Nucleophilic substitution 236445 219530938 2008-06-15T17:55:20Z 96.243.183.242 /* SN1 and SN2 reactions */ In [[organic chemistry|organic]] and [[inorganic chemistry]], '''nucleophilic substitution''' is a fundamental class of [[substitution reaction]] in which an "electron rich" [[nucleophile]] selectively bonds with or attacks the positive or partially positive charge of an atom ''attached to'' a group or atom called the [[leaving group]]; the positive or partially positive atom is referred to as an [[electrophile]]. The most general form for the reaction may be given as :Nuc''':''' + R-LG &rarr; R-Nuc + LG''':''' The electron pair (''':''') from the nucleophile (Nuc) attacks the substrate (R-LG) forming a new bond, while the leaving group (LG) departs with an electron pair. The principal product in this case is R-Nuc. The nucleophile may be electrically neutral or negatively charged, whereas the substrate is typically neutral or positively charged. An example of nucleophilic substitution is the [[hydrolysis]] of an [[alkyl]] [[bromide]], [[Alkyl|R]]-Br, under alkaline conditions, where the ''attacking'' nucleophile is the [[hydroxide|OH<sup>&minus;</sup>]] and the [[leaving group]] is [[bromide|Br<sup>-</sup>]]. :R-Br + OH<sup>&minus;</sup> &rarr; R-OH + Br<sup>&minus;</sup> Nucleophilic substitution reactions are commonplace in organic chemistry, and they can be broadly categorised as taking place at an [[aliphatic]] ([[Saturation (chemistry)|saturated]]) carbon or at (less often) an [[aromatic]] or other unsaturated carbon centre.<ref>L. G. Wade, ''Organic Chemistry'', 5th ed., Prentice Hall, Upper Saddle RIver, New Jersey, 2003.</ref> == Nucleophilic substitution at saturated carbon centres == === S<sub>N</sub>1 and S<sub>N</sub>2 reactions === In 1935, [[Edward D. Hughes]] and [[Christopher Kelk Ingold|Sir Christopher Ingold]] studied nucleophilic substitution reactions of [[alkyl halide]]s and related compounds. They proposed that there were two main mechanisms at work, both of them competing with each other. The two main mechanisms are the '''[[SN1 reaction|S<sub>N</sub>1 reaction]]''' and the '''[[SN2 reaction|S<sub>N</sub>2 reaction]]'''. S stands for chemical substitution, N stands for nucleophilic, and the number represents the [[order (chemistry)|kinetic order]] of the reaction.<ref>S. R. Hartshorn, ''Aliphatic Nucleophilic Substitution'', Cambridge University Press, London, 1973. [ISBN 0-521-09801-7]</ref> In the S<sub>N</sub>2 reaction, the addition of the nucleophile and the elimination of leaving group take place simultaneously. S<sub>N</sub>2 occurs where the central carbon atom is easily accessible to the nucleophile. By contrast the S<sub>N</sub>1 reaction involves two steps. S<sub>N</sub>1 reactions tend to be important when the central carbon atom of the substrate is surrounded by bulky groups, both because such groups interfere sterically with the S<sub>N</sub>2 reaction (discussed above) and because a highly substituted carbon forms a stable [[carbocation]]. Initially, the rate of the nucleophilic substitution was a little puzzling as the rate followed the pattern : CH<sub>3</sub>X > primary > [[secondary]] < [[tertiary]] The [[reaction kinetics]] changed from second order to first order. The S<sub>N</sub>1 and S<sub>N</sub>2 reactions are influenced by different factors S<sub>N</sub>1 reactivity rates follow the trend CH<sub>3</sub>X < primary < secondary < tertiary S<sub>N</sub>2 reactivity rates follow the trend CH<sub>3</sub>X > primary > secondary > tertiary The total reactivity is the sum of the two rates. [[Image:Sn2_Sn1_Graph.png]] A graph showing the relative reactivities of the different alkyl halides towards S<sub>N</sub>1 and S<sub>N</sub>2 reactions. Also see Table 1. <br/> {| border="1" cellspacing="0" cellpadding="5" style="margin: 0 0 0 0.5em; background: #FFFFFF; border-collapse: collapse; border-color: #C0C090;" ! {{chembox header}} colspan=8 | Table 1. Nucleophilic substitutions on RX (an alkyl halide or equivalent) |- |! {{chembox header}} colspan=1 | Factor ! {{chembox header}} colspan=1 | [[SN1 reaction|S<sub>N</sub>1]] ! {{chembox header}} colspan=1 | [[SN2 reaction|S<sub>N</sub>2]] ! {{chembox header}} colspan=1 | Comments |- | [[Chemical kinetics|Kinetics]] || Rate=k[RX] || Rate=k[RX][Nuc] |- | [[Primary alkyl]] substrate || Never unless<br/>additional stabilising<br/>groups present||Good unless<br/>a hindered nucleophile is used|| |- | [[Secondary alkyl]] substrate || Moderate || Moderate || |- | [[Tertiary alkyl]] substrate || Excellent || Never || [[Elimination reaction|Elimination]] likely<br/>if heated or if<br/>strong base used |- | [[Leaving group]] || Important || Important || For halogens,<br/>I > Br > Cl >> F |- | [[Nucleophilicity]] || Unimportant || Important || |- | Preferred [[solvent]] || [[Polar]] [[protic]] || Polar [[aprotic]] || |- | Stereochemistry || [[Racemisation]]<br/>(+ partial [[Stereochemistry|inversion]] <br/>possible) || Inversion || |- | [[Carbocation rearrangement|Rearrangements]] || Common || Rare || Side reaction |- | [[Elimination reaction|Eliminations]] || Common, especially<br/>with basic nucleophiles || Only with heat &<br/>basic nucleophiles || Side reaction<br/> esp. if heated |- |} == Nucleophilic substitution reactions == There are many reactions in organic chemistry that involve this type of mechanism. Common examples include * [[Organic reduction]]s with [[hydride]]s, for example :: [[Alkyl halide|R-X]] &rarr; [[Alkane|R-H]] using [[Lithium aluminium hydride|LiAlH<sub>4</sub>]] &nbsp; (S<sub>N</sub>2) * [[hydrolysis]] reactions such as :: R-Br + OH<sup>&minus;</sup> &rarr; [[Alcohol|R-OH]] + [[Bromide|Br<sup>&minus;</sup>]] (S<sub>N</sub>2) or :: R-Br + H<sub>2</sub>O &rarr; R-OH + [[Hydrobromic acid|HBr]] &nbsp; (S<sub>N</sub>1) * [[Williamson ether synthesis]] :: R-Br + [[Alkoxide|OR'<sup>&minus;</sup>]] &rarr; [[Ether|R-OR']] + Br<sup>&minus;</sup> &nbsp; (S<sub>N</sub>2) * The [[Wenker synthesis]] which is a ring-closing reaction of aminoalcohols * The [[Finkelstein reaction]] is an halide exchange reaction and phosphorus nucleophiles appear in the [[Perkow reaction]] and the [[Michaelis-Arbuzov reaction]]. * The [[Kolbe nitrile synthesis]], the reaction of alkyl halides with cyanides. === Other mechanisms === Besides S<sub>N</sub>1 and S<sub>N</sub>2, other mechanisms are known, although they are less common. The '''[[SNi|S<sub>N</sub>i]]''' mechanism is observed in reactions of [[thionyl chloride]] with [[alcohol]]s, and it is similar to S<sub>N</sub>1 except that the nucleophile is delivered from the same side as the leaving group. Nucleophilic substitutions can be accompanied by an [[allylic rearrangement]] as seen in reactions such as the [[Ferrier rearrangement]]. This type of mechanism is called an S<sub>N</sub>1' or S<sub>N</sub>2' reaction (depending on the kinetics). With [[allyl|allylic]] halides or sulphonates, for example, the nucleophile may attack at the &gamma; unsaturated carbon in place of the carbon bearing the leaving group. This may be seen in the reaction of 1-chloro-2-butene with [[sodium hydroxide]] to give a mixture of 2-buten-1-ol and 1-buten-3-ol: :CH<sub>3</sub>CH=CH-CH<sub>2</sub>-Cl &rarr; CH<sub>3</sub>CH=CH-CH<sub>2</sub>-OH + CH<sub>3</sub>CH(OH)-CH=CH</sub>2</sub> The [[Sn1CB mechanism]] appears in [[inorganic chemistry]]. == Nucleophilic substitution at unsaturated carbon centres == Nucleophilic substitution via the S<sub>N</sub>1 or S<sub>N</sub>2 mechanism does not generally occur with vinyl or aryl halides or related compounds. Under certain conditions nucleophilic substitutions may occur, via other mechanisms such as those described in the [[nucleophilic aromatic substitution]] article. When the substitution occurs at the [[carbonyl]] group, the [[acyl]] group may undergo [[nucleophilic acyl substitution]]. This is the normal mode of substitution with [[carboxylic acid]] derivatives such as [[acyl chloride]]s, [[ester]]s and [[amide]]s. <!--Content to be added --> <!-- == Nucleophilic substitution at atoms other than carbon == Content to be added --> == See also == *[[Nucleophilic acyl substitution]] == Notes== <references /> ==References== *J. March, ''Advanced Organic Chemistry'', 4th ed., Wiley, New York, 1992. *J. P. Clayden, N. Greeves, S. Warren, P. D. Wothers, ''Organic Chemistry'', Oxford University Press, Oxford, UK, 2001. *R. A. Rossi, R. H. de Rossi, ''Aromatic Substitution by the S<sub>RN</sub>1 Mechanism, ACS Monograph Series No. 178, American Chemical Society, 1983. [ISBN 0-8412-0648-1] {{Reaction mechanisms}} [[Category:Substitution reactions]] [[da:Nukleofil substitution]] [[de:Nukleophile Substitution]] [[es:Sustitución nucleófila]] [[fr:Substitution nucléophile]] [[id:Substitusi nukleofilik]] [[it:Sostituzione nucleofila]] [[he:התמרה נוקלאופילית]] [[mk:Нуклеофилна супституција]] [[ja:求核置換反応]] [[pt:Substituição nucleofílica]] [[simple:Nucleophilic substitution]] [[sk:Nukleofilná substitúcia]] [[zh:亲核取代反应]]