Copyright © 2007, Craig A. James

Content is available under GNU Free Documentation License 1.2

Contributors: Richard Apodaca, Noel O’Boyle, Andrew Dalke, John van Drie, Peter Ertl, Geoff Hutchison, Craig A. James, Greg Landrum, Chris Morley, Egon Willighagen, Hans De Winter, Tim Vandermeersch, John May

1. Introduction

"… we cannot improve the language of any science, without, at the same time improving the science itself; neither can we, on the other hand, improve a science, without improving the language or nomenclature which belongs to it …"

1.1. Purpose

This document formally defines an open specification version of the SMILES language, a typographical line notation for specifying chemical structure. It is hosted under the banner of the Blue Obelisk project, with the intent to solicit contributions and comments from the entire computational chemistry community.

1.2. Motivation

SMILES was originally developed as a proprietary specification by Daylight Chemical Information Systems Since the introduction of SMILES in the late 1980’s, it has become widely accepted as a defacto standard for exchange of molecular structures. Many independent SMILES software packages have been written in C, C++, Java, Python, LISP, and probably even FORTRAN.

At this point in the history of SMILES, is appropriate for the chemistry community to develop a new, non-proprietary specification for the SMILES language. Daylight’s SMILES Theory Manual has long been the "gold standard" for the SMILES language, but as a proprietary specification, it limits the universal adoption of SMILES, and has no mechanism for contributions from the chemistry community. We salute Daylight for their past contributions, and the excellent SMILES documentation they provided free of charge for the past two decades.

1.3. Audience

This document is intended for developers designing or improving a SMILES parser or writer. Readers are expected to be acquainted with SMILES. Due to the formality of this document, it is not a good tutorial for those trying to learn SMILES. This document is written with precision as the primary goal; readability is secondary.

1.4. What is a Molecule? The Valence Model of Chemistry

Before defining the SMILES language, it is important to state the physical model on which it is based: the valence model of chemistry, which uses a mathematician’s graph to represent a molecule. In a chemical graph, the nodes are atoms, and the edges are semi-rigid bonds that can be single, double, or triple according to the rules of valence bond theory.

This simple mental model has little resemblance to the underlying quantum-mechanical reality of electrons, protons and neutrons, yet it has proved to be a remarkably useful approximation of how atoms behave in close proximity to one another. However, the valence model is an imperfect representation of molecular structure, and the SMILES language inherits these imperfections. Chemical bonds are often tautomeric, aromatic or otherwise fractional rather than neat integer multiples. Delocalized bonds, bond-centered bonds, hydrogen bonds and various other inter-atom forces that are well characterized by a quantum-mechanics description simply don’t fit into the valence model.

"If you can build a molecule from a modeling kit, you can name it."

McLeod and Peters' quip captures the deficiencies of SMILES well: if you can’t build a molecule from a modeling kit, the deficiencies of SMILES and other connection-table formats become apparent.

2. Formal Grammar

2.1. Syntax versus Semantics

This SMILES specification is divided into two distinct parts: A syntactic specification specifies how the atoms, bonds, parentheses, digits and so forth are represented, and a semantic specification that describes how those symbols are interpreted as a sensible molecule. For example, the syntax specifies how ring closures are written, but the semantics require that they come in pairs. Likewise, the syntax specifies how atomic elements are written, but the semantics determines whether a particular ring system is actually aromatic.

For this specification, the syntax and semantics are explained separately; in practice, the syntax and semantics are usually mixed together in the code that implements a SMILES parser. This chapter is only concerned with syntax.

2.2. Grammar

Section Formal Grammar

ATOMS

Atoms

atom ::= bracket_atom | aliphatic_organic | aromatic_organic | '*'

ORGANIC SUBSET ATOMS

Organic Subset

aliphatic_organic ::= 'B' | 'C' | 'N' | 'O' | 'S' | 'P' | 'F' | 'Cl' | 'Br' | 'I'

aromatic_organic ::= 'b' | 'c' | 'n' | 'o' | 's' | 'p'

BRACKET ATOMS

Bracket Atoms

bracket_atom ::= '[' isotope? symbol chiral? hcount? charge? class? ']'

symbol ::= element_symbols | aromatic_symbols | '*'

isotope ::= NUMBER

element_symbols ::= 'H' | 'He' | 'Li' | 'Be' | 'B' | 'C' | 'N' | 'O' | 'F' | 'Ne' | 'Na' | 'Mg' | 'Al' | 'Si' | 'P' | 'S' | 'Cl' | 'Ar' | 'K' | 'Ca' | 'Sc' | 'Ti' | 'V' | 'Cr' | 'Mn' | 'Fe' | 'Co' | 'Ni' | 'Cu' | 'Zn' | 'Ga' | 'Ge' | 'As' | 'Se' | 'Br' | 'Kr' | 'Rb' | 'Sr' | 'Y' | 'Zr' | 'Nb' | 'Mo' | 'Tc' | 'Ru' | 'Rh' | 'Pd' | 'Ag' | 'Cd' | 'In' | 'Sn' | 'Sb' | 'Te' | 'I' | 'Xe' | 'Cs' | 'Ba' | 'Hf' | 'Ta' | 'W' | 'Re' | 'Os' | 'Ir' | 'Pt' | 'Au' | 'Hg' | 'Tl' | 'Pb' | 'Bi' | 'Po' | 'At' | 'Rn' | 'Fr' | 'Ra' | 'Rf' | 'Db' | 'Sg' | 'Bh' | 'Hs' | 'Mt' | 'Ds' | 'Rg' | 'Cn' | 'Fl' | 'Lv' | 'La' | 'Ce' | 'Pr' | 'Nd' | 'Pm' | 'Sm' | 'Eu' | 'Gd' | 'Tb' | 'Dy' | 'Ho' | 'Er' | 'Tm' | 'Yb' | 'Lu' | 'Ac' | 'Th' | 'Pa' | 'U' | 'Np' | 'Pu' | 'Am' | 'Cm' | 'Bk' | 'Cf' | 'Es' | 'Fm' | 'Md' | 'No' | 'Lr'

aromatic_symbols ::= 'b' | 'c' | 'n' | 'o' | 'p' | 's' | 'se' | 'as'

CHIRALITY

Chirality

chiral ::= '@' | '@@' | '@TH1' | '@TH2' | '@AL1' | '@AL2' | '@SP1' | '@SP2' | '@SP3' | '@TB1' | '@TB2' | '@TB3' | … | '@TB20' | '@OH1' | '@OH2' | '@OH3' | … | '@OH30' | '@TB' DIGIT DIGIT | '@OH' DIGIT DIGIT

HYDROGENS

Hydrogens

hcount ::= 'H' | 'H' DIGIT

CHARGES

Charge

charge ::= '-' | '-' DIGIT? DIGIT | '+' | '+' DIGIT? DIGIT | '--' deprecated | '++' deprecated

ATOM CLASS

Atom Class

class ::= ':' NUMBER

BONDS AND CHAINS

Bonds

bond ::= '-' | '=' | '#' | '$' | ':' | '/' | '\'

ringbond ::= bond? DIGIT | bond? '%' DIGIT DIGIT

branched_atom ::= atom ringbond* branch*

branch ::= '(' chain ')' | '(' bond chain ')' | '(' dot chain ')'

chain ::= branched_atom | chain branched_atom | chain bond branched_atom | chain dot branched_atom

dot ::= '.'

SMILES STRINGS

smiles ::= terminator | chain terminator

terminator ::= SPACE | TAB | LINEFEED | CARRIAGE_RETURN | END_OF_STRING

3. Reading SMILES

3.1. Atoms

3.1.1. Atomic Symbol

An atom is represented by its atomic symbol, enclosed in square brackets, []. The first character of the symbol is uppercase and the second (if any) is lowercase, except that for aromatic atoms (see below), the first character is lowercase. There are 114 valid atomic symbols , as defined by IUPAC (see also Web Elements).

The symbol '*' is also accepted as a valid atomic symbol, and represents a "wildcard" or unknown atom.

Examples:

SMILES Atomic Symbol

[U]

Uranium

[Pb]

Lead

[He]

Helium

[*]

Unkwown atom

3.1.2. Hydrogens

Hydrogens inside of brackets are specified as Hn where n is a number such as H3. If no Hn is specified, it is identical to H0. If H is specified without a number, it is identical to H1. For example, [C] and [CH0] are identical, and [CH] and [CH1] are identical.

Hydrogens that are specified in brackets with this notation have undefined isotope, no chirality, no other bound hydrogen, neutral charge, and an undefined atom class.

Examples:

SMILES Name Comments

[CH4]

methane

[ClH]

hydrochloric acid

H1 implied

[ClH1]

hydrochloric acid

A hydrogen atom cannot have a hydrogen count, for example, [HH1] is illegal. Hydrogens connected to other hydrogens must be represented as explicit atoms in square brackets. For example molecular hydrogen must be written as [H][H].

Question: are more than 9 hydrogens possible? Should they be supported?

3.1.3. Charge

Charge is specified by a +n or -n where n is a number; if the number is missing, it means either +1 or -1 as appropriate.

For backwards compatibility, a general-purpose SMILES parser should accept the symbols -- and ++ to mean charges of -2 and +2, but this is a deprecated form and should be avoided.

Examples:

SMILES Name Comments

[Cl-]

chloride anion

-1 charge, H0 implied

[OH1-]

hydroxyl anion

-1 charge, H1

[OH-1]

hydroxyl anion

-1 charge, H1

[Cu+2]

copper cation

+2 charge, H0 implied

[Cu++]

copper cation

+2 charge, H0 implied

An implementation is required to accept charges in the range -15 to +15.

3.1.4. Isotopes

Isotopic specification is placed inside the square brackets for an atom preceding the atomic symbol; for example:

SMILES Atomic Symbol

[13CH4]

methane

[2H+]

deuterium ion

[238U]

Uranium 238 atom

An isotope is interpreted as a number, so that [2H], [02H] and [002H] all mean deuterium. If the isotope field is not specified then the atom is assumed to have the naturally-occurring isotopic ratios. The isotope value 0 also indicates an isotope of zero, that is [0S] is not the same as [S].

There is no requirement that the isotope is a genuine isotope of the element. Thus, [36Cl] is allowed even though 35Cl and 37Cl are the actual known stable isotopes of chlorine.

A general-purpose SMILES parser must accept at least three digits for the isotope and values from 0 to 999.

3.1.5. Organic Subset

A special subset of elements called the "organic subset" of B, C, N, O, P, S, F, Cl, Br, I, and * (the "wildcard" atom) can be written using the only the atomic symbol (that is, without the square brackets, H-count, etc.). An atom is specified this way has the following properties:

  • "implicit hydrogens" are added such that valence of the atom is in the lowest normal state for that element

  • the atom’s charge is zero

  • the atom has no isotopic specification

  • the atom has no chiral specification

The implicit hydrogen count is determined by summing the bond orders of the bonds connected to the atom. If that sum is equal to a known valence for the element or is greater than any known valence then the implicit hydrogen count is 0. Otherwise the implicit hydrogen count is the difference between that sum and the next highest known valence.

The "normal valence" for these elements is defined as:

Element Valence

B

3

C

4

N

3 or 5

O

2

P

3 or 5

S

2, 4 or 6

halogens

1

*

unspecified

Examples:

SMILES Name

C

methane

N

ammonia

Cl

hydrochloric acid

Note: The remaining atom properties, chirality and ring-closures, are discussed in later sections.

3.1.6. The Wildcard '*' Atomic Symbol

The '*' atom represents an atom whose atomic number is unknown or unspecified. If it occurs inside brackets, it can have its isotope, chirality, hydrogen count and charge specified. If it occurs outside of brackets, it has no assumed isotope, a mass of zero, unspecified chirality, a hydrogen count of zero, and a charge of zero.

SMILES Name

Oc1c(*)cccc1

ortho-substituted phenol

The '*' atom does not have any specific electronic properties or valence. If specified outside of square brackets, it takes on the valence implied by its bonds. If it is inside square brackets, it takes on the valence implied by its bonds, hydrogens and/or charge.

A '*' atom can be part of an aromatic ring. When deducing the aromaticity of a ring system, the ring system is considered aromatic if there is an element which could replace the '*' and make the ring system meet the aromaticity rules (see Aromaticity, below).

3.1.7. Atom Class

An "atom class" is an arbitrary integer, a number that has no chemical meaning. It is used by applications to mark atoms in ways that are meaningful only to the application. Multiple atoms may be labeled with the same atom class.

The atom class is specified after all other properties in square brackets. For example:

SMILES Name

[CH4:2]

methane, atom’s class is 2

If the atom class is not specified then the atom class is zero. The atom class is interpreted as a number, so both [CH2:5] and [NH4+:005] have an atom class of 5.

3.2. Bonds

Atoms that are adjacent in a SMILES string are assumed to be joined by a single or aromatic bond (see Aromaticity). For example:

SMILES Name

CC

ethane

CCO

ethanol

NCCCC

n-butylamine

CCCCN

n-butylamine

Double, triple and quadruple bonds are represented by '=', '#', and '$' respectively:

SMILES Name

C=C

ethene

C#N

hydrogen cyanide

CC#CC

2-butyne

CCC=O

propanol

[Rh-](Cl)(Cl)(Cl)(Cl)$[Rh-](Cl)(Cl)(Cl)Cl

octachlorodirhenate (III)

A single bond can be explicitely represented with '-', but it is rarely necessary.

SMILES

C-C

same as: CC

C-C-O

same as: CCO

C-C=C-C

same as: CC=CC

Note: The remaining bond symbols, ':\/', are discussed in later sections.

3.3. Branches

An atom with three or more bonds is called a branched atom, and is represented using parentheses.

Depiction SMILES Name

depict/2-ethyl-1-butanol.gif

CCC(CC)CO

2-ethyl-1-butanol

Branches can be nested or "stacked" to any depth:

Depiction SMILES Name

depict/2-4-dimethyl-3-pentanone.gif

CC(C)C(=O)C(C)C

2,4-dimethyl-3-penthanone

pic here

OCC(CCC)C(C(C)C)CCC

2-propyl-3-isopropyl-1-propanol

depict/thiosulfate.gif

OS(=O)(=S)O

thiosulfate

The SMILES branch/chain rules allow nested parenthetical expressions (branches) to an arbitrary depth. For example, the following SMILES, though peculiar, is legal:

SMILES Formula

C(C(C(C(C(C(C(C(C(C(C(C(C(C(C(C(C(C(C(C(C))))))))))))))))))))C

C22H46

3.4. Rings

In a SMILES string such as "C1CCCCC1", the first occurrence of a ring-closure number (an "rnum") creates an "open bond" to the atom that precedes the ring-closure number (the "rnum"). When that same rnum is encountered later in the string, a bond is made between the two atoms, which typically forms a cyclic structure.

Depiction SMILES Name

depict/cyclohexane.gif

C1CCCCC1

cyclohexane

depict/perhydroisoquinoline.gif

N1CC2CCCC2CC1

perhydroisoquinoline

If a bond symbol is present between the atom and rnum, it can be present on either or both bonded atoms. However, if it appears on both bonded atoms, the two bond symbols must be the same.

Depiction SMILES Name

depict/cyclohexane.gif

C=1CCCCC=1

cyclohexene

C=1CCCCC1

cyclohexene (preferred from)

C1CCCCC=1

cyclohexene

C-1CCCCC=1

invalid

Ring closures must be matched pairs in a SMILES string, for example, C1CCC is not a valid SMILES.

It is permissible to re-use ring-closure numbers. Once a particular number has been encountered twice, that number is available again for subsequent ring closures.

Depiction SMILES Name Comment

depict/dicyclohexyl.gif

C1CCCCC1C1CCCCC1

dicyclohexyl

both SMILES are valid

C1CCCCC1C2CCCCC2

dicyclohexyl

Note that the ring number zero is valid, for example cyclohexane can be written C0CCCCC0.

Two-digit ring numbers are permitted, but must be preceded by the percent '%' symbol, such as C%25CCCCC%25 for cyclohexane. Three-digit numbers and larger are never permitted. However, note that three digits are not invalid; for example, C%123 is the same as C3%12, that is, an atom with two rnum specifications.

The digit(s) representing a ring-closure are interpreted as a number, not a symbol, and two rnums match if their numbers match. Thus, C1CCCCC%01 is a valid SMILES and is the same as C1CCCCC1. Likewise, C%00CCCCC%00 is a valid SMILES.

A single atom can have several ring-closure numbers, such as this spiro atom:

Depiction SMILES Name

depict/spiro.gif

C12(CCCCC1)CCCCC2

spiro[5.5]undecane

Two atoms cannot be joined by more than one bond, and an atom cannot be bonded to itself. For example, the following are not allowed:

SMILES Comments

C12CCCCC12

illegal, two bonds between one pair of atoms

C12C2CCC1

illegal, two bonds between one pair of atoms

C11

illegal, atom bonded to itself

3.5. Aromaticity

3.5.1. The Meaning of "Aromaticity" in SMILES

"Aromaticity" in SMILES is primarily for cheminformatics purposes. In a cheminformatics system, we’d like to have a single representation for each molecule. The Kekule form masks the inherent uniformity of the bonds in an aromatic ring. SMILES uses a simplified definition of aromaticity that facilitates substructure and exact-structure searches, as well as Normalization and Canonicalization of SMILES.

The definition of "aromaticity" in SMILES is not intended to imply anything about the physical or chemical properties of a substance. In many or most cases, the SMILES definition of aromaticity will match the chemist’s notion of what is aromatic, but in some cases it will not.

3.5.2. Kekule and Aromatic Representations

Aromaticity can be represented in one of two ways in a SMILES.

  • In the Kekule form, using alternating single and double bonds, with uppercase symbols for the atoms.

  • An atomic symbol that begins with a lowercase letter is an aromatic atom, such as 'c' for aromatic carbon. When aromatic symbols are used, no bond symbols are needed.

A lowercase aromatic symbol is defined as an atom in the sp2 configuration in an aromatic or anti-aromatic ring system. For example:

Depiction SMILES Name

depict/benzene.gif

c1ccccc1

benzene

C1=CC=CC=C1

depict/indane.gif

c1ccc2CCCc2c1

indane

C1=CC=CC(CCC2)=C12

depict/furan.gif

c1occc1

furan

C1OC=CC=1

depict/cyclobutadiene.gif

c1ccc1

cyclobutadiene

C1=CC=C1

The Kekule form is always acceptable for SMILES input. For output, the aromatic form (using lowercase letters) is preferred. The lowercase symbols eliminate the arbitrary choice of how to assign the single and double bonds, and provide a normalized form that more accurately reflects the electronic configuration.

3.5.3. Extended Hueckel’s Rule

THIS SECTION IS UNDER MAJOR REVISION, AND AT THIS POINT IS ONLY FOR DISCUSSION PURPOSES.

This proposed section is an attempt to simplify the rule-based system by enumerating all atom/bond configurations that are known to participate in aromatic systems.

A single, isolated ring that meets the following criteria is aromatic:

Each element that can participate in an aromatic ring is defined to have the following number of π electrons:

Configuration π Electrons Example Comment

depict/aromtype/BX3v3n.svg

0

depict/arom/BX3v3n_ex1.svg

OpenSMILES extension

depict/aromtype/BX2v3n.svg

1

depict/arom/BX2v3n_ex1.svg

OpenSMILES extension

depict/aromtype/CX3v3m.svg

2

depict/arom/CX3v3m_ex1.svg

depict/aromtype/CX3v4o.svg

0

depict/arom/CX3v4o_ex1.svg

depict/aromtype/CX3v3p.svg

0

depict/arom/CX3v3p_ex1.svg

depict/aromtype/CX2v3m.svg

1

depict/arom/CX2v3m_ex1.svg

depict/aromtype/CX3v4.svg

1

depict/arom/CX3v4_ex1.svg

depict/aromtype/CX2v3p.svg

1

depict/arom/CX2v3p_ex1.svg

depict/aromtype/NX2v2.svg

2

depict/arom/NX2v2_ex1.svg

depict/aromtype/NX3v3.svg

2

depict/arom/NX3v3_ex1.svg

depict/aromtype/NX2v3.svg

1

depict/arom/NX2v3_ex1.svg

depict/aromtype/NX3v4.svg

1

depict/arom/NX3v4_ex1.svg

depict/aromtype/NX3v5.svg

1

depict/arom/NX3v5_ex1.svg

Non-oxide contributes 2 in Daylight toolkit

depict/aromtype/PX2v2.svg

2

depict/arom/PX2v2_ex1.svg

depict/aromtype/PX3v3.svg

2

depict/arom/PX3v3_ex1.svg

depict/aromtype/PX2v3.svg

1

depict/arom/PX2v3_ex1.svg

depict/aromtype/PX3v4.svg

1

depict/arom/PX3v4_ex1.svg

depict/aromtype/PX3v5.svg

1

depict/arom/PX3v5_ex1.svg

Non-oxide contributes 2 in Daylight toolkit

depict/aromtype/AsX3v3.svg

2

depict/arom/AsX3v3_ex1.svg

depict/aromtype/AsX2v3.svg

1

depict/arom/AsX2v3_ex1.svg

OpenSMILES extension

depict/aromtype/AsX3v4.svg

1

depict/arom/AsX3v4_ex1.svg

OpenSMILES extension

depict/aromtype/OX2v2.svg

2

depict/arom/OX2v2_ex1.svg

depict/aromtype/OX2v3.svg

1

depict/arom/OX2v3_ex1.svg

depict/aromtype/SX2v2.svg

2

depict/arom/SX2v2_ex1.svg

depict/aromtype/SX2v3.svg

1

depict/arom/SX2v3_ex1.svg

depict/aromtype/SX3v4.svg

2

depict/arom/SX3v4_ex1.svg

Possibly chiral

depict/aromtype/SX3v3p.svg

2

depict/arom/SX3v3p_ex1.svg

Possibly chiral, OpenSMILES extension

depict/aromtype/SeX2v2.svg

2

depict/arom/SeX2v2_ex1.svg

depict/aromtype/SeX2v3.svg

1

depict/arom/SeX2v3_ex1.svg

depict/aromtype/SeX3v4.svg

2

depict/arom/SeX3v4_ex1.svg

Possibly chiral

depict/aromtype/SeX3v3p.svg

2

depict/arom/SeX3v3p_ex1.svg

Possibly chiral, OpenSMILES extension

3.5.4. Aromaticity Algorithm

In an aromatic system, all of the aromatic atoms must be sp2 hybridized, and the number of π electrons must meet Huckel’s 4n+2 criterion When parsing a SMILES, a parser must note the aromatic designation of each atom on input, then when the parsing is complete, the SMILES software must verify that electrons can be assigned without violating the valence rules, consistent with the sp2 markings, the specified or implied hydrogens, external bonds, and charges on the atoms.

The aromatic-bond symbol ':' can be used between aromatic atoms, but it is never necessary; a bond between two aromatic atoms is assumed to be aromatic unless it is explicitly represented as a single bond '-'. However, a single bond (nonaromatic bond) between two aromatic atoms must be explicitly represented. For example:

Depiction SMILES Name

depict/biphenyl.gif

c1ccccc1-c2ccccc2

biphenyl

Note: Some SMILES parsers interpret a lowercase letter as sp2 anywhere it appears; for example, CccccC would be interpreted as CC=CC=CC. The OpenSMILES specification does not allow this interpretation unless nonstandard parsing is explicitely allowed by the user.

3.6. More about Hydrogen

Hydrogens in a SMILES can be represented in three different ways:

Method SMILES Name Comments

implicit hydrogen

C

methane

h-count deduced from normal valence (4)

atom property

[CH4]

methane

h-count specified for heavy atom

explicit hydrogen

[H]C([H])([H])[H]

methane

hydrogens represented as normal atoms

All three forms are equivalent. However, some situations require that one form must be used:

  • Implicit hydrogen count may only be used for elements of the organic elements subset.

  • Any atom that is specified with square brackets must have its attached hydrogens explicitly represented, either as a hydrogen count or as normal atoms.

A hydrogen that meets one of the following criteria must be represented as an explicit atom:

  • hydrogens with charge ([H+])

  • a hydrogen connected to another hydrogen (such as molecular hydrogen, [H][H])

  • hydrogens with more than one bond (bridging hydrogens)

  • Deuterium [2H] and tritium [3H]

It is permissible to use a mixture of an atom h-count and explicit hydrogen. In such a case, the atom’s hydrogen count is the sum of the atomic h-count property and the number of attached hydrogens. For example:

SMILES Name

[CH4]

methane

[H][CH2][H]

methane

[2H][CH2]C

deuteroethane

3.7. Disconnected Structures

The dot '.' symbol (also called a "dot bond") is legal most places where a bond symbol would occur, but indicates that the atoms are not bonded. The most common use of the dot-bond symbol is to represent disconnected and ionic compounds.

Depiction SMILES Name

depict/sodium-chloride.gif

[Na+].[Cl-]

sodium chloride

depict/phenol-2-amino-ethanol.gif

Oc1ccccc1.NCCO

phenol, 2-amino ethanol

depict/diammonium-thiosulfate.gif

[NH4+].[NH4+].[O-]S(=O)(=O)[S-]

diammonium thiosulfate

The dot can appear most places that a bond symbol is allowed, for example, the phenol example above can also be written:

Depiction SMILES Name

depict/phenol-2-amino-ethanol.gif

c1cc(O.NCCO)ccc1

phenol, 2-amino ethanol

Oc1cc(.NCCO)ccc1

phenal, 2-amino ethanol

The second example above is an odd, but legal, use of parentheses and the dot bond, since the syntax allows a dot most places a regular bond could appear (the exception is that a dot can’t appear before a ring-closure digit).

Although dot-bonds are commonly used to represent compounds with disconnected parts, a dot-bond does not in itself mean that there are disconnected parts in the compound. See the following section regarding ring digits for some examples that illustrate this.

The dot bond cannot be used in front of a ring-closure digit. For example, C.1CCCCC.1 is illegal.

3.7.1. Other Uses of Ring Numbers and Dot Bond

A ring-number specifications ("rnum") is most commonly used to specify a ring-closure bond, but when used with the '.' dot-bond symbol, it can also specify a non-ring bond. Two rnums in a SMILES mean that the two atoms that precede the rnums are bonded. A dot-bond '.' means that the atoms to which it is adjacent in the SMILES string are not bonded to each other. By combining these two constructs, one can "piece together" fragments of SMILES into a whole molecule. The following SMILES illustrate this:

SMILES/Depiction Fragment SMILES Name

CC

C1.C1

ethane

CCC

C1.C12.C2

propane

depict/1-bromo-2-3-dichlorobenzene.gif

c1c2c3c4cc1.Br2.Cl3.Cl4

1-bromo-2,3-dichlorobenzene

This feature of SMILES provides a convenient method of enumerating the molecules of a combinatorial library using string concatenation.

3.8. Stereochemistry

3.8.1. Scope of Stereochemistry in SMILES

A SMILES string can specify the cis/trans configuration around a double bond, and can specify the chiral configuration of specific atoms in a molecule.

SMILES strings do not represent all types of stereochemistry. Examples of stereochemistry that cannot be encoded into a SMILES include:

  • Gross conformational left or right handedness such as helices

  • Mechanical interferences, such as rotatable bonds that are constrained by mechanical interferences

  • Gross conformational stereochemistry such as the shape of a protein after folding

3.8.2. Tetrahedral Centers

SMILES uses an atom-centered chirality specification, in which the atom’s left-to-right order in the SMILES string itself is used as the basis for the chirality marking.

Tetrahedral Chirality

look from N towards C (chiral center)

list the neighbors anticlockwise

depict/tetrahedral.gif

N[C@](Br)(O)C

…or clockwise

N[C@@](Br)(C)O

For the structure above, starting with the nitrogen atom, one "looks" toward the chiral center. The remaining three neighbor atoms are written by listing them in anticlockwise order using the '@' chiral property on the atom, or in clockwise order using the '@@' chiral property, as illustrated above. The '@' symbol is a "visual mnemonic" in that the spiral around the character goes in the anticlockwise direction, and means "anticlockwise" in the SMILES string (thus, '@@' can be thought of as anti-anti-clockwise).

A chiral center can be written starting anywhere in the SMILES string, and the choice of whether to list the remaining neighbor in clockwise or anticlockwise order is also arbitrary. The following SMILES are all equivalent and all specify the exact same chiral center illustrated above:

Equivalent SMILES

N[C@](Br)(O)C

Br[C@](O)(N)C

O[C@](Br)(C)N

Br[C@](C)(O)N

C[C@](Br)(N)O

Br[C@](N)(C)O

C[C@@](Br)(O)N

Br[C@@](N)(O)C

[C@@](C)(Br)(O)N

[C@@](Br)(N)(O)C

One exception to the atom order is when these atoms are bonded to the chiral center via a ring bond. In these cases, it is to order of the bonds to these atoms that should be considered. The two SMILES below are equivalent:

Equivalent SMILES

FC1C[C@](Br)(Cl)CCC1

[C@]1(Br)(Cl)CCCC(F)C1

If one of the neighbor atoms is a hydrogen and is represented as an atomic property of the chiral center (rather than explicitly as [H]), then it is considered to be the first atom in the clockwise or anticlockwise accounting. For example, if we replaced the bromine in the illustration above with a hydrogen atom, its SMILES would be:

Implicit Hydrogen

N[C@H](O)C

3.8.3. Cis/Trans configuration of Double Bonds

The configuration of atoms around double bonds is specified by the bond symbols '/' and '\'. These symbols always come in pairs, and indicate cis or trans with a visual "same side" or "opposite side" concept. That is:

Depiction SMILES Name

depict/trans-difluoroethene.gif

F/C=C/F

trans-difluoroethane (both SMILES are equivalent)

F\C=C\F

depict/cis-difluoroethene.gif

F\C=C/F

cis-difluoroethane (both SMILES are equivalent)

F/C=C\F

The "visual interpretation" of the '/' and '\' symbol is that they are thought of as bonds that "point" above or below the alkene bond. That is, F/C=C/Br means "The F is below the first carbon, and the Br is above the second carbon," leading to the interpretation of a trans configuration.

This notation can be confusing when parentheses follow one of the alkene carbons:

SMILES Name

F/C=C/F

trans-difluoroethane

C(\F)=C/F

F\C=C/F

cis-difluoroethane

C(/F)=C/F

The "visual interpretation" of the "up-ness" or "down-ness" of each single bond is relative to the carbon atom, not the double bond, so the sense of the symbol changes when the fluorine atom moved from the left to the right side of the alkene carbon atom.

Note: This point was not well documented in earlier SMILES specifications, and several SMILES interpreters are known to interpret the '/' and '\' symbols incorrectly.

A SMILES with conflicting up/down specifications is invalid:

SMILES Comment

C/C(\F)=C/F

Invalid SMILES: Both the methyl and fluorine are "down" relative to the first allenal carbon

It is permissible, but not required, that every atom attached to a double bond be marked. As long as at least two neighbor atoms, one on each end of the double bond, is marked, the "up-ness" or "down-ness" of the unmarked neighbors can be deduced.

SMILES Comment

F/C(CC)=C/F

trans-difluoro configuration, position of methyl is implied

Extended cis and trans configurations can be specified for conjugated allenes with an odd number of double bonds:

SMILES Name

F/C=C=C=C/F

trans-difluorobutatriene

F/C=C=C=C\F

cis-difluorobutatriene

3.8.4. Tetrahedral Allene-like Systems

Extended tetrahedral configurations can be specified for conjugated allenes with an even number of double bonds. The normal tetrahedral rules using '@' and '@@' apply, but the "neighbor" atoms to which the chirality refers are at the ends of the allene system. For example:

Depiction SMILES

depict/tetrahedral-allene.gif

NC(Br)=[C@]=C(O)C

To determine the correct clockwise or anticlockwise specification, the allene is conceptually "collapsed" into a single tetrahedral chiral center, and the resulting chirality is marked as a property of the center atom of the extended allene system.

3.8.5. Square Planar Centers

There are three tags to represent square planar stereochemistry: @SP1, @SP2 and @SP3. Since there is no way to determine to what chirality class an atom belongs based on the SMILES alone, the SP class is not the default class for tetravalent stereocenters. Therefore are the shorthand notations (@, @@) not equivalent to @SP1 and @SP2. That is, the full specification must be there (@SP followed by 1, 2 or 3). The square planar also differs from the other chiral primitives in that it does not use the notion of (anti-)clockwise. Instead, each primitive represents a shape that is formed by drawing a line starting from the atom that is first in the SMILES pattern to the next until the end atom is reached. This may result in 3 possible shaped which are referred to by a character with identical shape: 'U' for @SP1, '4' for @SP2 and 'Z' for @SP3. The graphical from of these shapes is illustrated in the image below.

images/SPshapes.png

Background:

Also note that each shape starts and ends at specific positions. Both U and Z start from atoms that are successors or predecessors when arranging the atoms in the plane in anti-clockwise or clockwise order. The start and end atoms for the Z shape are never adjacent in such an ordering. For each shape there are 4 possible ways to start (and end) drawing the line. Also, for all the drawn lines, the start and end point can be exchanged. Thus 3 shapes, 4 ways to start/end and 2 ways to order the atoms for a shape results in 3 * 4 * 2 or 24 combinations. This is the same as the number of permutations that can be made with 4 numbers (i.e. P(n) = n!). This allows for canonical SMILES writers to use any ordering to output the atoms.

3.8.6. Trigonal Bipyramidal Centers

The chiral atom’s neighbors are labeled a, b, c, d, and e in the order that they are parsed. For example, for S[As@@](F)(Cl)(Br)N S corresponds to a, F to b, Cl to c, Br to d and N to e. This order is the unit permutation, represented as the ordered set (a, b, c, d, e). In the simplest case @TB1 viewing from a towards e, (b, c, d) are anti-clockwise (@). Likewise, @TB2 is specified as viewing from a towards e, (b, c, d) are ordered clockwise (@@). The remaining TB’s permute the axis as indicated in the table below. A final example, for @TB6 the viewing axis is from a towards c and (b, d, e) are clockwise (@@).

Viewing Axis TB Number Order

From

Towards

a

e

TB1

@

TB2

@@

a

d

TB3

@

TB4

@@

a

c

TB5

@

TB6

@@

a

b

TB7

@

TB8

@@

b

e

TB9

@

TB11

@@

b

d

TB10

@

TB12

@@

b

c

TB13

@

TB14

@@

c

e

TB15

@

TB20

@@

c

d

TB16

@

TB19

@@

d

e

TB17

@

TB18

@@

The following SMILES are all equivalent:

Equivalent SMILES

S[As@TB1](F)(Cl)(Br)N

S[As@TB2](Br)(Cl)(F)N

S[As@TB5](F)(N)(Cl)Br

F[As@TB10](S)(Cl)(N)Br

F[As@TB15](Cl)(S)(Br)N

Br[As@TB20](Cl)(S)(F)N

A tool like Daylight’s depict match can help debugging

Background:

The trigonal Bipyramidal chirality is considerably more complex than any of the previous classes since the chiral atom has an extra neighbor. This increases the number of combinations to order the neighbors in a SMILES string from 24 to 120. Since every order of the atoms should be representable by a SMILES string, the 20 TB primitives suffice for this. In the trigonal bipyramidal geometry, 3 atoms lie in a plane and the remaining 2 atoms are perpendicular to this plane and are on the opposite sides of the plane forming an axis. The anti-clockwise and clockwise refers to the order of the 3 plane atoms when viewing along the axis in the specified direction. Unlike tetrahedral geometry, reordering the 3 atoms does not require that the axis be changed. Given an order of the axis atoms the 3 plane atoms are ordered either anti-clockwise or clockwise. Although there are P(3) = 3! or 6 possible permutations of 3 numbers, exchanging a pair inverts the parity and the 6 permutations are therefore divided in two groups (@, @@) containing 3 permutations each. Because there are now two atoms that determine the viewing direction along the axis, these atoms too can be in any of the 5 positions in a permutation. Given the atoms as the set {a, b, c, d, e}, there are C(5, 2) = 20 possible combinations of 5 things taken 2 at a time. However, the use of the @ and @@ symbols halve this to 10. These 10 combinations are the ordered sets (a, e), (a, d) (a, c), (a, b), (b, e), (b, d), (b, c), (c, e), (c, d) and (d, e). Each of these pairs correspond to an TB primitive.

3.8.7. Octahedral Centers

For 6 atoms, the unit permutation is (a, b, c ,d ,e ,f). @OH1 means when viewing from a towards f, (b, c, d, e) are ordered anti-clockwise (@). @OH2 uses the same axis but the 4 intermediate atoms are ordered clockwise. The interpretation of the 28 remaining numbers is more complex though. The concept of shapes (see square planar stereochemistry) to describe the orientation of 4 atoms in a plane is reused. However, this time these shapes also have a clockwise or anti-clockwise winding. For the U shape, this is trivial since it means that the 4 atoms are listed clockwise or anti-clockwise. For the Z shape, the connection between the first two atoms determines the winding. Finally, for the 4 shape, the connection between the second and third atom determines the winding. The table below lists the shapes, axes and orders.

Shape Viewing Axis OH Number Order

From

Towards

U

a

f

OH1

@

OH2

@@

a

e

OH3

@

OH16

@@

a

d

OH6

@

OH18

@@

a

c

OH19

@

OH24

@@

a

b

OH25

@

OH30

@@

Z

a

f

OH4

@

OH14

@@

a

e

OH5

@

OH15

@@

a

d

OH7

@

OH17

@@

a

c

OH20

@

OH23

@@

a

b

OH26

@

OH29

@@

4

a

f

OH10

@

OH8

@@

a

e

OH11

@

OH9

@@

a

d

OH13

@

OH12

@@

a

c

OH22

@

OH21

@@

a

b

OH28

@

OH27

@@

The following SMILES are all equivalent:

Equivalent SMILES

C[Co@](F)(Cl)(Br)(I)S

F[Co@@](S)(I)(C)(Cl)Br

S[Co@OH5](F)(I)(Cl)(C)Br

Br[Co@OH9](C)(S)(Cl)(F)I

Br[Co@OH12](Cl)(I)(F)(S)C

Cl[Co@OH15](C)(Br)(F)(I)S

Cl[Co@OH19](C)(I)(F)(S)Br

I[Co@OH27](Cl)(Br)(F)(S)C

Background:

Octahedral stereochemistry is even more complicated since there is yet another extra neighboring atom. This raises the number of permutations to P(6) = 720. There are three axis that can be chosen and the orientation of the remaining 4 atoms has to be described. To describe these 4 atoms, P(4) = 24 permutations are used together with a shape. An axis always starts from the first neighbor atom and can end at any of the other neighbor atoms giving rise to 5 axis. As a result, each OH number encodes the axis positions, a shape and an order. Since all 3 axis can be placed in this positions, the start/end can be exchanged and each shape can start from any of the 4 atoms, each number represents 3 * 2 * 4 = 24 of the 720 permutations. Finally, 24 * 30 = 720 so all permutations can be used to write a canonical SMILES.

3.8.8. Partial Stereochemistry

SMILES allows partial stereochemical specifications. It is permissible for some chiral centers or double bonds to have stereochemical markings in the SMILES, while others in the same SMILES string do not. For example:

SMILES Comment

F/C=C/C/C=C\C

completely specified

F/C=C/CC=CC

partially specified

N1[C@H](Cl)[C@@H](Cl)C(Cl)CC1

partially specified

3.8.9. Other Chiral Configurations

The SMILES language supports a number of atom-centered chiral configurations:

SMILES Configuration

TH

Tetrahedral

AL

Allenal

SP

Square Planar

TB

Trigonal Bipyramidal

OH

Octahedral

The shorthand notations '@' and '@@' correspond to anti-clockwise and clockwise tetrahedral chirality, and are the same a '@TH1' and '@TH2', respectively. Likewise, in an allenal configuration, the shorthand notations '@' and '@@' correspond to '@AL1' and '@AL2', respectively.

Very few SMILES systems actually implement the rules for SP, TB or OH chirality.

3.9. Parsing Termination

A SMILES string is terminated by a whitespace terminator character (space, tab, newline, carriage-return), or by the end of the string.

Other data or information, such as a name, properties, registration number, etc., may follow the SMILES on a line after the whitespace character. SMILES parsers will ignore this data, although applications that use the SMILES parser will often make use of it.

3.10. Programming Practices

OpenSMILES is designed to facilitate exchange of chemical information. To achieve that goal, it SMILES parsers should impose as few limits as possible on the language.

There is no formal limit to the length of a SMILES string; SMILES of over 1 million characters have been assembled for various purposes. There is no requirement that a SMILES parser must be able to parse these exceptionally long SMILES, but as a guideline, all implementations of SMILES parsers should, at a minimum, accept and correctly parse SMILES strings of 100,000 characters. If a SMILES parser encounters a string that is too long to parse, it should generate a relevant error message.

A SMILES parser should accept at least four digits for the atom class, and the values 0 to 9999.

There is no formal limit to the number of rings a molecule can contain. There are only 100 ring-closure numbers, but since numbers can be reused, a molecule can potentially have more than 100 rings. SMILES parsers should accept and correctly parse molecules with at least 1000 rings; it is preferable to place no limits on the number of rings a molecule can contain.

Branches (parentheses) can be nested to an arbitrary depth. Some SMILES strings in standard databases contain over 30 levels of branches, and much deeper nesting is possible. A general purpose parser must handle at least 100 levels; it is preferable to place no limits on nesting depth for parentheses.

There is no formal limit on the number of bonds an atom can have. SMILES parsers should allow at least ten bonds to each atom; it is preferable to place no limits on the number of bonds to each atom.

There is no limit to the number of "dot-disconnected" fragments in a SMILES. A SMILES of 100,000 atoms could in principle contain no bonds at all; SMILES parsers should place no limits on the number of fragments allowed (except that it is limited to the number of atoms the parser can manage).

Programmers are strongly encouraged to provide detailed and clear error messages. If possible, the error message should show exactly which character or "phrase" of the SMILES string triggered the error message.

4. Writing SMILES: Normalizations

4.1. What is Normalization?

A wide variety of SMILES strings are acceptable as input. For example, all of the following represent ethanol:

SMILES Name

CCO

ethanol

OCC

ethanol

C(O)C

ethanol

[CH3][CH2][OH]

ethanol

[H][C]([H])([H])C([H])([H])[O][H]

ethanol

However, it is desirable to write SMILES in more standard forms; the first two forms above are preferred by most chemists, and require fewer bytes to store on a computer. Several levels of normalization of SMILES are recommended for systems that generate SMILES strings. Although these are not mandatory in any sense, they should be considered guidelines for software engineers creating SMILES systems.

4.2. No Normalization

The simplest "normalization" is no normalization. SMILES can be written in any form whatsoever, as long as they meet the rules for SMILES. Some examples of systems that might produce un-normalized SMILES are:

  • A system that enumerates combinatorial libraries using the rnum/dot-bond technique discussed above. SMILES produced by such a system will typically be a series of partial SMILES that are concatenated with dots into a complete molecule.

  • Simple pass-through "filters" that don’t have a full SMILES writer, but merely copy the input SMILES to the output. An example might be a molecular modeling program that reads SMILES to generates logP values, but has no capability to convert its molecular data structures back to a SMILES; instead it just copies its input SMILES to its output.

4.3. Standard Form

The "standard form" of a SMILES is designed to produce a compact SMILES, and one that is human readable (for smaller molecules).

In addition, a normalized SMILES has the important property that it matches itself as a SMARTS string. This is a very important feature of normalized SMILES in cheminformatics systems.

Note: In the example below, the "Wrong" SMILES examples are all valid SMILES, but are "wrong" in the sense that they are not the preferred form for standard normalization.

4.3.1. Atoms

Correct Wrong Normalization Rule

CC

[CH3][CH3]

Write atoms in the "organic subset" as bare atomic symbols whenever possible.

[CH3-]

[CH3-1]

If the charge is +1 or -1, leave off the digit.

C[13CH](C)C

C[13CH1](C)C

If the hydrogen count is 1, leave off the digit.

[CH3-]

[C-H3]

Always write the atom properties in the order: Chirality, hydrogen-count, charge.

C[C@H](Br)Cl

C[CH@](Br)Cl

[CH3-]

[H][C-]([H])[H]

Represent hydrogens as a property of the heavy atom rather than as explicit atoms, unless other rules (e.g. [2H]) require that the hydrogen be explicit.

4.3.2. Bonds

Correct Wrong Normalization Rule

CC

C-C

Only write '-' (single bond) when it is between two aromatic atoms. Never write the ':' (aromatic bond) symbol. Bonds are single or aromatic by default (as appropriate).

c1ccccc1

c:1:c:c:c:c:c:1

c1ccccc1-c2ccccc2

c1ccccc1c2ccccc2

4.3.3. Cycles

Correct Wrong Normalization Rule

c1ccccc1C2CCCC2

c1ccccc1C1CCCC1

Don’t reuse ring-closure digits.

c1ccccc1C2CCCC2

c0ccccc0C1CCCC1

Begin ring numbering with 1, not zero (or any other number)

CC1=CCCCC1

CC=1CCCCC=1

Avoid making a ring-closure on a double or triple bond. For the ring-closure digits, choose a single bond whenever possible.

C1CC2CCCCC2CC1

C12(CCCCC1)CCCCC2

Avoid starting a ring system on an atom that is in two or more rings, such that two ring-closure bonds will be on the same atom.

C1CCCCC1

C%01CCCCC%01

Use the simpler single-digit form for rnums less than 10.

4.3.4. Starting Atom and Branches

Correct Wrong Normalization Rule

OCc1ccccc1

c1cc(CO)ccc1

Start on a terminal atom if possible.

CC(C)CCCCCC

CC(CCCCCC)C

Try to make "side chains" short; pick the longest chains as the "main branch" of the SMILES.

OCCC

CCCO

Start on a heteroatom if possible.

CC

C1.C1

Only use dots for disconnected components.

4.3.5. Aromaticity

Correct Wrong Normalization Rule

c1ccccc1

C1=CC=CC=C1

Write the aromatic form in preference to the Kekule form.

4.3.6. Chirality

Correct Wrong Normalization Rule

BrC(Br)C

Br[C@H](Br)C

Remove chiral markings for atoms that are not chiral.

FC(F)=CF

F/C(/F)=C/F

Remove cis/trans markings for double bonds that are not cis or trans.

4.4. Canonical SMILES

A Canonical SMILES is one that follows the Standard Form above, and additionally, always writes the atoms and bonds of any particular molecule in the exact same order, regardless of the source of the molecule or its history in the computer. Here are a few examples of Canonical versus non-Canonical SMILES:

Canonical SMILES Non-canonical Name

OCC

CCO

ethanol

C(C)O

Oc1ccccc1

c1ccccc1O

phenol

c1(O)ccccc1

c1(ccccc1)O

The primary use of Canonical SMILES is in cheminformatics systems. A molecule’s structure, when expressed as a canonical SMILES, will always yield the same SMILES string, which allows a chemical database system to:

  • Create a unique name (the SMILES) for each molecule in the system

  • Consolidate data about one molecule from a variety of sources into a single record

  • Given a molecule, find its record in the database

Canonical SMILES should not be considered a universal, global identifier (such as a permanent name that spans the WWW). Two systems that produces a canonical SMILES may use different rules in their code, or the same system may be improved or have bugs fixed as time passes, thus changing the SMILES it produces. A Canonical SMILES is primarily useful in a single database, or a system of related databases or information, in which all molecules were created using a single canonicalizer.

The rules (algorithms) by which the canonical ordering of the atoms in a SMILES are generated are quite complex, and beyond the scope of this document. There are many chemistry and mathematical graph-theory papers describing the canonical labeling of a graph, and writing a canonical SMILES string. See the Appendix for further information.

Those considering Canonical SMILES for a database system should also investigate InChI, a canonical naming system for chemicals that is an approved IUPAC naming convention.

4.5. SMILES Files

SMILES file consists of zero or more SMILES strings, one per line, optionally followed by at least one whitespace character (space or tab), and other data. There can be no leading whitespace before the SMILES string on a line. The optional whitespace character and data that follows it are not part of the SMILES specification, and interpretation of this data is up to applications that use the SMILES file. Each line of the file is terminated by either a singe LF character, or by a CR/LF pair of characters (commonly called the "Unix" and "Windows" line terminators, respectively). A SMILES parser must accept either line terminator. A blank line in the SMILES file, or a line that begins with a whitespace character, should be completely ignored by a SMILES parser.

5. Nonstandard Forms of SMILES

Several SMILES-generating systems are in use that either generate incorrect SMILES, or that interpreted some of the ambiguous features of the original SMILES specification in different ways. Although these SMILES are illegal according to this formal OpenSMILES specification, it is often useful to parse them, in order to make use of the information that accompanies these SMILES.

These "relaxed" SMILES rules should only be allowed when the user (presumably after thinking about the consequences) requests it. A SMILES parser that allows any or all of these "relaxed" rules must not do it by default. The user must specifically request these relaxed rules before a parser can accept such SMILES.

The following table lists "relaxed" rules that SMILES parsers may accept.

Rule Example Interpreted as … Details

Extra parentheses

C((C))O

C(C)O

Extra parentheses are ignored in places where there is no ambiguity as to the meaning. Note that the form (CO)N is never allowed, since it isn’t clear which atom the nitrogen should connect to.

C((C))O

C(C)O

(N1CCCC1)

N1CCCCC1

Misplaced dots

[Na+]..[Cl-]

[Na+].[Cl-]

Two or more dot-bonds in a row are condensed into one. A leading or trailing dot-bond is ignored. Note that a dot that starts a branch is legal in strict SMILES; for example, C1CC(.[Na+])CC1[O-] is a legal (though strange) SMILES.

.CCO

CCO

CCO.

CCO

Mismatched Ring Bonds

C1CCC

CCCC

Mismatched ring bonds are ignored. Note that this is almost always a bad idea. For example, C1CCCCC2 is almost certainly supposed to be cyclohexane C1CCCCC1, but with "relaxed" parsing would be interpreted as hexane.

Invalid Cis/Trans specification

C/C=C

CC=C

Mismatched or incomplete cis/trans bonds are ignored.

C/C=CC

CC=CC

CC/=C/C

CC=CC

Conflicting cis/trans specification

C/C(\F)=C/C

CC(F)=CC

Conflicting cis/trans bonds are ignored. (In this case, both the methyl and fluorine on the left are shown as trans to the methyl on the right, an impossible configuration.)

D and T

D[CH3]

[2H][CH3]

The symbols D and T are treated as synonyms for [2H] and [3H].

T[CH3]

[3H][CH3]

Lowercase as sp2

CccccC

CC=CC=CC 2,4-hexadiene

Lowercase letters are interpreted as sp2, even outside of ring systems.

Ccc

CC=C propene

6. Proposed Extensions

6.1. External R-Groups

Daylight proposed, and OpenEye actually implemented, an extension that specifies bonds to external R-groups. An external R-group is specified using ampersand '&' followed by a ring-closure specification (either a digit, or '%' and two digits). However, unlike ring-closures, the bond is to an external, unspecified R-group. Example: n1c(&1)c(&2)cccc1 - 2,3-substituted pyridine.

6.2. Polymers and Crystals

Daylight (Weininger) proposed, but never implemented, an extension for crystals and polymers. Daylight also used the ampersand '&' character, (which may conflict with the R-group proposal, above), but with the added rule that if a number appears more than once, it creates a repeating unit.

SMILES Name

c1ccccc1C&1&1

polystyrene

C&1&1&1&1

diamond

c&1&1&1

graphite

6.3. Atom-based Double Bond Configuration

The directional '/' and '\' marks for cis/trans bonds seem simple on the surface but are problematic for complex systems. The issue is that in conjugated systems one directional bond can be used in defining the configuration of two double bonds. When assigning the directional bonds the existing labels must be considered or rewritten. In a long series of conjugated double bonds, changing the configuration of one bond can require rewriting dozens of bond symbols.

More importantly, there is a theoretical flaw with the use of '/' and '\'. It is possible to write valid SMILES for the molecule cyclooctatetraene by alternating directional assignments for the cis configurations. However, as shown below attempting to change one configuration is not possible. Reassigning the directional labels for adjacent double bonds will not work as it reassignment propagates around the ring and the conflict is not resolved.

Including directional labels to explicit hydrogen atoms is a possible resolution but does not follow standard-form and complicates the assignment procedure.

Depiction SMILES Comment

depict/cyclooctatetraene.gif

C/1=C/C=C\C=C/C=C\1

cyclooctatetraene

Todo

C/1=C/C=C/C=C/C=C\1

one bond changes two configurations

The proposed syntax for double bond configurations uses the '@' and '@@' atom-based specification. For example:

Depiction SMILES Name

depict/trans-difluoroethene.gif

F[C@@H]=[C@H]F

trans-difluoroethene

F[C@H]=[C@@H]F

depict/cis-difluoroethene.gif

F[C@H]=[C@H]F

cis-difluoroethene

F[C@@H]=[C@@H]F

Interpretation of '@' and '@@' follows the tetrahedral convention: The atoms, as encountered in the SMILES string, are either in anticlockwise '@' or clockwise '@@' order as viewed on the page. Since cis/trans configurations are planar, they can also be "viewed from underneath the page", which results in the two valid SMILES shown for each compound, above.

As with the other atom-bases specifications one must consider the relative position of implicit atoms. It is not always true that a trans form has opposite "clock-ness" ('@','@@' or '@@','@'), and the cis form has the same "clock-ness" ('@','@' or '@@','@@').

Depiction SMILES Name

depict/trans-difluoroethene.gif

F[C@@H]=[C@H]F

trans-difluoroethene

[C@H](F)=[C@H]F

depict/cis-difluoroethene.gif

F[C@H]=[C@H]F

cis-difluoroethene

[C@@H](F)=[C@H]F

Atom-based '@' and '@@' for the stereo-specification of double bonds does not suffer from the theoretical flaw illustrated with cyclooctatetraene. The assignments are not-shared and adjacent configurations do not need to be considered. This is more flexible and and simplifies generation of canonical SMILES.

Depiction SMILES Name

depict/cyclooctatetraene.gif

[C@H]1=[C@@H][C@@H]=[C@@H][C@@H]=[C@@H][C@@H]=[C@@H]1

cyclooctatetraene

Note that the first stereo-specification carbon must be represented as '@' since the '1' follows the H, whereas the rest of the carbons use '@@' to characterize the cis configuration of each bond. Since this is a specification on the atom, rather than the single bond, no conflict arises at the ring-closure bond.

6.4. Radical

This section needs considerable work. The following text is courtesy Chris Morley, who commented: "I guess the last paragraph doesn’t look too good in a formal specification. There are two reasons for the frailty: lack of proof that the radical and aromatic uses can always be unambigous (I doubt anybody has tried); and a known deficiency in the parser." However, it is a good starting point…

A single lowercase symbol is interpreted as a radical center. CCc is an alternative to CC[CH2] and is the 1-propyl radical; CcC or C[CH]C is the 2-propyl radical, Co is the methoxy radical. An odd number of adjacent lowercase symbols is a delocalized conjugated radical. So Cccccc is CC=CC=C[CH2] or CC=C[CH]C=C or C[CH]C=CC=C Lowercase 'c' or 'n' can be used in a ring: C1cCCCC1 is the cyclohexyl radical.

The use of the non-aromatic lowercase symbol is a shorted form with improved intelligibility that allows the use of implicit hydrogen in radicals. However it is intended only for simple unambiguous molecules and is not reliable when combined with aromatic atoms.

6.5. Twisted SMILES

An interesting extension that specifies conformational information via bond dihedral angles and bond lengths was proposed by McLeod and Peters:

7. APPENDIX 1: References and Citations

7.1. Groups

Blue Obelisk

7.4. Some Key Scientific Papers

  • David Weininger, SMILES, a Chemical Language and Information System. 1. Introduction to Methodology and Encoding Rules, Journal of Chemical Information and Computer Sciences, 1988, 28:31-36.

  • David Weininger, Arthur Weininger, and Joseph L Weininger, SMILES 2. Algorithm for Generation of Unique SMILES Notation Journal of Chemical Information and Computer Sciences, 1989, 29:97-101.

  • Morgan’s original canonicalization paper: Morgan, H.L. J.Chem.Doc. 1965, 5, 107

  • G.M. Downs et al, Review of Ring Perception Algorithms for Chemical Graphs, J. Chem. Inf. Comput. Cci. 1989, 29, 172-187

  • R.Balducci and R, Pearlman, Novel Algorithms for the Rapid Perception of a Unique Optimal Set of Rings, J. Am. Chem. Soc. (date?)

7.5. Molecule Editors that can produce SMILES

8. Revision History

Revision Date Description Name

1.0

2007-11-13

Draft

Craig A. James

1.0

2012-09-29

Reformatting

Tim Vandermeersch

1.0

2012-09-29

Corrections

Andrew Dalke & Tim Vandermeersch

1.0

2012-11-17

SP, TB and OH stereochemistry

Tim Vandermeersch

1.0

2013-09-06

Corrections

Richard Apodaca

1.0

2013-09-17

Corrections

John May