SCHOOL OF BIOTECHNOLOGY
INTERNATIONAL UNIVERSITY, VNU-HCMC
SEMESTER II, 2021
INSTRUCTOR: DR. PHONG Q. LE
PREPARED AND PRESENTED BY
TRAN VU QUYNH THI
Review of the Bimolecular Nucleophile Substitution (SN2)
Phong Q. Le, Thi V.Q Tran,
School of Biotechnology, International University-Vietnam National University Ho Chi Minh city
Quarter 6, Linh Trung Ward, Thu Duc District, HCMC.
Corresponding author: quynhthitran01@gmail.com
ABSTRACT
There are many synthesis processes of organic compounds that are carried out following the SN2
mechanism reaction. SN2 reactions act as a necessary fundamental step to form the precursor for
subsequent synthesis reactions. This report provides a brief overview of the mechanism of the SN2
reaction. More importantly, there are general reports of some application on SN2 reaction to
synthesize several organic compounds that play a vital role in biochemistry. The first application is
the first-step oxidation of UDP-glucose dehydrogenase (UDGH) catalytic activity to convert UDPglucose (UDP-Glc) to UDP-glucuronic acid (UDP-GlcUA). The second one is the basis step in the
synthesis of an iNOS (inducible isoform of NO synthetases) inhibitor to regulate the overproduction
of NO. The last application will be mentioned is SN2 on quaternary centres of sulfamidates in the
synthesis of β2,2-amino acids.
INTRODUCTION
SN2 reaction is the most common type of nucleophile substitution in organic chemistry. SN2 is a
single-step reaction, therefore it does not produce any intermediates. Besides, SN2 reactions are
substantially more diversified than SN1 reactions, and they can be used in a wide range of synthetic
applications. Although the SN2 reaction is not the only mechanism for synthesis reactions, it is a
crucial building block for many other steps in synthesis process.
MECHANISM
The term SN2, where S stands for 'substitution,' N for 'nucleophilic,' and 2 denotes a bimolecular
reaction. In the SN2 reaction, the nucleophile (electron-rich species) attacks and turns away the
electrophile (electron-poor species) from the backside in the relation to the leaving group. SN2
reaction occurs in a single step (include a transition state) with the bond formation and bond
breaking occurring concurrently. The stereochemical structure of the core carbon inverts as the
reaction occurs as a result of this backside attack. In other words, the molecule is turned inside out
due to the SN2 reaction.
Figure 1. The mechanism of SN2 reaction.
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Factors affect the rate of SN2reaction.
Substrate. SN2 reaction occur easily with the presence of primary or secondary alkyl halides than
tertiary alkyl groups. Three bulky alkyl groups of tertiary alkyl halides linked to the reaction center
that behave as steric shields, preventing nucleophiles from approaching the reaction center. Because
primary alkyl halides have only one alkyl group connected to this core, they are easy to access.
Solvent. The SN2 reaction works best in polar, aprotic solvents which are high dipole moment and
without hydrogen-bond donating capability (O–H or N–H groups). These include solvents such as
acetonitrile (CH3CN) or dimethylformamide (DMF).
Nucleophile. A strong nucleophile helps to speed up the reaction because it is one of the ratedetermining elements in SN2 reactions The following are some guidelines for determining
nucleophilicity: Negatively charged nucleophiles are more powerful than neutral nucleophiles.
Nucleophilicity decreases across a period and increases within a group. The nucleophile of a small
group is stronger than that of a bulky group.
Leaving group. The excellent leaving group should be stable with electron pairing. Therefore, a weak
base is a good leaving group which is more stable due to a low ability to share electron pairs. So, the
general trend is: Leaving group become better from left to right within a row and from top to bottom
of the periodic table; The weaker the basicity of a group, the better leaving group it is.
APPLICATION
SN2 reaction in first-step oxidation of UDP-glucose dehydrogenase catalytic activity (UDGH).
UDP-glucuronic acid (UDP-GlcUA) plays a number of critical roles in human physiology. It is a
precursor for the production of extracellular matrix glycosaminoglycans, which are involved in a
variety of cellular activities including signaling, wound healing, inflammation, morphogenesis as
well as cancer pathobiology.
UDP-glucose dehydrogenase catalyzes the conversion of UDP-glucose to UDP-glucuronic acid via
two successive NAD+-dependent oxidations and hydrolysis stage. The single-step NAD+-assisted
SN2 reaction that involves the coupling reaction of nucleophilic addition of Cys-S- (ionized cysteine
thiol of the UDGH catalytic site) and the release of pro-R H. (in the form of NADH). Hydrolysis is the
next stage to convert the intermediate to UDP-glucuronate (Figure 2).
Figure 2. The catalytic mechanism of UGDH.
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SN2 reaction is the basis step in the synthesis of an iNOS inhibitor. The overproduction of NO by the
inducible isoform of NO synthetases (iNOS) has been linked to the pathophysiology of septic and
endotoxic shock, neurological disorders, and inflammatory diseases. As a result, an iNOS inhibitor 1
must be developed for therapeutic usage in order to control the excessive production of NO.
Figure 3. An iNOS inhibitor.
The formation of 8 is the critical step in the synthesis of 1 that is created by 4 and 7, following the
mechanism of SN2 reaction.
Figure 4. The formation of 8 following the SN2 mechanism.
Then, 8 continue with Cbz deprotection via hydrogenolysis to form 9 and prepare the amidine
intermediate 20 to synthesize 1.
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8
Figure 5. The final step to synthesize 1.
SN2 on quaternary centres of sulfamidates in the synthesis of β2,2-amino acids. Because of its
potential in medicinal chemistry and molecular identification, β-amino acids have recently gained a
lot of attention. In the synthesis of these compounds, five-membered cyclic α-methylisoserinederived sulfamidates were believed to be an excellent chiral building block for the synthesis of αmethylated β-amino acids by nucleophilic ring-opening processes via SN2 reaction on the
quaternary carbon.
(R)- 4
(S)-6 or (S)-7
(S)-11 or (S)-12
Figure 6. The synthesis of α-methylated β-amino acids by nucleophilic ring-opening reactions via
SN2 reaction.
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METHOD
The corresponding sulfamic acid intermediates were hydrolyzed in an acid medium to give the
desired SN2 products. Instead of methyl groups, a variety of substituents can be added to create β2,2amino acids (Figure 6). By hydrogenation of the azide group and subsequent acid hydrolysis, the
SN2 product (S)-6 was converted to β-amino-α-methylalanine (S)-11. Another new β2,2-amino acids:
S,α -dimethylisocysteine (S)-12 is yielded by hydrolysis of S-7 (Table 1)
These are condition of each step in the synthesis of β2,2-amino acids:
(e) i) Nuc (1.3 equiv.), DMF, 25–50 °C, 1-12h, ii) 20% H2SO4 (aq.)/CH2Cl2 (1:1), rt, 12h;
(f) i) H2, Pd–C, MeOH, rt, 12h, ii) 6 M HCl (aq.), 100 °C, 12h, iii) propylene oxide, EtOH, reflux, 2h;
(g) The same conditions described in steps ii) and iii).
Table 1. Synthesis of β2,2-amino acids from sulfamidates (Sul)
REFERENCES
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ACKNOWLEDGEMENTS
Thanks for the guidance on how to write articles from the instructor: Dr. Phong Q. Le
AUTHOR CONTRIBUTION STATEMENT
Egger S, Chaikuad A, Kavanagh KL, Oppermann U, Nidetzky B. Avenoza A, Busto JH, Jiménez-Osés
G, Peregrina JM. Corzana, Rassias, G., Hermitage, S. A., Sanganee, M. J., Kincey, P. M., Smith, N. M.,
Andrews, I. P., … Slater, G. R
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ADDITIONAL INFORMATION
Competing interests:
Title of Paper: Review of the Bimolecular Nucleophile Substitution (SN2)
Corresponding Author: Thi V.Q. Tran
I declare that we have no known competing financial interests or personal relationships that could
have appeared to influence the work reported in this paper.
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