A Simple Synthesis of a Pillar[n]arene Building Block–1,4-bis(4-Bromobenzyl)benzene?

Full text of DOI:10.1080/00304948.2021.1920789

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/uopp20
A Simple Synthesis of a Pillar[n]arene Building
Block – 1,4-bis(4-Bromobenzyl)benzene†
Charles F. Nutaitis & Gordon W. Gribble
To cite this article: Charles F. Nutaitis & Gordon W. Gribble (2021) A Simple Synthesis of a
Pillar[n]arene Building Block – 1,4-bis(4-Bromobenzyl)benzene†, Organic Preparations and
Procedures International, 53:4, 422-425, DOI: 10.1080/00304948.2021.1920789
To link to this article: https://doi.org/10.1080/00304948.2021.1920789
Published online: 16 Jul 2021.
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ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
2021, VOL. 53, NO. 4, 422–425
https://doi.org/10.1080/00304948.2021.1920789
OPPI BRIEF
A Simple Synthesis of a Pillar[n]arene Building Block –
1,4-bis(4-Bromobenzyl)benzene†
Charles F. Nutaitis and Gordon W. Gribble
Department of Chemistry, Dartmouth College, Hanover, New Hampshire
ARTICLE HISTORY Received 29 September 2020; Accepted 29 October 2020
Recent years have seen a veritable explosion of activity in the synthesis of
“pillar[n]arenes”1 (previously known as “[1n]paracyclophanes”) and their application in
the construction of host-guest molecules, supramolecular nanostructures, molecular
machines, biological catalysts, and other novel materials. The field has been extensively
reviewed,2–10 and recent work has expanded this exciting new area of supramolecular
chemistry.11–14
We now describe a two-step synthesis of 1,4-bis(4-bromobenzyl)benzene (1) from
readily available starting materials (Scheme 1). We previously prepared and utilized this
building block in the inaugural synthesis of [15]- and [16]-paracyclophanes, but without
experimental details,15 and it is the purpose of this paper to provide such details.
Monolithiation16 of 1,4-dibromobenzene (2) with n-BuLi in THF at –78 ꢀC generated 4-
lithiobromobenzene (3), which was treated with terephthalaldehyde (4) to give diol 5,
presumably as a mixture of diastereomers. Treatment of diol 5 with NaBH4/trifluoroace-
tic acid17 gave 1 in high yield.
We believe our method to be superior in terms of yield, simplicity, and cost of start-
ing materials to the procedures of Galun18 and Stephan,19 which are shown in Schemes
2 and 3, respectively. Moreover, ortho isomers are reported in Stephan’s synthesis and
are likely to occur in both of Galun’s syntheses, but are precluded by our method.
Experimental section
Melting points were obtained on a Thomas-Hoover Mel-Temp capillary apparatus and
are uncorrected. Infrared spectra (IR) were recorded on a Perkin-Elmer Model 599
spectrophotometer. Liquids were measured on NaCl plates (neat), while KBr pellets
were used for solids. Nuclear Magnetic Resonance spectra (NMR) were recorded on a
Perkin-Elmer R-24 or a Varian XL300 spectrometer using TMS as an internal standard.
Low resolution mass spectra were obtained with a Finnigan EI-CI gas chromatograph-
mass spectrometer, and high-resolution mass spectra were obtained at the NIH
Regional Facility at the Massachusetts Institute of Technology. Thin Layer
Chromatography (TLC) was carried out on precoated (0.2 mm) Silica Gel 60 F254
S
CONTACT Gordon W. Gribble
gordon.w.gribble@dartmouth.edu
Department of Chemistry, Dartmouth College,
Hanover, NH 03755
†Dedicated to the memory of Max L. Deinzer – climbing partner extraordinaire and a consummate chemist.
ß 2021 Taylor & Francis Group, LLC

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
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Scheme 1. Present synthesis of 1,4-bis(4-bromobenzyl)benzene.
Scheme 2. Two syntheses of 1 by Galun and co-workers.
Scheme 3. Synthesis of 1 by Stephan and co-workers.
plastic sheets. Microanalysis was performed by Atlantic Microlabs, Atlanta, Georgia.
Sodium borohydride was obtained from Morton Thiokol and was oven dried at 110 ꢀC
before use. Trifluoroacetic acid was provided by Halocarbon, Hackensack, New Jersey,
and was distilled before use. Tetrahydrofuran was dried over and distilled from sodium/
benzophenone. The n-BuLi was purchased from Aldrich and standardized by titration
against 2,5-dimethoxylbenzyl alcohol.

424
C. F. NUTAITIS AND G. W. GRIBBLE
1,4-Phenylenebis(4-bromophenylmethanol) (5)
To a magnetically stirred solution of p-dibromobenzene (2) (1.03 g, 4.36 mmol) in dry
THF (15 mL) at –78 ꢀC was added quickly via syringe a solution of n-BuLi/hexane (1.52
M, 2.90 mL, 4.41 mmol). The resulting solution was stirred at –78 ꢀC for 5 min, then a
solution of terephthalaldehyde (4) (0.29 g, 2.2 mmol) in dry THF (10 mL) was added
quickly via syringe. The resulting mixture was allowed to warm to 25 ꢀC, stirred at
25 ꢀC for 24 h, then poured into H2O (75 mL), diluted with brine (100 mL), and
extracted with Et2O (3 x 100 mL). The combined extracts were dried (Na2SO4), filtered,
and concentrated in vacuo to afford a yellow oil (0.84 g). Flash chromatography (2:1
hexane/Et2O) gave 5 (0.46 g, 47%) as a white solid (presumed mixture of diastereomers)
1
which was recrystallized from hexane/Et2O: mp 141–142 ꢀC; H NMR (acetone-d6) d
7.4–7.3 (m, 12H), 5.7 (broad, 2H); 13C NMR (DMSO-d6) d 145.0, 143.8, 130.8, 128.3,
126.0, 119.6, 73.3; IR (CHCl3): 3180 cmꢁ1 (broad).
Anal. Calcd for C20H16Br2O2: C, 53.60; H, 3.60; Br, 35.66. Found: C, 54.48; H, 3.92;
Br, 36.12. HRMS Calcd for C20H16Br2O2: 445.9517. Found: 445.9486.
1,4-bis(4-Bromobenzyl)benzene (1)
To trifluoroacetic acid (100 mL) under N2, magnetically stirred at 0–5ꢀC was added NaBH4
(15 pellets, 4.5 g, 120 mmol) over 10 min, and the resulting mixture was allowed to warm to
25 ꢀC and stirred at 25 ꢀC for 45 min. To this was added in portions over 2 h a suspension
of a,a’-bis(4-bromophenyl)-1,4-benzenedimethanol (5) (3.10 g, 6.92 mmol) in CH2Cl2
(25 mL). The resulting mixture was stirred at 25 ꢀC for 24 h, then carefully poured into 25%
aqueous NaOH (100 mL)/ice chips to make strongly alkaline (pH 11), diluted with brine
(200 mL), and extracted with Et2O (3 x 100 mL). The combined extracts were dried
(Na2SO4), filtered, and concentrated in vacuo to afford 1 (2.55 g, 89%) as a white solid,
which was recrystallized from hexane/Et2O to give colorless needles; mp 121–122.5 ꢀC; (lit.18
1
mp 127 ꢀC): H NMR (CDCl3) d 7.3–7.0 (m, 12H), 3.8 (s, 4H); 13C NMR (CDCl3) d 140.0,
138.3, 131.4, 130.5, 128.9, 119.8, 40.8; MS m/e (relative intensity) 418 (Mþ, 17), 416 (Mþ,
33), 414 (Mþ, 16), 337 (12), 335 (12), 247 (100), 245 (99), 166 (66); IR (CHCl3): 2945, 1605,
1085, 1025 cmꢁ1. A reduction of 4 on a 9.5-gram scale gave 1 in 91% yield.
Anal. Calcd for C20H16Br2: C, 57.72; H, 3.88; Br, 38.40. Found: C, 57.48; H, 3.91;
Br, 38.48.
Acknowledgement
We gratefully acknowledge support from Dartmouth College.
ORCID
Gordon W. Gribble
http://orcid.org/0000-0002-7573-0927

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
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