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Short Note

4-(4-Formyl-3,5-dimethoxyphenoxy)butyric Acid (BAL)

by
Alex Lovstedt
1,
Tracy R. Thompson
1,2 and
George Barany
1,*
1
Department of Chemistry, University of Minnesota, Minneapolis, MN 55455, USA
2
Department of Physical Sciences, Alverno College, Milwaukee, WI 53234, USA
*
Author to whom correspondence should be addressed.
Molbank 2025, 2025(3), M2029; https://doi.org/10.3390/M2029 (registering DOI)
Submission received: 1 April 2025 / Revised: 4 June 2025 / Accepted: 18 June 2025 / Published: 26 June 2025
(This article belongs to the Section Structure Determination)
Browse Figures
Versions Notes

Abstract

The title compound, 4-(4-formyl-3,5-dimethoxyphenoxy)butyric acid (BAL), is an important “handle” for solid-phase synthesis of peptides and related compounds. Reported here is an X-ray single crystal structural analysis of BAL. The molecule is almost entirely flat, and the crystal is held together by π-stacking and hydrogen bonding.

1. Introduction

Solid-phase peptide synthesis (SPPS) requires a suite of chemical, physical, and instrumental components, all of which have evolved and matured since the field was initiated in 1963 by the 1984 Nobel laureate in Chemistry, R.B. Merrifield [1,2]. Central to this are families of “handles” or “linkers” that serve to anchor the starting building block to the polymeric support or matrix upon which chain assembly will take place. The criteria for these molecules have been well reviewed [3,4,5], and quite a few of them are commercially available, either as the reagent itself or already coupled onto a suitable support. The present Short Note focuses on one such compound, namely 4-(4-formyl-3,5-dimethoxyphenoxy)butyric acid, which is also referred to as “BAL”, an acronym for “Backbone Amide Linker” (Scheme 1). The BAL compound (details in the legend to Scheme 1) was introduced in the late 1990s [6,7,8,9,10] but builds upon related chemistry of tris(alkoxy)benzylamides and alcohols epitomized by the acronyms PAL [11,12,13,14] and HAL [15]. BAL is a particularly versatile compound since it allows ready access to modified peptide species that are difficult to obtain otherwise [6,7,8,16,17,18,19,20,21,22], and its applications can easily be extended to the production of non-peptide target compounds such as small organic molecules with potential pharmaceutical uses [8,21,23,24,25,26,27,28,29,30], as well as a myriad of further ingenious uses [31,32,33].
This Short Note reports the X-ray single crystal structural analysis of the canonical BAL title compound and points out several interesting structural features. Lessons learned herein could inform the design and understanding of BAL variants [34,35,36] that are cleaved by acidolysis, photolysis, or other chemical mechanisms, along lines previously reported and described by Hammershøj et al. [37].
Molbank 2025 m2029 sch001
Scheme 1. Relationship between tris(alkoxy)benzyl BAL, PAL, and HAL. The title compound (BAL) is commercially available from multiple sources. The structure shown here includes a 3-carbon spacer between the benzene ring and the carboxyl function; other published variants have a 1- or 4-carbon spacer. In addition, note that the aldehyde and the spacer are para to each other; published variants can also be a mixture of ortho and para. BAL, PAL, and HAL are coupled to amino-functionalized polymeric supports to present starting points for SPPS chain assembly, and the completed products are cleaved by acidolysis, all as detailed in the primary and review literature cited in the text. Protocols are readily generalized to a range of non-peptide targets (solid-phase organic synthesis ≡ SPOS), as also covered by the cited literature. Because of the interrelationships between handle structures drawn in this scheme, the Barany lab informally referred to BAL as “PALdehyde”, and this nickname has been picked up by others. According to Google Scholar, the foundational BAL reference [6] has been cited well over 400 times since it was published in 1998.
Scheme 1. Relationship between tris(alkoxy)benzyl BAL, PAL, and HAL. The title compound (BAL) is commercially available from multiple sources. The structure shown here includes a 3-carbon spacer between the benzene ring and the carboxyl function; other published variants have a 1- or 4-carbon spacer. In addition, note that the aldehyde and the spacer are para to each other; published variants can also be a mixture of ortho and para. BAL, PAL, and HAL are coupled to amino-functionalized polymeric supports to present starting points for SPPS chain assembly, and the completed products are cleaved by acidolysis, all as detailed in the primary and review literature cited in the text. Protocols are readily generalized to a range of non-peptide targets (solid-phase organic synthesis ≡ SPOS), as also covered by the cited literature. Because of the interrelationships between handle structures drawn in this scheme, the Barany lab informally referred to BAL as “PALdehyde”, and this nickname has been picked up by others. According to Google Scholar, the foundational BAL reference [6] has been cited well over 400 times since it was published in 1998.
Molbank 2025 m2029 sch001

2. Results and Discussion

X-ray Structure Characterization

The canonical BAL compound (top center of Scheme 1) crystallizes in space group C2/c with a Z’ of 1 (Table 1). Excluding hydrogen atoms, the molecule (Figure 1) is remarkably planar, with all of the torsion angles within 5° of zero (Table S4) with the exception of the carboxylic acid group, which is rotated slightly out of plane with torsion angles of −159.92 (16)° and 21.9 (2)° for C11–C12–C13–O5 and C11–C12–C13–O6, respectively.
Table 1. Crystal structure and refinement data for BAL.
Table 1. Crystal structure and refinement data for BAL.
CCDC number2434833
Empirical formulaC13H16O6
Formula weight268.26
Temperature [K]100 (2)
Crystal systemmonoclinic
Space group (number) C 2 / c (15)
a [Å]26.8819 (15)
b [Å]7.3124 (3)
c [Å]16.6943 (9)
α [°]90
β [°]127.737 (2)
γ [°]90
Volume [Å3]2595.2 (2)
Z8
ρcalc [gcm−3]1.373
μ [mm−1]0.109
F (000)1136
Crystal size [mm3]0.030 × 0.140 × 0.150
Crystal color, shapeColorless, plate
RadiationMoKα (λ = 0.71073 Å)
2θ range [°]4.88 to 52.70 (0.80 Å)
Index ranges−31 ≤ h ≤ 33; −7 ≤ k ≤ 9; −20 ≤ l ≤ 20
Reflections collected18907
Independent reflections2656, Rint = 0.0427, Rsigma = 0.0266
Completeness to θ = 25.242°99.9%
Data/Restraints/Parameters2656/0/177
Absorption correction Tmin/Tmax (method)0.6801/0.7454 (multi-scan)
Goodness-of-fit on F21.042
Final R indexes [I ≥ 2σ (I)]R1 = 0.0384, wR2 = 0.0935
Final R indexes [all data]R1 = 0.0532, wR2 = 0.1029
Largest peak/hole [e Å−3]0.25/−0.21
Molbank 2025 m2029 g001
Figure 1. The crystal structure of BAL (top) and packed unit cell viewed along the crystallographic b-axis (bottom). Non-hydrogen atoms are drawn as thermal ellipsoids at the 50% probability level. Hydrogen atoms are drawn as fixed size spheres of radius 0.15 Å. All images of crystal structures were generated using the Mercury software package [38]. Note, the crystallographic numbering scheme differs from the IUPAC numbering scheme.
Figure 1. The crystal structure of BAL (top) and packed unit cell viewed along the crystallographic b-axis (bottom). Non-hydrogen atoms are drawn as thermal ellipsoids at the 50% probability level. Hydrogen atoms are drawn as fixed size spheres of radius 0.15 Å. All images of crystal structures were generated using the Mercury software package [38]. Note, the crystallographic numbering scheme differs from the IUPAC numbering scheme.
Molbank 2025 m2029 g001
Examining the packing of BAL, the carboxylic acid forms a hydrogen bond with the aldehyde of an adjacent molecule rather than with the carboxylic acid, thus not exhibiting the dimer motif that is often seen in carboxylic acids (Figure 2, top). Additionally, BAL molecules interact via π-stacking with molecules oriented in the opposite direction (Figure 2, middle). The distance between the benzene ring centroids of the π-stacked molecules is 3.752 Å. As a result of these two intermolecular interactions, chains of BAL are linked by hydrogen bonds oriented in one direction, and π-stacking with chains facing the opposite direction (Figure 2, bottom).
When a plane is defined using the atoms of benzene rings in hydrogen-bonded chains of BAL, the planes of adjacent chains along the c-axis of the crystal are offset by an angle of 44.29° (Figure 3). The packing of these offset, hydrogen-bonded, π-stacked chains viewed along the different unit cell axes is highlighted in Figure 4.
Searching the Cambridge Structural Database (Version 5.46) [39] for structures containing the 4-formyl-3,5-dimethoxy-1-alkoxy fragment yields three results, with two unique molecules: 4-hydroxy-2,6-dimethoxybenzaldehyde (CSD FAXXEI), 2,4,6-trimethoxybenzaldehyde (CSD XESJAH), and a cocrystal of 2,4,6-trimethoxybenzaldehyde and 4-nitroaniline (CSD YUPWOW) [40,41,42]. XESJAH was solved from powder diffraction data, and anisotropic thermal ellipsoids were not refined, and as such it will not be used in comparison to the other structures. Comparing the 4-formyl-3,5-dimethoxy-1-alkoxy fragment of BAL to FAXXEI and YUPWOW, only slight differences in the geometries of the fragment between the three structures are observed (Table 2). In the case of FAXXEI, the hydroxyl oxygen O4 is approximately 0.01 Å closer to the benzene ring compared to the alkoxy oxygens of BAL and YUPWOW. In BAL, the aldehyde group is the most planar, with an O1–C1–C2–C3 torsion angle of −0.4 (2)° compared to −4.7 (6)° and −9.3 (4)° for FAXXEI and YUPWOW, respectively.

3. Materials and Methods

3.1. General

Melting data was recorded from a Stanford Research Systems, Inc. digital melting point apparatus (SRS DigiMelt) (Stanford Research Systems, Inc., Sunnyvale, CA, USA) set at a 2 °C per min ramp rate. Infrared spectral data was obtained on a Perkin Elmer Spectrum Two FTIR Spectrometer (Perkin Elmer, Inc., Shelton, CT, USA) with a UATR Two accessory. NMR data were acquired at the University of Minnesota with CDCl3 as solvent at 25 °C on a Bruker spectrometer (Bruker Corporation, Billerica, MA, USA) with a 5 mm probe, operating at an 1H frequency of 400 MHz and a 13C frequency of 101 MHz. All reported chemical shifts were referenced to CDCl3 (δ 7.26 ppm in 1H and 77.0 ppm in 13C). Spectra were processed using MestreNova, version 15.0.1-35756 (Mestrelab Research, Santiago de Compostela, Spain).
High-resolution mass data was acquired at the University of Wisconsin–Milwaukee using a Shimadzu Nexera X2 liquid chromatography system coupled to a 9030 quadrupole time-of-flight (QTOF) mass spectrometer (Shimadzu, Kyoto, Japan) operated in positive ion mode with a scan range of m/z 140–1000, an event time of 0.1 s, and a data acquisition time of 1 min. Samples were introduced via flow injection (no column) at a flow rate of 0.3 mL/min using an isocratic mobile phase of 0.1% aqueous formic acid–acetonitrile (1:1). Optimized source parameters included a nebulizing gas flow of 3 L/min, heating gas flow of 10 L/min, drying gas flow of 10 L/min, interface temperature of 300 °C, desolvation temperature of 526 °C, desolvation line (DL) temperature of 250 °C, and heat block temperature of 400 °C.
X-ray data collection and structure solution were conducted at the X-ray Crystallographic Laboratory, Department of Chemistry, University of Minnesota. X-ray data collection and structure refinement details are given below and in the Supplemental Information (Tables S1–S5).

3.2. Experimental

The title compound, 4-(4-formyl-3,5-dimethoxyphenoxy)butyric acid (BAL) (CAS 197304-21-5), was prepared by methods outlined and detailed elsewhere [6,9,14]. Its chemical structure and purity were confirmed with 1H and 13C NMR spectral data. At the request of a reviewer, IR, mass spectrometry, and melting data were also acquired. Crystals appropriate for X-ray diffraction were grown from CDCl3 through slow evaporation of the solvent in an NMR tube. 1H NMR (400 MHz, CDCl3) δ 10.33 (s, 1H), 6.07 (s, 2H), 4.10 (t, J = 6.2 Hz, 2H), 3.87 (s, 6H), 2.60 (t, J = 7.1 Hz, 2H), 2.20–2.08 (m, 2H) (Figure S1); 13C NMR (101 MHz, CDCl3) δ 187.9, 177.7, 165.5, 164.15, 108.8, 90.7, 66.8, 56.0, 30.0, 24.1 (Figure S2); FTIR: 3000–2400 (br w), 1715 (m), 1643 (m), 1599 (s), 1459 (s), 1446 (m), 1289 (m), 1266 (s), 1219 (vs), 1200 (s), 1128 (vs), 1096 (s), 1049 (m), 1024 (m), 971 (m), 929 (m), 888 (m), 879 (m), 809 (vs), 767 (m), 714 (s), 671 (m), 650 (m), 561 (s), 512 (m), 480 (m) (Figure S3); FIA-QTOF-MS: m/z: obs. 269.1020, theor. 269.1020 [M + H]+; obs. 291.0830, theor. 291.0839 [M + Na]+; mp 164–166 °C (dec) (lit. mp 170–171 °C [9]).

3.3. X-ray Data Collection

A crystal (approximate dimensions 0.150 × 0.140 × 0.030 mm) was placed onto the tip of a 0.15 mm MiTeGen loop and mounted on a Bruker Photon-III CPAD diffractometer for data collection at 100 (2) K [43]. A preliminary set of cell constants was calculated from reflections harvested from three sets of frames. These initial sets of frames were oriented such that orthogonal wedges of reciprocal space were surveyed. This produced initial orientation matrices determined from 427 reflections. The data collection was carried out using MoKα radiation (graphite monochromator) with a frame time of 30 s and a detector distance of 5.0 cm. A strategy program was used to assure complete coverage of all unique data to a resolution of 0.80 Å. All major sections of frames were collected with 1.2° steps in ω or φ at different detector positions in 2θ. The intensity data were corrected for absorption and decay (SADABS) [44]. Final cell constants were calculated from the xyz centroids of 4938 strong reflections from the actual data collection after integration (SAINT) [45]. Additional crystal and refinement information can be found in Table 1.

3.4. X-ray Structure Solution and Refinement

The structure was solved using SHELXT 2018/2 [46] and refined using SHELXL-2019/1 [47]. The space group C2/c was determined based on systematic absences and intensity statistics. A direct-methods solution was calculated, which provided most non-hydrogen atoms from the E-map. Full-matrix least squares/difference Fourier cycles were performed, which located the remaining non-hydrogen atoms. All non-hydrogen atoms were refined with anisotropic displacement parameters. All hydrogen atoms were placed in ideal positions and refined as riding atoms with relative isotropic displacement parameters. The final full matrix least squares refinement converged to R1 = 0.0384 and wR2 = 0.1029 (F2, all data). This report was generated using FinalCif [48].

4. Conclusions

We report here the X-ray single crystal structural analysis of 4-(4-formyl-3,5-dimethoxyphenoxy)butyric acid (BAL), which is an important “handle” for solid-phase synthesis of peptides and related compounds. The BAL molecule is almost entirely flat, and the crystal is held together by π-stacking and hydrogen bonding. 1H and 13C NMR data confirm the chemical structure and purity of BAL. Given how little structural information is available about related compounds, the present studies may contribute to the understanding and development of molecules with useful properties for polymer-supported synthesis (SPPS and SPOS) and other exciting applications.

Supplementary Materials

mol file, cif file and checkcif file for BAL; Table S1: Atomic coordinates and Ueq [Å2] for BAL; Table S2: Anisotropic displacement parameters [Å2] for BAL; Table S3: Bond lengths [Å] and angles [°] for BAL; Table S4: Torsion angles [°] for BAL; Table S5: Hydrogen bonds for BAL; Figure S1: 1H NMR for BAL; Figure S2: 13C NMR for BAL; Figure S3: FTIR for BAL.

Author Contributions

G.B. was responsible for conceptualization and overall supervision; A.L. collected the X-ray data and solved the structure; A.L., T.R.T. and G.B. all contributed to data acquisition and analysis, as well as writing of the paper. All authors have read and agreed to the published version of the manuscript.

Funding

The research specifically reported here received no external funding. During the late 1980s through the full 1990s, the Barany lab was generously supported by NIH for research to develop new handles for solid-phase peptide synthesis.

Data Availability Statement

X-ray data is deposited at the Cambridge Crystallographic Data Centre as 2434833 and can be obtained free of charge at http://www.ccdc.cam.ac.uk/structures. (accessed on 27 March 2025).

Acknowledgments

The X-ray studies were overseen by Victor G. Young, Jr., X-ray Crystallographic Laboratory Director. Mass spectral studies were overseen by Shama Mirza and conducted by Anna Benko at the University of Wisconsin–Milwaukee State-of-the-Art Analytical Instrumentation Laboratory and Research Core (SAILARC). We thank Fernando Albericio, Jordi Alsina, Derek Hudson, Knud Jensen, Nancy Kneib-Cordonier, Michael Songster, and Josef Vágner for critical contributions to PAL and BAL chemistry, and Jed Fisher for discussions and critical reading of the manuscript.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

BAL4-(4-formyl-3,5-dimethoxyphenoxy)butyric acid
or “Backbone Amide Linker,” depending on context
Fmoc9-fluorenylmethyloxycarbonyl
PGprotecting group (in Scheme 1)
QTOFquadrupole time-of-flight
SPOSsolid-phase organic synthesis
SPPSsolid-phase peptide synthesis
Trttriphenylmethyl ≡ trityl

References

  1. Merrifield, R.B. Solid Phase Peptide Synthesis. I. The Synthesis of a Tetrapeptide. J. Am. Chem. Soc. 1963, 85, 2149–2154. [Google Scholar] [CrossRef]
  2. Merrifield, R.B. Solid Phase Synthesis. Science 1986, 232, 341–347. [Google Scholar] [CrossRef] [PubMed]
  3. Barany, G.; Merrifield, R.B. Solid-Phase Peptide Synthesis. In The Peptides; Gross, E., Meienhofer, J., Eds.; Academic Press: New York, NY, USA, 1979; Volume 2, pp. 1–284. [Google Scholar] [CrossRef]
  4. Songster, M.F.; Barany, G. [8] Handles for Solid-Phase Peptide Synthesis. Meth. Enzymol. 1997, 289, 126–174. [Google Scholar] [CrossRef]
  5. Guillier, F.; Orain, D.; Bradley, M. Linkers and Cleavage Strategies in Solid-Phase Organic Synthesis and Combinatorial Chemistry. Chem. Rev. 2000, 100, 3859. [Google Scholar] [CrossRef]
  6. Jensen, K.J.; Alsina, J.; Songster, M.F.; Vágner, J.; Albericio, F.; Barany, G. Backbone Amide Linker (BAL) Strategy for Solid-Phase Synthesis of C-Terminal-Modified and Cyclic Peptides. J. Am. Chem. Soc. 1998, 120, 5441–5452. [Google Scholar] [CrossRef]
  7. Alsina, J.; Yokum, T.S.; Albericio, F.; Barany, G. Backbone Amide Linker (BAL) Strategy for Na-9-Fluorenylmethoxycarbonyl (Fmoc) Solid-Phase Synthesis of Unprotected Peptide p-Nitroanilides and Thioesters. J. Org. Chem. 1999, 64, 8761–8769. [Google Scholar] [CrossRef]
  8. Alsina, J.; Jensen, K.J.; Albericio, F.; Barany, G. Solid-Phase Synthesis with Tris(alkoxy)benzyl Backbone Amide Linkage (BAL). Chem. A Eur. J. 1999, 5, 2787–2795. [Google Scholar] [CrossRef]
  9. Jin, J.; Graybill, T.L.; Wang, M.A.; Davis, L.D.; Moore, M.L. Convenient Preparation of 4-Formyl-3,5-Dimethoxyphenol and Its Incorporation into Linkers and Resins for Solid-Phase Synthesis. J. Comb. Chem. 2001, 3, 97–101. [Google Scholar] [CrossRef]
  10. Fisher, J.F. Convergence of the Orthogonal: A Tribute to the Imaginative Chemistry of George Barany. Int. J. Pept. Res. Ther. 2025, 31, 54. [Google Scholar] [CrossRef]
  11. Albericio, F.; Słomczyñska, U.; Barany, G. New Handles for the Synthesis of C-Terminal Peptide Amides. In Forum Peptides Le Cap d’Agde 1984; Castro, B., Martinez, J., Eds.; Les Impressions Dohr: Nancy, France, 1986; pp. 1–5. [Google Scholar]
  12. Albericio, F.; Barany, G. An acid-labile anchoring linkage for solid-phase synthesis of C-terminal peptide amides under mild conditions. Int. J. Pept. Protein Res. 1987, 30, 206–216. [Google Scholar] [CrossRef]
  13. Albericio, F.; Kneib-Cordonier, N.; Biancalana, S.; Gera, L.; Masada, R.I.; Hudson, D.; Barany, G. Preparation and Application of the 5-(4-(9-Fluorenylmethyloxycarbonyl)aminomethyl-3,5-dimethoxyphenoxy)valeric acid (PAL) Handle for the Solid-Phase Synthesis of C-Terminal Peptide Amides under Mild Conditions. J. Org. Chem. 1990, 55, 3730–3743. [Google Scholar] [CrossRef]
  14. Sharma, S.K.; Songster, M.F.; Colpitts, T.L.; Hegyes, P.; Barany, G.; Castellino, J. Reductive Amination with Tritylamine as an Ammonia Equivalent: Efficient Preparation of the 5-[4-[[(9-Fluorenylmethyloxycarbonyl)amino]methyl]-3,5-dimethoxyphenoxy]valeric Acid (PAL) Handle for Peptide Synthesis. J. Org. Chem. 1993, 58, 4993–4996. [Google Scholar] [CrossRef]
  15. Albericio, F.; Barany, G. Hypersensitive Acid-Labile (HAL) Tris(alkoxy)Benzyl Ester Anchoring for Solid-Phase Synthesis of Protected Peptide Segments. Tetrahedron Lett. 1991, 32, 1015–1018. [Google Scholar] [CrossRef]
  16. Alsina, J.; Yokum, T.S.; Albericio, F.; Barany, G. A modified Backbone Amide Linker (BAL) solid-phase peptide synthesis strategy accommodating prolyl, N-alkylamino acyl, or histidyl derivatives at the C-Terminus. Tetrahedron Lett. 2000, 41, 7277–7280. [Google Scholar] [CrossRef]
  17. Kappel, J.C.; Barany, G. Solid-Phase Synthesis of Peptide Aldehydes by a Backbone Amide Linker Strategy. J. Pept. Sci. 2005, 11, 525–535. [Google Scholar] [CrossRef]
  18. Virta, P.; Karskela, M.; Lönnberg, H. Orthogonally Protected Cyclo-β-Tetrapeptides as Solid-Supported Scaffolds for the Synthesis of Glycoclusters. J. Org. Chem. 2006, 71, 1989–1999. [Google Scholar] [CrossRef]
  19. Boas, U.; Brask, J.; Jensen, K.J. Backbone Amide Linker in Solid-Phase Synthesis. Chem. Rev. 2009, 109, 2092–2118. [Google Scholar] [CrossRef]
  20. Valverde, I.E.; Lecaille, F.; Lalmanach, G.; Aucagne, V.; Delmas, A.F. Synthesis of a Biologically Active Triazole-Containing Analogue of Cystatin A Through Successive Peptidomimetic Alkyne-Azide Ligations. Angew. Chem. Int. Ed. 2012, 51, 718–722. [Google Scholar] [CrossRef]
  21. Shelton, P.T.; Jensen, K.J. Backbone Amide Linker Strategy: Protocols for the Synthesis of C-Terminal Peptide Aldehydes. In Peptide Synthesis and Applications; Jensen, K.J., Shelton, P.T., Pedersen, S.L., Eds.; Humana Press: Totowa, NJ, USA, 2013; Volume 1047, pp. 131–139. [Google Scholar] [CrossRef]
  22. Jobin, S.; Beaumont, C.; Biron, E. Development of a solid-phase traceless-Ugi multicomponent reaction for backbone anchoring and cyclic peptide synthesis. Pept. Sci. 2019, 111, e24044. [Google Scholar] [CrossRef]
  23. Gray, N.S.; Kwon, S.; Schultz, P.G. Combinatorial Synthesis of 2,9-Substituted Purines. Tetrahedron Lett. 1997, 38, 1161–1164. [Google Scholar] [CrossRef]
  24. Boojamra, C.G.; Burow, K.M.; Thompson, L.A.; Ellman, J.A. Solid-Phase Synthesis of 1,4-Benzodiazepine-2,5-diones. Library Preparation and Demonstration of Synthesis Generality. J. Org. Chem. 1997, 62, 1240–1256. [Google Scholar] [CrossRef]
  25. Ngu, K.; Patel, D.V. A New and Efficient Solid-Phase Synthesis of Hydroxamic Acids. J. Org. Chem. 1997, 62, 7088–7089. [Google Scholar] [CrossRef]
  26. Yamashita, D.S.; Dong, X.; Oh, H.-J.; Brook, C.S.; Tomaszek, T.A.; Szewczuk, L.; Tew, D.G.; Veber, D.F. Solid-Phase Synthesis of a Combinatorial Array of 1,3-Bis(acylamino)-2-butanones, Inhibitors of the Cysteine Proteases Cathepsins K and L. J. Comb. Chem. 1999, 1, 207–215. [Google Scholar] [CrossRef] [PubMed]
  27. Forns, P.; Sevilla, S.; Erra, M.; Ortega, A.; Fernández, J.-C.; de la Figuera, N.; Fernández-Forner, D.; Albericio, F. BAL resin for the preparation of secondary amines. Tetrahedron Lett. 2003, 44, 6907–6910. [Google Scholar] [CrossRef]
  28. Kappel, J.C.; Yokum, T.S.; Barany, G. Parallel Solid-Phase Syntheses of 1,3,4-Thiadiazolium-2-Aminides. J. Comb. Chem. 2004, 6, 746–752. [Google Scholar] [CrossRef] [PubMed]
  29. Scott, W.L.; Zhou, Z.; Martynow, J.G.; O’Donnell, M.J. Solid-Phase Synthesis of Amino- and Carboxyl-Functionalized Unnatural α-Amino Acid Amides. Org. Lett. 2009, 11, 3558–3561. [Google Scholar] [CrossRef]
  30. Zajdel, P.; Król, J.; Grychowska, K.; Pawłowski, M.; Subra, G.; Nomezine, G.; Martinez, J.; Satała, G.; Bojarski, A.J.; Zhou, Z.; et al. Solid-Phase Synthesis of Arylpiperazine Derivatives and Implementation of the Distributed Drug Discovery (D3) Project in the Search for CNS Agents. Molecules 2011, 16, 4104–4121. [Google Scholar] [CrossRef]
  31. Congreve, M.S.; Ladlow, M.; Marshall, P.; Parr, N.; Scicinski, J.J.; Sheppard, T.; Vickerstaffe, E.; Carr, R.A.E. Reporter Resins for Solid-Phase Chemistry. Org. Lett. 2001, 3, 507–510. [Google Scholar] [CrossRef]
  32. Galan, J.A.; Guo, M.; Sanchez, E.E.; Cantu, E.; Rodriguez-Acosta, A.; Perez, J.C.; Tao, W.A. Quantitative Analysis of Snake Venoms Using Soluble Polymer-Based Isotope Labeling. Mol. Cell Proteom. 2008, 7, 785–799. [Google Scholar] [CrossRef]
  33. Okorochenkov, S.; Burglova, K.; Popa, I.; Hlavac, J. Solid-Supported Hydrazone of 4-(4′-Formyl-3′-Methoxyphenoxy)Butyric Acid As a New Traceless Linker for Solid-Phase Synthesis. Org. Lett. 2015, 17, 180–183. [Google Scholar] [CrossRef]
  34. Pittelkow, M.; Boas, U.; Jessing, M.; Jensen, K.J.; Christensen, J.B. Role of the peri-effect in synthesis and reactivity of highly substituted naphthaldehydes: A novel backbone amide linker for solid-phase synthesis. Org. Biomol. Chem. 2005, 3, 508–514. [Google Scholar] [CrossRef] [PubMed]
  35. Jessing, M.; Brandt, M.; Jensen, K.J.; Christensen, J.B.; Boas, U. Thiophene Backbone Amide Linkers, a New Class of Easily Prepared and Highly Acid-Labile Linkers for Solid-Phase Synthesis. J. Org. Chem. 2006, 71, 6734–6741. [Google Scholar] [CrossRef] [PubMed]
  36. Neidrauer, M.L.; Hostetler, M.A.; Khan, K.R.; Kang, S.S.; Lipton, M.A. A Photolabile Backbone Amide Linker for the Solid-Phase Synthesis of Cyclic Peptides and C-Terminal Thioesters. 2025; Manuscript in process. [Google Scholar]
  37. Hammershøj, P.; Jessing, M.; Madsen, A.Ø.; Jensen, K.J.; Christensen, J.B.; Boas, U. X-Ray Crystal Structure of a Highly Functionalized Thiophene as a New Backbone Amide Linker for Solid-phase Peptide Synthesis. Relationship between Crystal Structure and Reactivity. Int. J. Pept. Res. Ther. 2007, 13, 209–212. [Google Scholar] [CrossRef]
  38. MacRae, C.F.; Sovago, I.; Cottrell, S.J.; Galek, P.T.A.; McCabe, P.; Pidcock, E.; Platings, M.; Shields, G.P.; Stevens, J.S.; Towler, M.; et al. Mercury 4.0: From Visualization to Analysis, Design and Prediction. J. Appl. Crystallogr. 2020, 53, 226–235. [Google Scholar] [CrossRef] [PubMed]
  39. Groom, C.R.; Bruno, I.J.; Lightfoot, M.P.; Ward, S.C. The Cambridge Structural Database. Acta Crystallogr. B 2016, 72, 171–179. [Google Scholar] [CrossRef]
  40. Wuyts, C.; Vande Velde, C.M.L.; Geise, H.J.; Blockhuys, F. 4-Hydroxy-2,6-Dimethoxybenzaldehyde. Acta Crystallogr. E 2005, 61, o79–o80. [Google Scholar] [CrossRef]
  41. Pan, Z.; Xu, M.; Cheung, E.Y.; Platts, J.A.; Harris, K.D.M.; Constable, E.C.; Housecroft, C.E. Solid-State Structural Properties of 2,4,6-Trimethoxybenzene Derivatives, Determined Directly from Powder X-Ray Diffraction Data in Conjunction with Other Techniques. J. Solid State Chem. 2006, 179, 3214–3223. [Google Scholar] [CrossRef]
  42. Asiri, A.M.; Khan, S.A.; Tan, K.W.; Ng, S.W. 4-Nitroaniline–2,4,6-Trimethoxybenzaldehyde (1/1). Acta Crystallogr. E 2010, 66, o1765. [Google Scholar] [CrossRef]
  43. Bruker AXS. APEX5; Bruker AXS: Madison, WI, USA, 2023. [Google Scholar]
  44. Krause, L.; Herbst-Irmer, R.; Sheldrick, G.M.; Stalke, D. Comparison of silver and molybdenum microfocus X-ray sources for single-crystal structure determination. J. Appl. Crystallogr. 2015, 48, 3–10. [Google Scholar] [CrossRef]
  45. Bruker. SAINT; Bruker AXS Inc.: Madison, WI, USA, 2023. [Google Scholar]
  46. Sheldrick, G.M. SHELXT—Integrated space-group and crystal-structure determination. Acta Crystallogr. 2015, 71, 3–8. [Google Scholar] [CrossRef]
  47. Sheldrick, G.M. Crystal structure refinement with SHELXL. Acta Crystallogr. 2015, 71, 3–8. [Google Scholar] [CrossRef]
  48. Kratzert, D. FinalCif, V150; Available online: https://dkratzert.de/finalcif.html.
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Figure 2. Intermolecular interactions between BAL molecules: hydrogen bonding (top), π-stacking, with the blue spheres indicating the centroid of the BAL benzene rings (middle); and the arrangement of hydrogen-bonded, π-stacked, oppositely oriented chains of BAL molecules (bottom).
Figure 2. Intermolecular interactions between BAL molecules: hydrogen bonding (top), π-stacking, with the blue spheres indicating the centroid of the BAL benzene rings (middle); and the arrangement of hydrogen-bonded, π-stacked, oppositely oriented chains of BAL molecules (bottom).
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Figure 3. Intersection of planes defined by hydrogen-bonded chains of BAL. The angle between planes is 44.29°.
Figure 3. Intersection of planes defined by hydrogen-bonded chains of BAL. The angle between planes is 44.29°.
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Figure 4. Packing of BAL viewed along the crystallographic a-axis (top), b-axis (middle), and c-axis (bottom) of the unit cell. Different π-stacked chains are colored red and blue to highlight the offset packing of the chains.
Figure 4. Packing of BAL viewed along the crystallographic a-axis (top), b-axis (middle), and c-axis (bottom) of the unit cell. Different π-stacked chains are colored red and blue to highlight the offset packing of the chains.
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Table 2. Comparison of selected bond lengths, angles, and torsion angles of the 4-formyl-3,5-dimethoxy-1-alkoxy fragment 1.
Table 2. Comparison of selected bond lengths, angles, and torsion angles of the 4-formyl-3,5-dimethoxy-1-alkoxy fragment 1.
Length/AngleBALFAXXEIYUPWOW
C1–C21.446 (2) Å1.425 (4) Å1.454 (3) Å
C3–O21.3502 (18) Å1.356 (3) Å1.357 (3) Å
C5–O31.3543 (17) Å1.342 (4) Å1.358 (3) Å
C7–O41.3586 (17) Å1.350 (3) Å1.360 (3) Å
O1–C1–C2126.35 (15)°127.8 (3)°127.8 (2)°
C8–O2–C3118.22 (12)°117.9 (3)° 118.10 (19)°
C9–O4–C7117.75 (11)°117.7 (3)°117.03 (19)°
O1–C1–C2–C3−0.4 (2)°−4.7 (6)°−9.3 (4)°
C2–C3–O2–C8178.94 (13)°−174.7 (3)°−177.9 (2)°
C2–C7–O4–C9−178.51 (13)°179.7 (3)°−179.4 (2)°
1 Atom numbers for FAXXEI and YUPWOW are adjusted to align with the numbering of BAL that is defined in Figure 1.
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Lovstedt, A.; Thompson, T.R.; Barany, G. 4-(4-Formyl-3,5-dimethoxyphenoxy)butyric Acid (BAL). Molbank 2025, 2025, M2029. https://doi.org/10.3390/M2029

AMA Style

Lovstedt A, Thompson TR, Barany G. 4-(4-Formyl-3,5-dimethoxyphenoxy)butyric Acid (BAL). Molbank. 2025; 2025(3):M2029. https://doi.org/10.3390/M2029

Chicago/Turabian Style

Lovstedt, Alex, Tracy R. Thompson, and George Barany. 2025. "4-(4-Formyl-3,5-dimethoxyphenoxy)butyric Acid (BAL)" Molbank 2025, no. 3: M2029. https://doi.org/10.3390/M2029

APA Style

Lovstedt, A., Thompson, T. R., & Barany, G. (2025). 4-(4-Formyl-3,5-dimethoxyphenoxy)butyric Acid (BAL). Molbank, 2025(3), M2029. https://doi.org/10.3390/M2029

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