chemistry Chemistry is the scientific study of the properties and behavior of matter. It is a natural science that covers the elements that make up matter to the compounds made of atoms, molecules and ions: their composition, structure, proper ...

, solid-phase synthesis is a method in which

molecule A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and b ...

s are covalently bound on a

solid Solid is one of the four fundamental states of matter (the others being liquid, gas, and plasma). The molecules in a solid are closely packed together and contain the least amount of kinetic energy. A solid is characterized by structur ...

support material and synthesised step-by-step in a single reaction vessel utilising selective protecting group chemistry. Benefits compared with normal

synthesis Synthesis or synthesize may refer to: Science Chemistry and biochemistry * Chemical synthesis, the execution of chemical reactions to form a more complex molecule from chemical precursors **Organic synthesis, the chemical synthesis of organ ...

in a liquid state include: * High efficiency and throughput * Increased simplicity and speed The reaction can be driven to completion and high yields through the use of excess reagent. In this method, building blocks are protected at all reactive

functional group In organic chemistry, a functional group is a substituent or moiety in a molecule that causes the molecule's characteristic chemical reactions. The same functional group will undergo the same or similar chemical reactions regardless of the r ...

s. The order of functional group reactions can be controlled by the order of deprotection. This method is used for the synthesis of peptides, deoxyribonucleic acid ( DNA), ribonucleic acid ( RNA), and other molecules that need to be synthesised in a certain alignment. More recently, this method has also been used in combinatorial chemistry and other synthetic applications. The process was originally developed in the 1950s and 1960s by Robert Bruce Merrifield in order to synthesise peptide chains, and which was the basis for his 1984

Nobel Prize in Chemistry ) , image = Nobel Prize.png , alt = A golden medallion with an embossed image of a bearded man facing left in profile. To the left of the man is the text "ALFR•" then "NOBEL", and on the right, the text (smaller) "NAT•" then "M ...

. In the basic method of solid-phase synthesis, building blocks that have two functional groups are used. One of the functional groups of the building block is usually protected by a protective group. The starting material is a bead which binds to the building block. At first, this bead is added into the solution of the protected building block and stirred. After the reaction between the bead and the protected building block is completed, the solution is removed and the bead is washed. Then the protecting group is removed and the above steps are repeated. After all steps are finished, the synthesised compound is chemically cleaved from the bead. If a compound containing more than two kinds of building blocks is synthesised, a step is added before the deprotection of the building block bound to the bead; a functional group which is on the bead and did not react with an added building block has to be protected by another protecting group which is not removed at the deprotective condition of the building block. Byproducts which lack the building block of this step only are prevented by this step. In addition, this step makes it easy to purify the synthesised compound after cleavage from the bead.

Solid-Phase Peptide Synthesis (SPPS)

Solid-phase synthesis is a common technique for peptide synthesis. Usually, peptides are synthesised from the carbonyl group side (C-terminus) to amino group side (N-terminus) of the

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...

chain in the SPPS method, although peptides are biologically synthesised in the opposite direction in cells. In peptide synthesis, an amino-protected amino acid is bound to a solid phase material or resin (most commonly, low cross-linked

polystyrene Polystyrene (PS) is a synthetic polymer made from monomers of the Aromatic hydrocarbon, aromatic hydrocarbon styrene. Polystyrene can be solid or foamed. General-purpose polystyrene is clear, hard, and brittle. It is an inexpensive resin pe ...

beads), forming a

covalent bond A covalent bond is a chemical bond that involves the sharing of electrons to form electron pairs between atoms. These electron pairs are known as shared pairs or bonding pairs. The stable balance of attractive and repulsive forces between ato ...

between the carbonyl group and the resin, most often an

amido In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent organic groups or hydrogen atoms. The amide group is called a peptide bond when it i ...

or an

ester In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ...

bond. Then the amino group is deprotected and reacted with the carbonyl group of the next, N-protected, amino acid. The solid phase now bears a dipeptide. This cycle is repeated to form the desired peptide chain. After all reactions are complete, the synthesised peptide is cleaved from the bead. The protecting groups for the amino groups mostly used in the peptide synthesis are 9-fluorenylmethyloxycarbonyl group ( Fmoc) and t-butyloxycarbonyl ( Boc). A number of amino acids bear functional groups in the side chain which must be protected specifically from reacting with the incoming N-protected amino acids. In contrast to Boc and Fmoc groups, these have to be stable over the course of peptide synthesis although they are also removed during the final deprotection of peptides.

Solid-phase synthesis of DNA and RNA

Relatively short fragments of DNA, RNA, and modified oligonucleotides are also synthesised by the solid-phase method. Although oligonucleotides can be synthesised in a flask, they are almost always synthesised on solid phase using a DNA/RNA synthesizer. For a more comprehensive review, see

oligonucleotide synthesis Oligonucleotide synthesis is the chemical synthesis of relatively short fragments of nucleic acids with defined chemical structure ( sequence). The technique is extremely useful in current laboratory practice because it provides a rapid and inexpe ...

. The method of choice is generally phosphoramidite chemistry, developed in the 1980s.

Solid-Phase Peptide Synthesis (SPPS)

Solid-phase synthesis of DNA and RNA

See also

References

Further reading