; Krieger, C.; Rodewald,

H.; Staab, H. A. Synthese und Struktur von [2.2][2.7]Pyrenophan.

411

J. Org. Chem. 2021, 86, 4405−4412

The Journal of Organic Chemistry

Carruthers, R. J.; Zwinkels, J. C. Straining Strained Molecules - I.

Article

Tetrahedron Lett. 1977, 18, 1425 −1428. (b) Mitchell, R. H.;

The Synthesis of the First Cyclophane Within a Cyclophane -

(19) Bodwell, G. J.; Nandaluru, P. R. Olefination Reactions in the

Synthesis of Cyclophanes. Isr. J. Chem. 2012, 52, 105−138.

(20) Williams, A. T. R.; Winfield, S. A.; Miller, J. N. Relative

Fluorescence Quantum Yields Using a Computer-controlled

Luminescence Spectrometer. Analyst 1983, 108, 1067 −1071.

(21) Bodwell, G. J.; Ernst, L.; Haenel, M.; Hopf, H. Syn - and Anti -

585 −2588. (c) Umemoto, T.; Satani, S.; Sakata, Y.; Misumi, S.

2.2]Paracyclo([2.2]metacyclophane). Tetrahedron Lett. 1976, 17,

Layered Compounds. XXIX. [2.2](2,7)Pyrenophane and its 1,13-

2.2]Orthometacyclophane. Angew. Chem. 1989 , 101 , 509 −510.

Diene. Tetrahedron Lett. 1975, 16, 3159−3162.

22) (a) Zhao, Y.; Truhlar, D. G. The M06 Suite of Density

(7) Kawashima, T.; Otsubo, T.; Sakata, Y.; Misumi, S. Synthesis of

Functional for Main Group Thermochemistry, Thermochemical

Kinetics, Noncovalent Interactions, Excited States, and Transition

Elements: Two new Functionals and Systematic Testing of Four

M06-Class Functionals and 12 Other Functionals. Theor. Chem. Acc.

Three [2.2]Pyrenophanes as an Excimer Model. Tetrahedron Lett.

978, 19, 5115−5118.

8) (a) Unikela, K. S.; Ghasemabadi, P. G.; Houska, V.; Dawe, L.;

Zhao, Y.; Bodwell, G. J. Gram-Scale Synthesis of the 1,1,n ,n -

Tetramethyl[n ](2,11)teropyrenophanes. Chem. - Eur. J. 2021, 27,

(

2008 , 120 , 215 −241. (b) Mardirossian, N.; Head-Gordon, M. How

Accurate are the Minnesota Density Functionals for Noncovalent

Interactions, Isomerization Energies, Thermochemistry, and Barrier

Heights Involving Molecules Composed of Main-Group Elements? J.

Chem. Theory Comput. 2016 , 12 , 4303 −4325. (c) Leang, S. S.;

Zahariev, F.; Gordon, M. S. Benchmarking the Performance of Time-

Dependent Density Functional Methods. J. Chem. Phys. 2012, 136,

390−400. (b) Unikela, K. S.; Roemmele, T. L.; Houska, V.; McGrath,

K. E.; Tobin, D. M.; Dawe, L. N.; Boeré, R. T.; Bodwell, G. J. Gram-

Scale Synthesis and Highly Regioselective Bromination of 1,1,9,9-

Tetramethyl[9](2,11)teropyrenophane. Angew. Chem., Int. Ed. 2018,

57, 1707−1711. See also: (c) Unikela, K. S.; Merner, B. L.;

Ghasemabadi, P. G.; Warford, C. C.; Qiu, C. S.; Dawe, L. N.; Zhao,

Y.; Bodwell, G. J. The Development of Synthetic Routes to 1,1,n ,n -

Tetramethyl[n ](2,11)teropyrenophanes. Eur. J. Org. Chem. 2019,

04101. Jacquemin, D.; Perpete, E. A.; Ciofini, I.; Adamo, C.; Valero,

R.; Zhao, Y.; Truhlar, D. G. On the Performances of the M06 Family

of Density Functionals for Electronic Excitation Energies. J. Chem.

Theory Comput. 2010, 6, 2071−2085.

2019, 4546−4560. (d) Merner, B. L.; Unikela, K. S.; Dawe, L. N.;

Thompson, D. W.; Bodwell, G. J. 1,1,n ,n -Tetramethyl[n ](2,11)-

teropyrenophanes (n = 7 −9) a Series of Armchair SWCNT Segments.

Chem. Commun. 2013 , 49 , 5930 −5932. (e) Merner, B. L.; Dawe, L.

N.; Bodwell, G. J. 1,1,8,8-Tetramethyl[8](2,11)teropyrenophane:

Half of an Aromatic Belt and a Segment of an (8,8)Single-Walled

Carbon Nanotube. Angew. Chem., Int. Ed. 2009 , 48 , 5487 −5491.

(9) Bodwell, G. J.; Fleming, J. J.; Miller, D. O. Non-Planar Aromatic

Compounds. 4. Fine Tuning the Degree of Bend in the Pyrene Unit

of [7](2,7)Pyrenophanes by Modifying the Nature of the Bridge.

Tetrahedron 2001, 57, 3577−3585.

(10) Bodwell, G. J.; Bridson, J. N.; Cyranski, M.; Kennedy, J. W. J.;

Krygowski, T. M.; Mannion, M. R.; Miller, D. O. Nonplanar aromatic

Compounds. 8. Synthesis, Structure and HOMA Investigation of 1,n -

Dioxa[n ](2,7)pyrenophanes. How Does Bending Affect the Cyclic Pi

Electron Delocalization of the Pyrene Unit? J. Org. Chem. 2003, 68,

(

089−2098.

11) (a) Yang, Y.; Mannion, M. R.; Dawe, L. N.; Kraml, C. M.;

Pascal, Jr. R. A.; Bodwell, G. J. A Synthetic Approach to

n ](1,6)Pyrenophanes - Inherently Chiral [n ]Cyclophanes. J. Org.

Mannancherry, R.; Devereux, M.; Häussinger, D.; Mayor, M.

Chem. 2012, 77, 57−67. For a less strained [n](1,6)pyrenophane, see:

Molecular Ansa-Basket: Synthesis of Inherently Chiral All-Carbon

Dawe, L. N.; Thompson, D. W.; Bodwell, G. J. Concise,

12](1,6)Pyrenophane. J. Org. Chem. 2019, 84, 5271−5276.

(

12) Nandaluru, P. R.; Dongare, P.; Kraml, C. M.; Pascal, R. A., Jr.;

Aromatization-Based Synthesis of an Elaborate C -Symmetric

Pyrenophane. Chem. Commun. 2012 , 48, 7747−7749.

(

13) Pascal, R. A., Jr. Twisted Acenes. Chem. Rev. 2006, 106, 4809−

4819.

(14) Bodwell, G. J.; Bridson, J. N.; Houghton, T. J.; Kennedy, J. W.

J.; Mannion, M. R. 1,7-Dioxa[7](2,7)pyrenophane: The Pyrene Unit

is More Bent Than That of C . Chem. - Eur. J. 1999, 5, 1823−1827.

(15) Biswas, S.; Qiu, C. S.; Dawe, L. N.; Zhao, Y.; Bodwell, G. J.

Contractive Annulation: A Strategy for the Synthesis of Small,

Strained Cyclophanes and its Application in the Synthesis of

16) (a) Winnik, F. M. Photophysics of Preassociated Pyrenes in

2](6,1)Naphthaleno[1]paracyclophane. Angew. Chem., Int. Ed.

019, 58, 9166−9170.

Aqueous Polymer Solutions and Other Organized Media. Chem. Rev.

993, 93, 587−614. (b) Birks, J. B. Photophysics of Aromatic Molecules;

Wiley-Interscience: London, 1970.

17) Maeda, H.; Akai, T.; Segi, M. Photo-Fries Rearrangement of 1-

Pyrenyl Esters. Tetrahedron Lett. 2017 , 58 , 4377 −4380.

18) Zych, D. Non-K -Region Disubstituted Pyrenes (1,3-, 1,6-, and

1,8-) by (Hetero)Aryl Groups-Review. Molecules 2019, 24, 2551−

2583 and references therein.

412