View source for Hydrogen bond

{{short description|Intermolecular attraction between a hydrogen-donor pair and an acceptor}}

[[Image:3D model hydrogen bonds in water.svg|right|thumb|Model of hydrogen bonds (1) between molecules of [[Properties of water|water]]]]
[[File:NTCDI AFM2a.jpg|thumb|[[Non-contact atomic force microscopy|AFM]] image of [[naphthalenetetracarboxylic diimide]] molecules on silver-terminated silicon, interacting via hydrogen bonding, taken at 77 K.<ref>{{cite journal|doi=10.1038/ncomms4931|title=Mapping the force field of a hydrogen-bonded assembly|journal=Nature Communications|volume=5|pages=3931|year=2014|last1=Sweetman|first1=A. M.|last2=Jarvis|first2=S. P.|last3=Sang|first3=Hongqian|last4=Lekkas|first4=I.|last5=Rahe|first5=P.|last6=Wang|first6=Yu|last7=Wang|first7=Jianbo|last8=Champness|first8=N.R.|last9=Kantorovich|first9=L.|last10=Moriarty|first10=P.|bibcode=2014NatCo...5.3931S|pmid=24875276|pmc=4050271}}</ref> ("Hydrogen bonds" in the top image are exaggerated by artifacts of the imaging technique.<ref>{{Cite journal|last1=Hapala|first1=Prokop|last2=Kichin|first2=Georgy|last3=Wagner|first3=Christian|last4=Tautz|first4=F. Stefan|last5=Temirov|first5=Ruslan|last6=Jelínek|first6=Pavel|date=2014-08-19|title=Mechanism of high-resolution STM/AFM imaging with functionalized tips|journal=Physical Review B|volume=90|issue=8|pages=085421|doi=10.1103/PhysRevB.90.085421|arxiv=1406.3562|bibcode=2014PhRvB..90h5421H|s2cid=53610973}}</ref><ref>{{cite journal |last1=De Luca |first1=S. |last2=Chen |first2=F. |last3=Seal |first3=P. |last4=Stenzel |first4=M. H. |last5=Smith |first5=S. C. |date=2017 |title=Binding and Release between Polymeric Carrier and Protein Drug: pH-Mediated Interplay of Coulomb Forces, Hydrogen Bonding, van der Waals Interactions, and Entropy |url=https://doi.org/10.1021/acs.biomac.7b00657 |journal=Biomacromolecules |volume=18 |issue=11 |pages=3665–3677 | pmid=28880549 | doi=10.1021/acs.biomac.7b00657|hdl=1959.4/unsworks_55160 |hdl-access=free }}</ref><ref>{{Cite journal|last1=Hämäläinen|first1=Sampsa K.|last2=van der Heijden|first2=Nadine|last3=van der Lit|first3=Joost|last4=den Hartog|first4=Stephan|last5=Liljeroth|first5=Peter|last6=Swart|first6=Ingmar|date=2014-10-31|title=Intermolecular Contrast in Atomic Force Microscopy Images without Intermolecular Bonds|journal=Physical Review Letters|volume=113|issue=18|pages=186102|doi=10.1103/PhysRevLett.113.186102|pmid=25396382|url=http://dspace.library.uu.nl:8080/handle/1874/307996|bibcode=2014PhRvL.113r6102H|url-status=dead|archive-url=https://web.archive.org/web/20180120232850/http://dspace.library.uu.nl:8080/handle/1874/307996|archive-date=2018-01-20|arxiv=1410.1933|hdl=1874/307996|s2cid=8309018|access-date=2017-08-30}}</ref>)]]

'''In [[chemistry]], a hydrogen bond (H-bond)''' is a specific type of molecular interaction that exhibits '''partial''' covalent character and cannot be described as a purely [[electrostatic force]]'''.''' It occurs when a [[hydrogen]] (H) atom, [[Covalent bond|covalently]] bonded to a more [[Electronegativity|electronegative]] donor atom or group ('''Dn'''), interacts with another electronegative atom bearing a [[lone pair]] of electrons—the hydrogen bond acceptor ('''Ac'''). Unlike simple [[Dipole–dipole attraction|dipole–dipole]] interactions, hydrogen bonding arises from charge transfer (nB → σ*AH), [[Atomic orbital|orbital]] interactions, and quantum mechanical [[Delocalized electron|delocalization]], making it a '''resonance-assisted interaction''' rather than a mere electrostatic attraction.<ref name=":1">{{Cite journal |last=Weinhold |first=Frank |last2=Klein |first2=Roger A. |date=2014-07-08 |title=What is a hydrogen bond? Resonance covalency in the supramolecular domain |url=https://pubs.rsc.org/en/content/articlelanding/2014/rp/c4rp00030g |journal=Chemistry Education Research and Practice |language=en |volume=15 |issue=3 |pages=276–285 |doi=10.1039/C4RP00030G |issn=1756-1108}}</ref>

The general notation for hydrogen bonding is '''Dn−H···Ac''', where the solid line represents a polar covalent bond, and the dotted or dashed line indicates the hydrogen bond.<ref name=":0">{{Cite journal |last1=Arunan |first1=Elangannan |last2=Desiraju |first2=Gautam R. |last3=Klein |first3=Roger A. |last4=Sadlej |first4=Joanna |last5=Scheiner |first5=Steve |last6=Alkorta |first6=Ibon |last7=Clary |first7=David C. |last8=Crabtree |first8=Robert H. |last9=Dannenberg |first9=Joseph J. |date=2011-07-08 |title=Definition of the hydrogen bond (IUPAC Recommendations 2011) |journal=Pure and Applied Chemistry |volume=83 |issue=8 |pages=1637–1641 |doi=10.1351/PAC-REC-10-01-02 |issn=1365-3075 |s2cid=97688573 |doi-access=free}}</ref> The most frequent donor and acceptor atoms are [[nitrogen]] (N), [[oxygen]] (O), and [[fluorine]] (F), due to their high electronegativity and ability to engage in stronger hydrogen bonding.

The term "hydrogen bond" is generally used for well-defined, localized interactions with significant charge transfer and orbital overlap, such as those in DNA base pairing or ice. In contrast, "hydrogen-bonding interactions" is a broader term used when the interaction is weaker, more dynamic, or delocalized, such as in liquid water, supramolecular assemblies (e.g.: [[Lipid bilayer|lipid membranes]], [[Protein–protein interaction|protein-protein interactions]]), or weak C-H···O interactions. This distinction is particularly relevant in [[structural biology]], [[materials science]], and [[computational chemistry]], where hydrogen bonding spans a continuum from weak van der Waals-like interactions to nearly covalent bonding.<ref name=":1" />

Hydrogen bonding can occur between separate molecules (intermolecular) or within different parts of the same molecule (intramolecular).<ref>Pimentel, G. ''The Hydrogen Bond''  Franklin Classics, 2018), {{ISBN|0343171600}}</ref><ref>Jeffrey, G. A.; ''An introduction to hydrogen bonding''; Oxford university press New York, 1997. {{ISBN|0195095499}}</ref><ref>Jeffrey, G. A.; Saenger, W. ''Hydrogen bonding in biological structures''; Springer: Berlin, '''1994, 2012'''  Springer; {{ISBN|3540579036}}</ref><ref>{{GoldBookRef|file=H02899|title=hydrogen bond}}</ref> Its strength varies considerably, depending on geometry, environment, and the donor-acceptor pair, typically ranging from 1 to 40 kcal/mol.<ref name="The Hydrogen Bond in the Solid Stat">{{cite journal |last1=Steiner |first1=Thomas |year=2002 |title=The Hydrogen Bond in the Solid State |journal=[[Angew. Chem. Int. Ed.]] |volume=41 |issue=1 |pages=48–76 |doi=10.1002/1521-3773(20020104)41:1<48::AID-ANIE48>3.0.CO;2-U |pmid=12491444}}</ref> This places hydrogen bonds stronger than [[Van der Waals force|van der Waals interactions]] but generally weaker than [[Covalent bond|covalent]] or [[Ionic bonding|ionic bonds]].

Hydrogen bonding plays a fundamental role in chemistry, biology, and materials science. It is responsible for the anomalously high boiling point of water, the stabilization of protein and nucleic acid structures, and key properties of materials like paper, wool, and hydrogels. In biological systems, hydrogen bonds mediate molecular recognition, enzyme catalysis, and DNA replication, while in materials science, they contribute to self-assembly, adhesion, and supramolecular organization.

==Bonding==
[[Image:Hydrogen Bond Quadruple AngewChemIntEd 1998 v37 p75.jpg|thumb|300px|An example of [[intermolecular]] hydrogen bonding in a [[molecular self-assembly|self-assembled]] dimer complex.<ref>{{cite journal| journal=[[Angew. Chem. Int. Ed.]] |title= Self-Complementarity Achieved through Quadruple Hydrogen Bonding| year= 1998|volume=37|issue=1–2 |pages= 75–78| doi=10.1002/(SICI)1521-3773(19980202)37:1/2<75::AID-ANIE75>3.0.CO;2-R|last1= Beijer|first1= Felix H.|last2= Kooijman|first2= Huub|last3= Spek|first3= Anthony L.|last4= Sijbesma|first4= Rint P.|last5= Meijer|first5= E. W.}}</ref> The hydrogen bonds are represented by dotted lines.]]
[[File:Acetylacetone tautomerism.svg|thumb|300x300px|[[Intramolecular force|Intramolecular]] hydrogen bonding in [[acetylacetone]] helps stabilize the [[enol]] [[tautomer]].]]

===Definitions and general characteristics===
In a hydrogen bond, the electronegative atom not covalently attached to the hydrogen is named the proton acceptor, whereas the one covalently bound to the hydrogen is named the proton donor. This nomenclature is recommended by the IUPAC.<ref name=":0"/> The hydrogen of the donor is protic and therefore can act as a Lewis acid and the acceptor is the Lewis base. Hydrogen bonds are represented as {{chem2|H***Y}} system, where the dots represent the hydrogen bond. Liquids that display hydrogen bonding (such as water) are called '''associated liquids'''.{{cn|date=June 2023}}
[[File:H-donor-acceptor.svg|alt=|thumb|320x320px|Examples of hydrogen bond donating (donors) and hydrogen bond accepting groups (acceptors)]]
[[File:Acetic Acid Hydrogenbridge V.1.svg|thumb|300px|Cyclic dimer of acetic acid; dashed <span style="color:green;">'''green'''</span> lines represent hydrogen bonds]]

Hydrogen bonds arise from a combination of electrostatics (multipole-multipole and multipole-induced multipole interactions), covalency (charge transfer by orbital overlap), and dispersion ([[London dispersion force|London forces]]).<ref name=":0" />

In weaker hydrogen bonds,<ref>Desiraju, G. R. and Steiner, T. The Weak Hydrogen Bond: In Structural Chemistry and Biology, International Union of Crystallography;'''2001''', {{ISBN|0198509707}}</ref> hydrogen atoms tend to bond to elements such as sulfur (S) or chlorine (Cl); even carbon (C) can serve as a donor, particularly when the carbon or one of its neighbors is electronegative (e.g., in chloroform, aldehydes and terminal acetylenes).<ref>Nishio, M.; Hirota, M.; Umezawa, Y. ''The CH–π Interactions''; Wiley-VCH, New York, 1998. •  Wiley-VCH; 1998) {{ISBN|0471252905}}</ref><ref>{{cite journal | last1 = Nishio | first1 = M | year = 2011 | title = The CH/[small pi] hydrogen bond in chemistry. "Title | journal = Phys. Chem. Chem. Phys. | volume = 13 | issue = 31 | pages = 13873–13900 | doi=10.1039/c1cp20404a| pmid = 21611676 }}</ref> Gradually, it was recognized that there are many examples of weaker hydrogen bonding involving donor other than N, O, or F and/or acceptor Ac with electronegativity approaching that of hydrogen (rather than being much more electronegative). Although weak (≈1&nbsp;kcal/mol), "non-traditional" hydrogen bonding interactions are ubiquitous and influence structures of many kinds of materials.{{cn|date=June 2023}}

The definition of hydrogen bonding has gradually broadened over time to include these weaker attractive interactions. In 2011, an [[IUPAC]] Task Group recommended a modern evidence-based definition of hydrogen bonding, which was published in the IUPAC journal ''[[Pure and Applied Chemistry]]''. This definition specifies:
{{blockquote|The hydrogen bond is an attractive interaction between a hydrogen atom from a molecule or a molecular fragment {{chem2|X\sH}} in which X is more electronegative than H, and an atom or a group of atoms in the same or another molecule, in which there is evidence of bond formation.<ref name="arunen2011">{{cite journal|title = Definition of the hydrogen bond|journal = [[Pure Appl. Chem.]]|year = 2011|volume = 83|issue = 8|pages = 1637–1641|doi = 10.1351/PAC-REC-10-01-02 |last1 = Arunan|first1 = Elangannan|last2 = Desiraju|first2 = Gautam R.|last3 = Klein|first3 = Roger A.|last4 = Sadlej|first4 = Joanna|last5 = Scheiner|first5 = Steve|last6 = Alkorta|first6 = Ibon|last7 = Clary|first7 = David C.|last8 = Crabtree|first8 = Robert H.|last9 = Dannenberg|first9 = Joseph J.|last10 = Hobza|first10 = Pavel|last11 = Kjaergaard|first11 = Henrik G.|last12 = Legon|first12 = Anthony C.|last13 = Mennucci|first13 = Benedetta|last14 = Nesbitt|first14 = David J.|s2cid = 97688573|doi-access = free}}</ref>}}

===Bond strength===
Hydrogen bonds can vary in strength from weak (1–2&nbsp;kJ/mol) to strong (161.5&nbsp;kJ/mol in the [[bifluoride]] ion, {{chem2|HF2-}}).<ref name=halide>{{cite journal|doi=10.1021/ic00182a010|title=Gas-phase bihalide and pseudobihalide ions. An ion cyclotron resonance determination of hydrogen bond energies in XHY- species (X, Y = F, Cl, Br, CN)|year=1984|last1=Larson|first1=J. W.|last2=McMahon|first2=T. B.|journal=Inorganic Chemistry|volume=23|issue=14|pages=2029–2033|title-link=ion cyclotron resonance}}</ref><ref name= Emsley>{{cite journal|author = Emsley, J.|title = Very Strong Hydrogen Bonds|journal = [[Chemical Society Reviews]]|year = 1980|volume = 9|issue = 1|pages = 91–124|doi = 10.1039/cs9800900091}}</ref> Typical [[Enthalpy|enthalpies]] in vapor include:<ref>V. David, N. Grinberg, S. C. Moldoveanu in ''Advances in Chromatography Volume 54'' (Eds.: E. Grushka, N. Grinberg), CRC Press, Boca Raton, '''2018''', chapter 3.</ref>
* {{chem2|F\sH***:F-}}  (161.5&nbsp;kJ/mol or 38.6&nbsp;kcal/mol), illustrated uniquely by {{chem2|HF2-}}
* {{chem2|O\sH***:N}}  (29&nbsp;kJ/mol or 6.9&nbsp;kcal/mol), illustrated water-ammonia
* {{chem2|O\sH***:O}}  (21&nbsp;kJ/mol or 5.0&nbsp;kcal/mol), illustrated water-water, alcohol-alcohol
* {{chem2|N\sH***:N}}  (13&nbsp;kJ/mol or 3.1&nbsp;kcal/mol), illustrated by ammonia-ammonia
* {{chem2|N\sH***:O}}  (8&nbsp;kJ/mol or 1.9&nbsp;kcal/mol), illustrated water-amide
* {{chem2|OH3+***:OH2}}  (18&nbsp;kJ/mol<ref>Data obtained using [[molecular dynamics]] as detailed in the reference and should be compared to 7.9 kJ/mol for bulk water, obtained using the same calculation.{{cite journal|title = Structure and energetics of the hydronium hydration shells|author1 = Markovitch, Omer|author2 = Agmon, Noam|journal = [[J. Phys. Chem. A]]|year = 2007|volume = 111|issue = 12|pages = 2253–2256|doi = 10.1021/jp068960g|pmid = 17388314|bibcode = 2007JPCA..111.2253M|url = http://www.fh.huji.ac.il/~agmon/Fullpaper/JPCA111-2253.pdf|url-status = dead|archive-url = https://web.archive.org/web/20140813174617/http://www.fh.huji.ac.il/%7Eagmon/Fullpaper/JPCA111-2253.pdf|archive-date = 2014-08-13|citeseerx = 10.1.1.76.9448|access-date = 2017-10-25}}</ref> or 4.3&nbsp;kcal/mol)
The strength of intermolecular hydrogen bonds is most often evaluated by measurements of equilibria between molecules containing donor and/or acceptor units, most often in solution.<ref>{{cite journal | vauthors = Biedermann F, Schneider HJ | title = Experimental Binding Energies in Supramolecular Complexes | journal = Chemical Reviews | volume = 116 | issue = 9 | pages = 5216–300 | date = May 2016 | pmid = 27136957 | doi = 10.1021/acs.chemrev.5b00583 }}</ref> The strength of intramolecular hydrogen bonds can be studied with equilibria between conformers with and without hydrogen bonds. The most important method for the identification of hydrogen bonds also in complicated molecules is [[crystallography]], sometimes also NMR-spectroscopy. Structural details, in particular distances between donor and acceptor which are smaller than the sum of the van der Waals radii can be taken as indication of the hydrogen bond strength. One scheme gives the following somewhat arbitrary classification: those that are 15 to 40&nbsp;kcal/mol, 5 to 15&nbsp;kcal/mol, and >0 to 5&nbsp;kcal/mol are considered strong, moderate, and weak, respectively.<ref name= Emsley/>

Hydrogen bonds involving C-H bonds are both very rare and weak.<ref>{{cite journal |doi=10.1021/ja991795g |title=Fundamental Properties of the CH···O Interaction: Is It a True Hydrogen Bond? |date=1999 |last1=Gu |first1=Yanliang |last2=Kar |first2=Tapas |last3=Scheiner |first3=Steve |journal=Journal of the American Chemical Society |volume=121 |issue=40 |pages=9411–9422 |bibcode=1999JAChS.121.9411G }}</ref>

===Resonance assisted hydrogen bond===
The '''resonance assisted hydrogen bond''' (commonly abbreviated as RAHB) is a strong type of hydrogen bond. It is characterized by the π-delocalization that involves the hydrogen and cannot be properly described by the [[electrostatic]] model alone. This description of the hydrogen bond has been proposed to describe unusually short distances generally observed between {{chem2|O\dC\sOH***}} or {{chem2|***O\dC\sC\dC\sOH}}.<ref>{{cite journal |doi=10.1021/acs.jpca.7b09425 |title=The Origin of the Non-Additivity in Resonance-Assisted Hydrogen Bond Systems |year=2017 |last1=Lin |first1=Xuhui |last2=Zhang |first2=Huaiyu |last3=Jiang |first3=Xiaoyu |last4=Wu |first4=Wei |last5=Mo |first5=Yirong |journal=The Journal of Physical Chemistry A |volume=121 |issue=44 |pages=8535–8541 |pmid=29048895 |bibcode=2017JPCA..121.8535L }}</ref>

===Structural details===
The {{chem2|X\sH}} distance is typically ≈110&nbsp;[[picometre|pm]], whereas the {{chem2|H***Y}} distance is ≈160 to 200&nbsp;pm. The typical length of a hydrogen bond in water is 197&nbsp;pm. The ideal bond angle depends on the nature of the hydrogen bond donor. The following hydrogen bond angles between a hydrofluoric acid donor and various acceptors have been determined experimentally:<ref>{{cite journal|doi=10.1039/CS9871600467|title=Angular geometries and other properties of hydrogen-bonded dimers: a simple electrostatic interpretation of the success of the electron-pair model|year=1987|last1=Legon|first1=A. C.|last2=Millen|first2=D. J.|journal=Chemical Society Reviews|volume=16|pages=467}}</ref>
{|class="wikitable" style="text-align:left"
|-
!{{nowrap|Acceptor···donor}}||VSEPR geometry||Angle (°)
|-
|{{chem2|HCN***HF}}||linear||style="text-align:right"|180
|-
|{{chem2|H2CO***HF}}||trigonal planar||style="text-align:right"|120
|-
|{{chem2|H2O***HF}}||pyramidal||style="text-align:right"|46
|-
|{{chem2|H2S***HF}}||pyramidal||style="text-align:right"|89
|-
|{{chem2|SO2***HF}}{{verification needed|reason=Is it the oxygen(s) acceptor, or by analogy to rest of table should it be O2S...HF with S acceptor?|date=October 2022}}||trigonal ||style="text-align:right"|142
|-
|}

===Spectroscopy===
Strong hydrogen bonds are revealed by downfield shifts in the [[proton NMR spectroscopy|<sup>1</sup>H NMR spectrum]]. For example, the acidic proton in the enol tautomer of [[acetylacetone]] appears at {{tmath|\delta_\text{H} }}&nbsp;15.5, which is about 10&nbsp;ppm downfield of a conventional alcohol.<ref>Friebolin, H., "Basic One- and Two- Dimensional NMR Spectroscopy, 4th ed.," VCH: Weinheim, 2008. {{ISBN|978-3-527-31233-7}}</ref>

In the IR spectrum, hydrogen bonding shifts the {{chem2|X\sH}} stretching frequency to lower energy (i.e. the vibration frequency decreases). This shift reflects a weakening of the {{chem2|X\sH}} bond. Certain hydrogen bonds - improper hydrogen bonds - show a blue shift of the {{chem2|X\sH}} stretching frequency and a decrease in the bond length.<ref>{{cite journal |vauthors=Hobza P, Havlas Z |title=Blue-Shifting Hydrogen Bonds |journal=Chem. Rev. |volume=100 |issue=11 |pages=4253–4264 |year=2000 |doi=10.1021/cr990050q |pmid=11749346 }}</ref> H-bonds can also be measured by IR vibrational mode shifts of the acceptor. The amide I mode of backbone carbonyls in α-helices shifts to lower frequencies when they form H-bonds with side-chain hydroxyl groups.<ref name="Feldblum 2014 4085–4090">{{cite journal|last=Feldblum|first=Esther S.|author2=Arkin, Isaiah T.|title=Strength of a bifurcated H bond|journal=Proceedings of the National Academy of Sciences|volume=111|issue=11|pages=4085–4090|year=2014|doi=10.1073/pnas.1319827111|pmid=24591597|pmc=3964065|bibcode=2014PNAS..111.4085F|doi-access=free}}</ref> The dynamics of hydrogen bond structures in water can be probed by this OH stretching vibration.<ref name="cowan">{{cite journal |author=Cowan ML |title=Ultrafast memory loss and energy redistribution in the hydrogen bond network of liquid H<sub>2</sub>O |journal=Nature |volume=434 |issue=7030 |pages=199–202 |year=2005 |pmid=15758995 |doi=10.1038/nature03383 |author2=Bruner BD |author3=Huse N |display-authors=3 |last4=Dwyer |first4=J. R. |last5=Chugh |first5=B. |last6=Nibbering |first6=E. T. J. |last7=Elsaesser |first7=T. |last8=Miller |first8=R. J. D.|bibcode = 2005Natur.434..199C |s2cid=4396493 }}</ref> In the hydrogen bonding network in protic organic ionic plastic crystals (POIPCs), which are a type of phase change material exhibiting solid-solid [[phase transition]]s prior to melting, variable-temperature infrared spectroscopy can reveal the temperature dependence of hydrogen bonds and the dynamics of both the anions and the cations.<ref name="1,2,4-Triazolium perfluorobutanesulfonate as an archetypal pure protic organic ionic plastic crystal electrolyte for all-solid-state fuel cells"/> The sudden weakening of hydrogen bonds during the solid-solid phase transition seems to be coupled with the onset of orientational or rotational disorder of the ions.<ref name="1,2,4-Triazolium perfluorobutanesulfonate as an archetypal pure protic organic ionic plastic crystal electrolyte for all-solid-state fuel cells">
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===Theoretical considerations===
Hydrogen bonding is of persistent theoretical interest.<ref>{{ Cite journal|last1=Weinhold|first1=Frank|last2=Klein|first2=Roger A.|year=2014|volume=15|pages=276–285|title=What is a hydrogen bond? Resonance covalency in the supramolecular domain|journal=Chemistry Education Research and Practice|issue=3|doi=10.1039/c4rp00030g}}</ref> According to a modern description {{chem2|O:H\sO}} integrates both the intermolecular O:H lone pair ":" nonbond and the intramolecular {{chem2|H\sO}} polar-covalent bond associated with {{chem2|O\sO}} repulsive coupling.<ref>{{cite book|title= The Attribute of Water: Single Notion, Multiple Myths|year= 2016|isbn=978-981-10-0178-9|author= Sun, C. Q. |author2 = Sun, Yi |publisher= Springer}}</ref>

Quantum chemical calculations of the relevant interresidue potential constants ([[Compliance Constants|compliance constants]]) revealed{{how|date=December 2015}} large differences between individual H bonds of the same type. For example, the central interresidue {{chem2|N\sH***N}} hydrogen bond between guanine and cytosine is much stronger in comparison to the {{chem2|N\sH***N}} bond between the adenine-thymine pair.<ref>{{cite journal|doi=10.1021/ja046282a|pmid=15600318|title=Direct Assessment of Interresidue Forces in Watson−Crick Base Pairs Using Theoretical Compliance Constants|journal=Journal of the American Chemical Society|volume=126|issue=50|pages=16310–1|year=2004|last1=Grunenberg|first1=Jörg|bibcode=2004JAChS.12616310G }}</ref>

Theoretically, the bond strength of the hydrogen bonds can be assessed using NCI index, [[non-covalent interactions index]], which allows a visualization of these [[non-covalent interactions]], as its name indicates, using the electron density of the system.{{cn|date=June 2023}}

Interpretations of the [[anisotropy|anisotropies]] in the [[Compton scattering|Compton profile]] of ordinary ice claim that the hydrogen bond is partly covalent.<ref>{{cite journal|last1=Isaacs |first1=E.D.|last2=Shukla|first2=A.|last3=Platzman|first3=P.|last4=Hamann|first4=D.R.|last5=Barbiellini|first5=B.|last6=Tulk|first6=C.A.|journal= Physical Review Letters |doi=10.1103/PhysRevLett.82.600|title=Covalency of the Hydrogen Bond in Ice: A Direct X-Ray Measurement|year=1999|volume=82|issue=3|pages=600–603|bibcode = 1999PhRvL..82..600I}}</ref> However, this interpretation was challenged <ref>{{Cite journal|last1=Ghanty|first1=Tapan K.|last2=Staroverov|first2=Viktor N.|last3=Koren|first3=Patrick R.|last4=Davidson|first4=Ernest R.|date=2000-02-01|title=Is the Hydrogen Bond in Water Dimer and Ice Covalent?|journal=Journal of the American Chemical Society|volume=122|issue=6|pages=1210–1214|doi=10.1021/ja9937019|bibcode=2000JAChS.122.1210G |issn=0002-7863}}</ref> and subsequently clarified. <ref>{{Cite journal|last1=Barbiellini|first1=B.| last2=Shukla|first2=A.|date=2002|title= Ab initio calculations of the hydrogen bond |journal=Physical Review B |volume=66|issue=23|pages=235101|doi=10.1103/PhysRevB.66.235101|arxiv=cond-mat/0210316|bibcode=2002PhRvB..66w5101B }} </ref>

Most generally, the hydrogen bond can be viewed as a [[metric (mathematics)|metric]]-dependent [[electrostatic]] [[scalar field]] between two or more intermolecular bonds. This is slightly different from the [[Intramolecular force|intramolecular]] [[bound states]] of, for example, [[covalent bond|covalent]] or [[ionic bond]]s. However, hydrogen bonding is generally still a [[bound state]] phenomenon, since the [[interaction energy]] has a net negative sum. The initial theory of hydrogen bonding proposed by [[Linus Pauling]] suggested that the hydrogen bonds had a partial covalent nature. This interpretation remained controversial until [[nuclear magnetic resonance|NMR techniques]] demonstrated information transfer between hydrogen-bonded nuclei, a feat that would only be possible if the hydrogen bond contained some covalent character.<ref>{{cite journal|title = Observation of through-hydrogen-bond (2h)J(HC') in a perdeuterated protein|journal = [[J Magn Reson]]|year = 1999|volume = 140|pages = 510–2|doi = 10.1006/jmre.1999.1899|pmid = 10497060|issue = 2|bibcode = 1999JMagR.140..510C |last1 = Cordier|first1 = F|last2 = Rogowski|first2 = M|last3 = Grzesiek|first3 = S|last4 = Bax|first4 = A|s2cid = 121429}}</ref>

==History==
The concept of hydrogen bonding once was challenging.<ref>{{cite journal|title=Hydrogen bonding: Homing in on a tricky chemical concept|author=Needham, Paul |journal=Studies in History and Philosophy of Science Part A|volume=44|year=2013|issue=1 |pages=51–65|doi=10.1016/j.shpsa.2012.04.001|bibcode=2013SHPSA..44...51N }}</ref> [[Linus Pauling]] credits T. S. Moore and T. F. Winmill with the first mention of the hydrogen bond, in 1912.<ref>{{cite book
 |last=Pauling |first=L.
 |title=The nature of the chemical bond and the structure of molecules and crystals; an introduction to modern structural chemistry
 |url=https://archive.org/details/natureofchemical00paul |url-access=registration |publisher=Cornell University Press
 |location=Ithaca (NY)
 |year=1960
 |edition=3rd
 |page=[https://archive.org/details/natureofchemical00paul/page/450 450]
 |isbn=978-0-8014-0333-0
}}</ref><ref>{{cite journal|journal=J. Chem. Soc. |volume=101|page=1635|author1=Moore, T. S.|author2=Winmill, T. F. |title=The state of amines in aqueous solution|doi=10.1039/CT9120101635|year=1912}}</ref> Moore and Winmill used the hydrogen bond to account for the fact that trimethylammonium hydroxide is a weaker base than [[tetramethylammonium hydroxide]]. The description of hydrogen bonding in its better-known setting, water, came some years later, in 1920, from [[Wendell Mitchell Latimer|Latimer]] and Rodebush.<ref>{{cite journal|doi=10.1021/ja01452a015|year=1920|last1=Latimer|first1=Wendell M.|last2=Rodebush|first2=Worth H.|journal=Journal of the American Chemical Society|volume=42|issue=7|pages=1419–1433|title=Polarity and ionization from the standpoint of the Lewis theory of valence|bibcode=1920JAChS..42.1419L |url=https://zenodo.org/record/1428832}}</ref> In that paper, Latimer and Rodebush cited the work of a fellow scientist at their laboratory, [[Maurice Loyal Huggins]], saying, "Mr. Huggins of this laboratory in some work as yet unpublished, has used the idea of a hydrogen kernel held between two atoms as a theory in regard to certain organic compounds."

==Hydrogen bonds in small molecules==
[[Image:Hex ice.GIF|thumb|right|Crystal structure of hexagonal ice. Gray dashed lines indicate hydrogen bonds]]
[[File:NIMGLO12.png|right|thumb|120px|Structure of [[nickel bis(dimethylglyoximate)]], which features two linear hydrogen-bonds.]]

===Water===
An ubiquitous example of a hydrogen bond is found between [[water]] molecules. In a discrete water molecule, there are two hydrogen atoms and one oxygen atom.  The simplest case is a pair of [[water]] molecules with one hydrogen bond between them, which is called the [[water dimer]] and is often used as a model system. When more molecules are present, as is the case with liquid water, more bonds are possible because the oxygen of one water molecule has two lone pairs of electrons, each of which can form a hydrogen bond with a hydrogen on another water molecule. This can repeat such that every water molecule is H-bonded with up to four other molecules, as shown in the figure (two through its two lone pairs, and two through its two hydrogen atoms). Hydrogen bonding strongly affects the [[crystal structure]] of [[ice]], helping to create an open hexagonal lattice. The density of ice is less than the density of water at the same temperature; thus, the solid phase of water floats on the liquid, unlike most other substances.{{cn|date=June 2023}}

[[Liquid]] water's high [[boiling point]] is due to the high number of hydrogen bonds each molecule can form, relative to its low [[molecular mass]]. Owing to the difficulty of breaking these bonds, water has a very high boiling point, melting point, and viscosity compared to otherwise similar liquids not conjoined by hydrogen bonds. Water is unique because its oxygen atom has two lone pairs and two hydrogen atoms, meaning that the total number of bonds of a water molecule is up to four.<ref>{{Cite web |date=2017-06-29 |title=11.9: Water - An Extraordinary Substance |url=https://chem.libretexts.org/Courses/Sacramento_City_College/Chem_400%3A_General_Chemistry_I/11%3A_Liquids%2C_Solids%2C_and_Intermolecular_Forces/11.09%3A_Water%3A_An_Extraordinary_Substance |access-date=2024-06-22 |website=Chemistry LibreTexts |language=en}}</ref>

The number of hydrogen bonds formed by a molecule of liquid water fluctuates with time and temperature.<ref name="Jorgensen1985"/>   From [[water model|TIP4P]] liquid water simulations at 25&nbsp;°C, it was estimated that each water molecule participates in an average of 3.59 hydrogen bonds. At 100&nbsp;°C, this number decreases to 3.24 due to the increased molecular motion and decreased density, while at 0&nbsp;°C, the average number of hydrogen bonds increases to 3.69.<ref name="Jorgensen1985">{{cite journal|author1=Jorgensen, W. L.  |author2=Madura, J. D. | title=Temperature and size dependence for Monte Carlo simulations of TIP4P water| journal=[[Mol. Phys.]]|year=1985| volume=56 |issue=6 |pages=1381 |doi=10.1080/00268978500103111|bibcode = 1985MolPh..56.1381J }}</ref> Another study found a much smaller number of hydrogen bonds: 2.357 at 25&nbsp;°C.<ref>{{cite journal|author=Zielkiewicz, Jan |title= Structural properties of water: Comparison of the SPC, SPCE, TIP4P, and TIP5P models of water| journal=[[J. Chem. Phys.]]|volume= 123|pages=104501|year=2005| doi=10.1063/1.2018637|pmid=16178604|issue=10|bibcode = 2005JChPh.123j4501Z }}</ref> Defining and counting the hydrogen bonds is not straightforward however.

Because water may form hydrogen bonds with solute proton donors and acceptors, it may competitively inhibit the formation of solute intermolecular or intramolecular hydrogen bonds. Consequently, hydrogen bonds between or within solute molecules dissolved in water are almost always unfavorable relative to hydrogen bonds between water and the donors and acceptors for hydrogen bonds on those solutes.<ref>{{cite journal|author=Jencks, William |title= Hydrogen Bonding between Solutes in Aqueous Solution| journal=[[J. Am. Chem. Soc.]]|volume= 108|pages=4196|year=1986|issue=14|doi=10.1021/ja00274a058|last2=Jencks|first2=William P.|bibcode= 1986JAChS.108.4196S}}</ref> Hydrogen bonds between water molecules have an average lifetime of 10<sup>−11</sup> seconds, or 10 picoseconds.<ref name="Dillon">{{cite book|last=Dillon|first=P. F.|title=Biophysics: A Physiological Approach|url=https://books.google.com/books?id=5IYKLIx-Jt4C|year=2012|publisher=Cambridge University Press|isbn=978-1-139-50462-1|page=37}}</ref>

=== Bifurcated and over-coordinated hydrogen bonds in water ===
A single hydrogen atom can participate in two hydrogen bonds. This type of bonding is called "bifurcated" (split in two or "two-forked"). It can exist, for instance, in complex organic molecules.<ref>{{cite journal|doi=10.1139/v84-087|journal=Can. J. Chem.|volume= 62|issue= 3|pages= 526–530|title=Hétérocycles à fonction quinone. V. Réaction anormale de la butanedione avec la diamino-1,2 anthraquinone; structure cristalline de la naphto \2,3-f] quinoxalinedione-7,12 obtenue|year=1984|last1=Baron|first1=Michel|last2=Giorgi-Renault|first2=Sylviane|last3=Renault|first3=Jean|last4=Mailliet|first4=Patrick|last5=Carré|first5=Daniel|last6=Etienne|first6=Jean|doi-access=free}}</ref> It has been suggested that a bifurcated hydrogen atom is an essential step in water reorientation.<ref>{{cite journal|title = A Molecular Jump Mechanism for Water Reorientation|author1=Laage, Damien  |author2=Hynes, James T.|journal = [[Science (journal)|Science]]|year = 2006|volume = 311|pages = 832–5|doi = 10.1126/science.1122154|pmid = 16439623|issue = 5762|bibcode = 2006Sci...311..832L |s2cid=6707413 }}</ref>

Acceptor-type hydrogen bonds (terminating on an oxygen's lone pairs) are more likely to form bifurcation (it is called overcoordinated oxygen, OCO) than are donor-type hydrogen bonds, beginning on the same oxygen's hydrogens.<ref>{{cite journal|title =  The Distribution of Acceptor and Donor Hydrogen-Bonds in Bulk Liquid Water|author1=Markovitch, Omer  |author2=Agmon, Noam |journal = Molecular Physics|year = 2008|volume = 106|issue =  2|pages = 485|doi =  10.1080/00268970701877921|bibcode = 2008MolPh.106..485M |s2cid=17648714 }}</ref>

===Other liquids===
For example, [[hydrogen fluoride]]—which has three lone pairs on the F atom but only one H atom—can form only two bonds; ([[ammonia]] has the opposite problem: three hydrogen atoms but only one lone pair).

:<chem>H-F***H-F***H-F</chem>

===Further manifestations of solvent hydrogen bonding===
* Increase in the [[melting point]], [[boiling point]], [[solubility]], and viscosity of many compounds can be explained by the concept of hydrogen bonding.
* Negative [[Azeotrope|azeotropy]] of mixtures of HF and water.
* The fact that ice is less dense than liquid water is due to a crystal structure stabilized by hydrogen bonds.
* Dramatically higher boiling points of {{chem2|NH3}}, {{chem2|H2O}}, and HF compared to the heavier analogues {{chem2|PH3}}, {{chem2|H2S}}, and HCl, where hydrogen-bonding is absent.
* Viscosity of anhydrous [[phosphoric acid]] and of [[glycerol]].
* Dimer formation in [[carboxylic acid]]s and hexamer formation in [[hydrogen fluoride]], which occur even in the gas phase, resulting in gross deviations from the [[ideal gas law]].
* Pentamer formation of water and alcohols in apolar solvents.

==Hydrogen bonds in polymers==
Hydrogen bonding plays an important role in determining the three-dimensional structures and the properties adopted by many proteins. Compared to the {{chem2|C\sC}}, {{chem2|C\sO}}, and {{chem2|C\sN}} bonds that comprise most polymers, hydrogen bonds are far weaker, perhaps 5%. Thus, hydrogen bonds can be broken by chemical or mechanical means while retaining the basic structure of the polymer backbone. This hierarchy of bond strengths (covalent bonds being stronger than hydrogen-bonds being stronger than van der Waals forces) is relevant in the properties of many materials.<ref>{{cite book|title=Hydrogen Bonding in Polymer Materials|author=Shiao-Wei Kuo|year=2018|publisher=Wiley-VCH }}</ref>

===DNA===
[[File:DNA animation.gif|thumb|The structure of part of a DNA [[double helix]]]]
[[File:Base pair GC.svg|thumb|Hydrogen bonding between [[guanine]] and [[cytosine]], one of two types of [[base pair]]s in DNA]]

In these macromolecules, bonding between parts of the same macromolecule cause it to fold into a specific shape, which helps determine the molecule's physiological or biochemical role. For example, the double helical structure of [[DNA]] is due largely to hydrogen bonding between its [[base pair]]s (as well as [[pi stacking]] interactions), which link one complementary strand to the other and enable [[DNA replication|replication]].{{cn|date=June 2023}}

===Proteins===
In the [[Protein secondary structure|secondary structure of proteins]], hydrogen bonds form between the backbone oxygens and [[amide]] hydrogens. When the spacing of the [[amino acid]] residues participating in a hydrogen bond occurs regularly between positions ''i'' and {{nowrap|''i'' + 4}}, an [[alpha helix]] is formed. When the spacing is less, between positions ''i'' and {{nowrap|''i'' + 3}}, then a [[3 10 helix|3<sub>10</sub> helix]] is formed. When two strands are joined by hydrogen bonds involving alternating residues on each participating strand, a [[beta sheet]] is formed. Hydrogen bonds also play a part in forming the [[Protein tertiary structure|tertiary structure of protein]] through interaction of R-groups. (See also [[protein folding]]).{{cn|date=January 2025}}

[[Bifurcated H-bond]] systems are common in alpha-helical [[transmembrane proteins]] between the backbone amide {{chem2|C\dO}} of residue ''i'' as the H-bond acceptor and two H-bond donors from residue {{nowrap|''i'' + 4}}: the backbone amide {{chem2|N\sH}} and a side-chain hydroxyl or thiol {{chem2|H+}}. The energy preference of the bifurcated H-bond hydroxyl or thiol system is -3.4&nbsp;kcal/mol or -2.6&nbsp;kcal/mol, respectively. This type of bifurcated H-bond provides an intrahelical H-bonding partner for polar side-chains, such as [[serine]], [[threonine]], and [[cysteine]] within the hydrophobic membrane environments.<ref name="Feldblum 2014 4085–4090"/>

The role of hydrogen bonds in protein folding has also been linked to osmolyte-induced protein stabilization. Protective osmolytes, such as [[trehalose]] and [[sorbitol]], shift the protein folding equilibrium toward the folded state, in a concentration dependent manner. While the prevalent explanation for osmolyte action relies on excluded volume effects that are entropic in nature, [[circular dichroism]] (CD) experiments have shown osmolyte to act through an enthalpic effect.<ref>{{cite journal|last=Politi|first=Regina|author2=Harries, Daniel|title=Enthalpically driven peptide stabilization by protective osmolytes|journal=ChemComm|year=2010|volume=46|pages=6449–6451|doi=10.1039/C0CC01763A|pmid=20657920|issue=35}}</ref> The molecular mechanism for their role in protein stabilization is still not well established, though several mechanisms have been proposed. Computer [[molecular dynamics]] simulations suggest that osmolytes stabilize proteins by modifying the hydrogen bonds in the protein hydration layer.<ref>{{cite journal|last=Gilman-Politi|first=Regina|author2=Harries, Daniel|title=Unraveling the Molecular Mechanism of Enthalpy Driven Peptide Folding by Polyol Osmolytes|journal=Journal of Chemical Theory and Computation|year=2011|volume=7|issue=11|pages=3816–3828|doi=10.1021/ct200455n|pmid=26598272}}</ref>

Several studies have shown that hydrogen bonds play an important role for the stability between subunits in multimeric proteins. For example, a study of sorbitol dehydrogenase displayed an important hydrogen bonding network which stabilizes the tetrameric quaternary structure within the mammalian sorbitol dehydrogenase protein family.<ref>{{cite journal|last=Hellgren|first=M.|author2=Kaiser, C.|author3=de Haij, S.|author4=Norberg, A.|author5=Höög, J. O.|title=A hydrogen-bonding network in mammalian sorbitol dehydrogenase stabilizes the tetrameric state and is essential for the catalytic power|journal=Cellular and Molecular Life Sciences |date=December 2007|volume=64|issue=23|pages=3129–38|pmid=17952367|doi=10.1007/s00018-007-7318-1|s2cid=22090973|pmc=11136444}}</ref>

A protein backbone hydrogen bond incompletely shielded from water attack is a [[dehydron]]. Dehydrons promote the removal of water through proteins or [[ligand|ligand binding]]. The exogenous dehydration enhances the [[electrostatic]] interaction between the [[amide]] and [[carbonyl]] groups by de-shielding their [[charge (physics)|partial charges]]. Furthermore, the dehydration stabilizes the hydrogen bond by destabilizing the [[nonbonded interactions|nonbonded state]] consisting of dehydrated [[charge (physics)|isolated charges]].<ref>{{cite journal|last=Fernández|first=A.|author2=Rogale K.|author3=Scott Ridgway|author4=Scheraga H. A.|title=Inhibitor design by wrapping packing defects in HIV-1 proteins|journal= Proceedings of the National Academy of Sciences|date=June 2004|volume=101|issue=32|pages=11640–5|pmid=15289598|doi=10.1073/pnas.0404641101|pmc=511032|bibcode=2004PNAS..10111640F|doi-access=free}}</ref>

[[Wool]], being a protein fibre, is held together by hydrogen bonds, causing wool to recoil when stretched. However, washing at high temperatures can permanently break the hydrogen bonds and a garment may permanently lose its shape.{{cn|date=January 2025}}

===Other polymers===
[[Image:Kevlar chemical structure H-bonds.svg|thumb|400px|Para-aramid structure]]
[[Image:Cellulose strand.svg|thumb|right|260px|A strand of cellulose (conformation I<sub>α</sub>), showing the hydrogen bonds (dashed) within and between cellulose molecules]]

The properties of many polymers are affected by hydrogen bonds within and/or between the chains.  Prominent examples include [[cellulose]] and its derived fibers, such as [[cotton]] and [[flax]]. In [[nylon]], hydrogen bonds between [[carbonyl]] and the [[amide]] N''H'' effectively link adjacent chains, which gives the material mechanical strength. Hydrogen bonds also affect the [[aramid]] [[fibre]], where hydrogen bonds stabilize the linear chains laterally. The chain axes are aligned along the fibre axis, making the fibres extremely stiff and strong. Hydrogen-bond networks make both polymers sensitive to [[humidity]] levels in the atmosphere because water molecules can diffuse into the surface and disrupt the network. Some polymers are more sensitive than others. Thus [[nylon]]s are more sensitive than [[aramid]]s, and [[nylon 6]] more sensitive than [[nylon-11]].{{cn|date=June 2023}}

==Symmetric hydrogen bond==
A [[symmetric hydrogen bond]] is a special type of hydrogen bond in which the proton is spaced exactly halfway between two identical atoms. The strength of the bond to each of those atoms is equal. It is an example of a [[three-center four-electron bond]]. This type of bond is much stronger than a "normal" hydrogen bond. The effective bond order is 0.5, so its strength is comparable to a covalent bond. It is seen in ice at high pressure, and also in the solid phase of many anhydrous acids such as [[hydrofluoric acid]] and [[formic acid]] at high pressure. It is also seen in the [[bifluoride]] ion {{chem2|[F***H***F]-}}. Due to severe steric constraint, the protonated form of Proton Sponge (1,8-bis(dimethylamino)naphthalene) and its derivatives also have symmetric hydrogen bonds ({{chem2|[N***H***N]+}}),<ref>Khashayar Rajabimoghadam Yousef Darwish Umyeena Bashir Dylan Pitman Sidney Eichelberger Maxime A. Siegler Marcel Swart Isaac Garcia-Bosch Aerobic Oxidation of Alcohols by Copper Complexes Bearing Redox-Active Ligands with Tunable H-Bonding https://doi.org/10.1021/jacs.8b08748</ref> although in the case of protonated Proton Sponge, the assembly is bent.<ref>{{Cite journal|last1=Ozeryanskii|first1=Valery A.|last2=Pozharskii|first2=Alexander F.|last3=Bieńko|first3=Agnieszka J.|last4=Sawka-Dobrowolska|first4=Wanda|last5=Sobczyk|first5=Lucjan|date=2005-03-01|title=[NHN]+ Hydrogen Bonding in Protonated 1,8-Bis(dimethylamino)-2,7-dimethoxynaphthalene. X-ray Diffraction, Infrared, and Theoretical ab Initio and DFT Studies|journal=The Journal of Physical Chemistry A|volume=109|issue=8|pages=1637–1642|doi=10.1021/jp040618l|pmid=16833488|bibcode=2005JPCA..109.1637O|issn=1089-5639}}</ref>

==Dihydrogen bond==
The hydrogen bond can be compared with the closely related [[dihydrogen bond]], which is also an [[Intermolecular force|intermolecular]] bonding interaction involving hydrogen atoms. These structures have been known for some time, and well characterized by [[X-ray crystallography|crystallography]];<ref name=crab>{{cite journal|title = A New Intermolecular Interaction: Unconventional Hydrogen Bonds with Element-Hydride Bonds as Proton Acceptor|last1 = Crabtree|first1 = Robert H. |author-link1=Robert H. Crabtree|last2 =Siegbahn |first2= Per E. M. |first3= Odile |last3 =Eisenstein |first4 =Arnold L. |last4 =Rheingold |first5 = Thomas F. |last5 =Koetzle|journal = [[Acc. Chem. Res.]]|year = 1996|volume = 29|issue = 7|pages = 348–354|doi = 10.1021/ar950150s|pmid = 19904922}}</ref> however, an understanding of their relationship to the conventional hydrogen bond, [[ionic bond]], and [[covalent bond]] remains unclear. Generally, the hydrogen bond is characterized by a proton acceptor that is a lone pair of electrons in nonmetallic atoms (most notably in the [[nitrogen group|nitrogen]], and [[chalcogen]] groups). In some cases, these proton acceptors may be [[pi-bond]]s or [[metal complexes]]. In the dihydrogen bond, however, a metal hydride serves as a proton acceptor, thus forming a hydrogen-hydrogen interaction. [[Neutron diffraction]] has shown that the [[molecular geometry]] of these complexes is similar to hydrogen bonds, in that the bond length is very adaptable to the metal complex/hydrogen donor system.<ref name=crab/>

==Application to drugs==
The Hydrogen bond is relevant to drug design. According to [[Lipinski's rule of five]] the majority of orally active drugs have no more than five hydrogen bond donors and fewer than ten hydrogen bond acceptors. These interactions exist between [[nitrogen]]–[[hydrogen]] and [[oxygen]]–hydrogen centers.<ref name="Lipinski_2004">{{cite journal | author = Lipinski CA | title = Lead- and drug-like compounds: the rule-of-five revolution | journal = Drug Discovery Today: Technologies |date=December 2004 | volume = 1 | issue = 4 | pages = 337–341 | doi = 10.1016/j.ddtec.2004.11.007 | pmid = 24981612 }}</ref> Many drugs do not, however, obey these "rules".<ref>{{cite journal |doi=10.1007/s11306-014-0733-z |title=A 'rule of 0.5' for the metabolite-likeness of approved pharmaceutical drugs |year=2015 |last1=o′Hagan |first1=Steve |last2=Swainston |first2=Neil |last3=Handl |first3=Julia |last4=Kell |first4=Douglas B. |journal=Metabolomics |volume=11 |issue=2 |pages=323–339 |pmid=25750602 |pmc=4342520 }}</ref>

==References==
{{reflist|35em}}

==Further reading==
* George A. Jeffrey. ''An Introduction to Hydrogen Bonding (Topics in Physical Chemistry)''. Oxford University Press, US (March 13, 1997). {{ISBN|0-19-509549-9}}

==External links==
* [https://web.archive.org/web/20141203035841/http://www.magnet.fsu.edu/education/tutorials/slideshows/bubblewall/index.html The Bubble Wall] (Audio slideshow from the National High Magnetic Field Laboratory explaining cohesion, surface tension and hydrogen bonds)
* [http://scitation.aip.org/content/aip/journal/jcp/129/19/10.1063/1.3006032 isotopic effect on bond dynamics]
{{Chemical bonds}}

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{{DEFAULTSORT:Hydrogen Bonds}}
[[Category:Chemical bonding]]
[[Category:Hydrogen physics]]
[[Category:Supramolecular chemistry]]
[[Category:Intermolecular forces]]