# Evidence: intramolecular hydrogen bonding

Parent: hydrogen bonding · class: molecular interaction · names merged here: intramolecular hydrogen bonding

6 papers measured or used it, 0 only mentioned it (of 207 kept papers). Papers in year order; each section heading ends with the paper's category / subcategory. Generated by tools/build_evidence.py from registry/concepts.csv and the cards; do not edit.

## 2011 Kestur — Influence of polymer chemistry on crystal growth inhibition of two chemically diverse organic molecules · Solid state stability / Miscibility and drug-polymer interactions

[2011-kestur-polymer-chemistry-crystal-growth-bifonazole-nimesulide](../../../cards/2011-kestur-polymer-chemistry-crystal-growth-bifonazole-nimesulide/paper.html) · Solid state stability / Miscibility and drug-polymer interactions · measured · as: intramolecular hydrogen bonding

| id | kind | content | locator |
|---|---|---|---|
| R10 | record, simulated | optimized geometry of nimesulide — DFT (P11), in vacuum — intramolecular hydrogen bond drawn (dashed line) between the sulfonamide N-H and the ether oxygen; bond length, angle and energy not printed | Fig. 5, p.6716; text p.6716 |
| R11 | record, measured | NH stretching position of nimesulide in solution — dichloromethane, 1-100 mg ml−1 (P9) — text: 3345 cm−1 at every concentration; figure: maximum ≈3345 cm−1 for all seven spectra | p.6716; Fig. S1, SI pdf p.1 |
| R12 | record, measured | NH region of crystalline and amorphous nimesulide — KBr pellet (P7) and spin-coated film (P8) — text: NH position of the undercooled melt similar to the crystal; figure: maximum ≈3288 cm−1 (crystalline, narrow band) and ≈3276 cm−1 (amorphous, broader band) | Fig. 6, p.6717; text p.6717 |
| R19 | record, cited | hydrogen bonding in the nimesulide crystal — crystal structure (ref 19); motif frequency (ref 20) — intramolecular NH···O and intermolecular NH···NO2 hydrogen bonds formed by the same NH donor; the intramolecular pattern described as a common motif occurring in crystals with high probability | p.6716 |
| C20 | claim, conclusion, authors: "also pointed to" | The nimesulide crystal shows intra- and intermolecular hydrogen bonds from the same NH donor, the intramolecular one being a common motif; DFT optimization also points to this intramolecular hydrogen bond [rests on: R19, R10] | p.6716 |
| C21 | claim, conclusion, authors: "it can be concluded" | The constant NH position (3345 cm−1) over 1-100 mg ml−1 in a non-polar solvent is consistent with a hydrogen bonded NH, so nimesulide forms an intramolecular hydrogen bond in solution [rests on: R11; cited: refs 22-24] | p.6716 |
| C22 | claim, conclusion, authors: abstract: "strongly suggested"; discussion: "it is expected"; "possibly"; "This supposition is supported" | Amorphous (supercooled) nimesulide also forms the intramolecular hydrogen bond and possibly additional intermolecular ones; the similar NH position in the undercooled melt and the crystal supports this [rests on: R12, R10, R11] | p.6712, p.6716-6717 |
| C27 | claim, mechanism, authors: discussion: "it appears"; "lend support"; "most likely explain"; abstract: asserted ("was hampered") | Involvement of the nimesulide NH in an intramolecular hydrogen bond considerably diminishes drug-polymer hydrogen bonding, supported by minimal NH changes on adding 1-ethyl-2-pyrrolidinone or acetic acid in solution; this most likely explains why the differences between polymers are smaller than anticipated [rests on: R17, R13, R14, R10-R12] | p.6712, p.6717 |

## 2011 Eerdenbrugh — An ab initio polymer selection methodology to prevent crystallization in amorphous solid dispersions by application of crystal engineering principles · Solid state stability / Miscibility and drug-polymer interactions

[2011-van-eerdenbrugh-ab-initio-polymer-selection-asd-crystallization](../../../cards/2011-van-eerdenbrugh-ab-initio-polymer-selection-asd-crystallization/paper.html) · Solid state stability / Miscibility and drug-polymer interactions · measured · as: intramolecular hydrogen bonding

| id | kind | content | locator |
|---|---|---|---|
| R5 | record, simulated | DFT equilibrium geometry of flufenamic acid — B3LYP/6-311++G(3d2f, 2p) (P6) — intramolecular hydrogen bond (dotted line) between the aniline N–H and the carboxylic acid carbonyl oxygen in the equilibrium geometry | Fig. 2a, p.6174; text p.6174 |
| R6 | record, simulated | relative energy of anthranilic acid versus C(NH2)–C–C–O(H) dihedral angle — constrained DFT scan, 0-180° in 10° steps (P6) — sub-table below; text: at dihedral angles ≤40° an intramolecular hydrogen bond between the carboxylic acid hydrogen and the aniline nitrogen; energy maximum at 80°; at 140° an intramolecular hydrogen bond forms between the aniline hydrogen and the carbonyl oxygen; energy minimum at 180°; no bifurcated intramolecular hydrogen bond | Fig. 2b, p.6174; text p.6174-6175 |
| C12 | claim, assumption, authors: "potentially" | Favourable intramolecular hydrogen bonds potentially keep good donors and acceptors out of intermolecular bonds and are rarely disrupted; 5-, 6- or 7-membered rings form in 95% of cases [rests on: cited: refs 23, 24] | p.6172 |
| C18 | claim, conclusion, authors: "confirmed"; "unlikely" | DFT confirmed the intramolecular hydrogen bond of flufenamic acid, so its aniline hydrogen is unlikely to form intermolecular bonds (donor potential lost); anthranilic acid keeps a second aniline hydrogen that can still donate, although a relatively weak donor [rests on: R5, R6, R7, R1.c, R1.g] | p.6174-6175; Table 1 footnotes c, d |

## 2012 Trasi — Effect of Additives on Crystal Growth and Nucleation of Amorphous Flutamide · Solid state stability / Physical stability

[2012-trasi-flutamide-additives-growth-nucleation](../../../cards/2012-trasi-flutamide-additives-growth-nucleation/paper.html) · Solid state stability / Physical stability · used · as: intramolecular hydrogen bonding

| id | kind | content | locator |
|---|---|---|---|
| C35 | claim, mechanism, authors: "highly likely"; "it appears"; "Clearly" | The flutamide carbonyl is a poor acceptor because part of its oxygen charge is used in an intramolecular CH···O bond with the aromatic C(5)-H, which keeps the molecule planar and, per the vacuum calculation, is highly likely kept in the amorphous state; this leaves only a partial negative charge for intermolecular bonds, so the carbonyl competes poorly for polymer donors [rests on: R23, R24, R26] | p.3228 |
| C51 | claim, mechanism, authors: "most likely" | Polymers with good donor groups were not effective growth inhibitors, most likely because the flutamide acceptor group is engaged in an intramolecular hydrogen bond [rests on: R3, R18, R19, R23] | p.3229 |
| R23 | record, simulated | lowest-energy single-molecule conformation in vacuum — flutamide (P9) — planar structure; intramolecular CH···O bond of the C=O maintained | p.3228 |
| R26 | record, cited (ref 20) | hydrogen bonding in crystalline flutamide (CSD WEZCOT) — flutamide crystal structure — amide NH bonded intermolecularly to the nitro group; amide C=O in a bifurcated bond with one intermolecular and one intramolecular CH···O contact (activated aromatic CH); intramolecular contact gives a planar molecule | p.3225, p.3228 |

## 2013 Wegiel — Mid-infrared spectroscopy as a polymer selection tool for formulating amorphous solid dispersions · Solid state stability / Miscibility and drug-polymer interactions

[2013-wegiel-mid-ir-polymer-selection-polyphenol-asd-stability](../../../cards/2013-wegiel-mid-ir-polymer-selection-polyphenol-asd-stability/paper.html) · Solid state stability / Miscibility and drug-polymer interactions · used · as: intramolecular hydrogen bonding

| id | kind | content | locator |
|---|---|---|---|
| C7 | claim, prior hypothesis, authors: "may affect" | Unlike resveratrol, naringenin and quercetin have intramolecular as well as intermolecular hydrogen bonds in the crystal, and the intramolecular bonding may affect their ability to interact with polymers; quercetin's dihydrate makes the storage condition of interest [rests on: argument only (Fig. 1)] | p.2 |
| C28 | claim, prior hypothesis, authors: "it is expected" | Because naringenin and quercetin have donors that take part only in intermolecular bonds besides intramolecularly bonded ones, some stabilization through polyphenol-polymer hydrogen bonds is expected (unlike curcumin, like resveratrol) [rests on: R16] | p.8 |
| C30 | claim, mechanism, authors: "may not be available"; "unlikely"; "most likely" | Intramolecularly bonded phenolic OH groups and the ketone acceptors are unlikely to contribute much to intermolecular bonding, so intermolecular hydrogen bonds most likely form between polyphenol phenolic OH donors and polymer acceptor groups [rests on: argument only (Fig. 1; M1, M2)] | p.9 |
| M1 | material | naringenin (±)-naringenin, 95% purity; Sigma-Aldrich (St Louis, MO) | p.2 |
| M2 | material | quercetin quercetin dihydrate; Alfa Aesar (Ward Hill, MA) | p.2 |

## 2014 Wegiel — Curcumin amorphous solid dispersions: the influence of intra and intermolecular bonding on physical stability · Solid state stability / Physical stability

[2014-wegiel-curcumin-asd-intramolecular-bonding-physical-stability](../../../cards/2014-wegiel-curcumin-asd-intramolecular-bonding-physical-stability/paper.html) · Solid state stability / Physical stability · measured · as: intramolecular hydrogen bonding

| id | kind | content | locator |
|---|---|---|---|
| R2 | record, measured | IR spectra of crystalline (stable polymorph, monoclinic form) and amorphous curcumin — P4 — crystalline: no strong carbonyl band near 1700 cm-1, prominent band at 1626 cm-1; amorphous: pattern of peaks in the 1700-1500 cm-1 region very similar to crystalline, band at 1626 cm-1 present, OH peak 3400 cm-1 (R3.a); figure: crystalline OH band sharper, near ≈3500 cm-1 (read from Fig. 3) | Fig. 3, p.979 |
| C11 | claim, conclusion, authors: "As expected"; "consistent with"; "indicating"; "to be expected" | The crystalline curcumin spectrum (no carbonyl band near 1700 cm-1, prominent band at 1626 cm-1) fits a keto-enol tautomer with a strong intramolecular hydrogen bond, and the similar amorphous spectrum shows that amorphous curcumin is predominantly this intramolecularly hydrogen-bonded keto-enol tautomer [rests on: R2, R19] | p.979 |
| C3 | claim, mechanism, authors: abstract: asserted; conclusions: asserted | Curcumin's intramolecular hydrogen bonding reduced the extent of its hydrogen bonding with polymers, so most polymers were not highly effective inhibitors and inhibition was limited [rests on: R2, R3, R4, R13] | p.976, p.985 |
| C33 | claim, mechanism, authors: "it can be supposed"; "indeed" | Since resveratrol and curcumin have similar phenol hydrogen-bonding groups, curcumin's intramolecular hydrogen bond is the critical factor that diminishes its ability to interact with PVP [rests on: R8, R9, R19] | p.984 |
| C35 | claim, generalisation, authors: discussion: "it appears"; conclusions: asserted ("Thus") | For a compound like curcumin that forms intramolecular hydrogen bonds, hydrogen bonding with polymers is impeded and crystallization is more difficult to inhibit [rests on: R3, R4, R13, R22] | p.984, p.985 |

## 2019 Que — Insights into the Dissolution Behavior of Ledipasvir-Copovidone Amorphous Solid Dispersions: Role of Drug Loading and Intermolecular Interactions · Dissolution / A. Release mechanism and LoC

[2019-que-ledipasvir-copovidone-asd-loc-interactions](../../../cards/2019-que-ledipasvir-copovidone-asd-loc-interactions/paper.html) · Dissolution / A. Release mechanism and LoC · used · as: intramolecular hydrogen bonding

| id | kind | content | locator |
|---|---|---|---|
| C26 | claim, mechanism, authors: "potentially can"; asserted | Ledipasvir F can accept a hydrogen bond from the NH of a neighbouring molecule; of the four NH groups, the two imidazole NH form stronger intramolecular hydrogen bonds to a carbonyl (seven-member ring), giving larger, higher-shift peaks little affected by VP, while the other two NH can bond intermolecularly to F [rests on: R24] | p.26 |
| R24 | record, measured | 1H NMR NH peaks with VP monomer — P8; as R23 — four NH peaks above 10 ppm (text); at 0 mg/mL VP ≈11.18 and ≈10.99 ppm (larger) and ≈10.74 and ≈10.56 ppm (smaller); at 80 mg/mL ≈11.27, ≈11.16, ≈11.03, ≈10.97 ppm; across 0 to 80 mg/mL the two smaller peaks move downfield by ≈0.4 ppm, the two larger by ≤ ≈0.1 ppm (read from Fig. 14; peaks tracked across traces by the extractor) | Fig. 14, p.31; text p.26, p.35 |