US20040034223A1 - Amphiphilic molecular modules and constructs based thereon - Google Patents

Amphiphilic molecular modules and constructs based thereon Download PDF

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Publication number
US20040034223A1
US20040034223A1 US10/071,377 US7137702A US2004034223A1 US 20040034223 A1 US20040034223 A1 US 20040034223A1 US 7137702 A US7137702 A US 7137702A US 2004034223 A1 US2004034223 A1 US 2004034223A1
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Prior art keywords
group
alkyl
synthon
bonded
module
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US10/071,377
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English (en)
Inventor
Timothy Karpishin
Josh Kriesel
Grant Merrill
Donald Bivin
Thomas Smith
Martin Edelstein
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Covalent Partners LLC
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Covalent Partners LLC
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Priority to US10/071,377 priority Critical patent/US20040034223A1/en
Assigned to COVALENT PARTNERS, LLC reassignment COVALENT PARTNERS, LLC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BIVIN, DONALD B., EDELSTEIN, MARTIN S., KARPISHIN, TIMOTHY B., KRIESEL, JOSH, MERRILL, GRANT, SMITH, THOMAS S.
Priority to US10/226,400 priority patent/US20030199688A1/en
Priority to KR10-2004-7012275A priority patent/KR20050009981A/ko
Priority to EA200401044A priority patent/EA200401044A1/ru
Priority to AU2003212974A priority patent/AU2003212974B2/en
Priority to EP03709017A priority patent/EP1481268A4/en
Priority to US10/359,894 priority patent/US7432371B2/en
Priority to CNA038075407A priority patent/CN1646501A/zh
Priority to EA200401045A priority patent/EA007470B1/ru
Priority to JP2003566582A priority patent/JP4688418B2/ja
Priority to KR1020047012272A priority patent/KR100979423B1/ko
Priority to CA002475567A priority patent/CA2475567A1/en
Priority to CN03807571.7A priority patent/CN1646116A/zh
Priority to PCT/US2003/003829 priority patent/WO2003067286A2/en
Priority to PCT/US2003/003830 priority patent/WO2003066646A2/en
Priority to CA002475646A priority patent/CA2475646A1/en
Priority to EP03709018A priority patent/EP1480635A4/en
Priority to MXPA04007680A priority patent/MXPA04007680A/es
Priority to JP2003566017A priority patent/JP2005517017A/ja
Priority to AU2003212973A priority patent/AU2003212973B2/en
Priority to MXPA04007679A priority patent/MXPA04007679A/es
Publication of US20040034223A1 publication Critical patent/US20040034223A1/en
Priority to IL163367A priority patent/IL163367A/en
Priority to ZA200406352A priority patent/ZA200406352B/en
Priority to ZA200406351A priority patent/ZA200406351B/en
Priority to US11/199,913 priority patent/US7767810B2/en
Priority to US11/207,383 priority patent/US7563890B2/en
Priority to US12/183,469 priority patent/US8110679B2/en
Priority to US12/504,610 priority patent/US20100152438A1/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D259/00—Heterocyclic compounds containing rings having more than four nitrogen atoms as the only ring hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C211/44—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring
    • C07C211/49—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring having at least two amino groups bound to the carbon skeleton
    • C07C211/50—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring having at least two amino groups bound to the carbon skeleton with at least two amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/74—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C215/76—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton of the same non-condensed six-membered aromatic ring
    • C07C215/78—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton of the same non-condensed six-membered aromatic ring containing at least two hydroxy groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/74—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C215/76—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton of the same non-condensed six-membered aromatic ring
    • C07C215/80—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton of the same non-condensed six-membered aromatic ring containing at least two amino groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/46—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton

Definitions

  • This invention is related to the fields of organic chemistry and nanotechnology. In particular, it relates to materials and methods for the construction of amphiphilic modules and the formation of nanomembranes, from the modules.
  • the loop is cleaved at the restriction site, and another double stranded polynucleotide segment, itself having a loop containing an endonuclease recognizable sequence different from that of the first segment, is ligated to the first segment at the cleavage site.
  • the loop of the second segment is then cleaved and a third polynucleotide segment is ligated into the system. The process is continued until the desired structure is achieved.
  • Michl Another approach to the synthesis of molecular scale constructs was patented in 1999 by Michl, et al. (U.S. Pat. No. 5,876,830). Michl analogized his approach to the children's construction toy “TINKERTOYTM” (Playskool, Inc., Pawtucket, R.I.). That is, Michl builds macromolecular structures by linking together complex molecular modules using connectors, spacers, binders, etc. The procedure requires adhering modules to a surface and then reacting connector groups on adjacent modules with molecular “rods” to form monomolecular grids or nets.
  • the present invention provides novel, extremely versatile molecular modules, methods for their synthesis and fabrication into nanoscale devices, in particular selectively permeable membranes.
  • the present invention relates to an amphiphilic module, comprising 3-24 synthons independently selected from the group consisting of aryl, heteroaryl, alicyclic and heteroalicyclic, provided at least one of the synthons is different from the others.
  • the synthons are arranged such that a first synthon is bonded to a second synthon through a linker, the second synthon is bonded to a third synthon through a second linker, the third synthon is bonded to a fourth synthon, if four synthons are desired in the module, the fourth to a fifth, etc., until an nth synthon is bonded to its predecessor through an (n ⁇ 1) th linker, where n is 4-24.
  • n th synthon is then bonded to the first synthon through an nth linker to form a closed ring of synthons.
  • nth linker There are also one or more lipophilic moieties bonded to one or more of the synthons and one or more hydrophilic moieties bonded to one or more of the synthons.
  • each synthon is independently selected from the group consisting of benzene, naphthalene, anthracene, phenylene, phenathracene, pyrene, triphenylene, phenanthrene, pyridine, pyrimidine, pyridazine, biphenyl, bipyridyl, cyclohexane, cyclohexene, decaline, piperidine, pyrrolidine, tetrahydropyran, tetranhydrothiane, 1,3-dioxane, 1,3-dithiane, 1,3-diazane, tetrahydrothiophene, tetrahydrofuran, pyrrole, cyclopentane, triptycene, adamantane, bicyclo[2.2.1]heptane, bicyclo[2.2.1]heptene, 7-azabicyclo[2.2.1]h
  • the lipophilic moiety is selected from the group consisting of -(8C-28C)alkyl, —O(8C-28C)alkyl, —NH(8C-28C)alkyl, OC(O)-(8C--28C)alkyl, —C(O)O-(8C-28C)alkyl, —NHC(O)-(8C-28C)alkyl, —C(O)NH-(8C-28C)alkyl, —CH ⁇ CH-(8C-28C)alkyl and —C ⁇ -C-(8C-28C)alkyl.
  • the carbon atoms of the (8C-28C)alkyl group may be interrupted by one or more —S—, double bond, triple bond or —SiR′R′′— groups, substituted with one or more fluorine atoms or any combination of these.
  • R′ and R′′ independently comprise (1C-18C)alkyl.
  • the hydrophilic moiety is selected from the group consisting of —OH, —OCH 3 , —NH 2 , —C ⁇ N, —NO 2 , — + NRR′R′′, —SO 3 ⁇ , —OPO 2 2 ⁇ , —OC(O)CH ⁇ CH 2 , —SO 2 NH 2 , SO 2 NRR′, —OP(O)(OCH 2 CH 2 N + RR′R′′)O ⁇ , —C(O)OH, —C(O)O ⁇ , guanidinium, aminate, pyridinium, —C(O)OCH 3 , —C(O)OCH 2 CH 3 , —C(O)OCH ⁇ CH 2 , —O(CH 2 ) y C(O)NH 2 , —O(CH 2 CH 2 O) z R′′′ and
  • R, R′ and R′′ are independently selected from the group consisting of hydrogen and (1 C-4C)alkyl
  • R′′′ is selected from the group consisting of hydrogen, —CH 2 C(O)OH and —CH 2 C(O)NH 2 .
  • y is 1-6 and z is 1-50.
  • each linker is independently selected from the group consisting of —O—, —S—, —NR 17 —, —SS—, —(CR 17 R 18 ) m —, —CH(OH)—, —C(OH)R 17 —CH 2 N R 18 —, —C(OH)CH(NHR 17 )—, —CR 17 ⁇ CR 18 —, —C ⁇ C—, —C(O)O—, —C(O)S—, —OC(O)O—, C(O)NR 17 —, —CR 17 ⁇ N—, —CR 17 ⁇ NNH—, —NHC(O)O—, —NHC(O)NR 17 —, —CH(OH)CH 2 (CO 2 R 17 ) —, —CH ⁇ CR 17 C(O)—, —C ⁇ C—C ⁇ C—, —C(CH R 17 R 18 )S—,
  • R 17 and R 18 are independently selected from the group consisting of hydrogen, (1C-4C)alkyl and a group that confers a selected chemical or physical characteristic, or a combination thereof, on the module.
  • every other synthon is the same; that the first, third, and if present, fifth, seventh, etc., synthons are the same and the second, and if present, the fourth, sixth, eighth, etc., synthons are the same.
  • An aspect of this invention is an amphiphilic module comprising 12 synthons.
  • An aspect of this invention is an amphiphilic module comprising 10 synthons.
  • An aspect of this invention is an amphiphilic module comprising 8 synthons.
  • An aspect of this invention is an amphiphilic module comprising 6 synthons.
  • An aspect of this invention is an amphiphilic module comprising 4 synthons.
  • An aspect of this invention is an amphiphilic module of claim 1, comprising the formula:
  • a 1 -A 8 are synthons.
  • L 1 -L 8 are linkers.
  • One or more of R 1 , R 3 , R 5 , R 7 , R 9 , R 11 , R 13 and R 15 comprises a lipophilic group, which may be same as, or different from, each of the other lipophilic groups.
  • One or more of R 2 , R 4 , R 6 , R 8 , R 10 , R 12 , R 14 and R 16 comprises a hydrophilic group, which may be the same as, or different from, each other hydrophilic group.
  • Each R group that is not a lipophilic or a hydrophilic group is independently either absent or comprises a group that confers a selected chemical or physical characteristic or combination thereof on the module.
  • Each A and each L may also optionally be bonded to one or more additional substituents that confer selected chemical or physical characteristics or combinations thereof on the module.
  • a 1 , A 3 , A 5 and A 7 comprise the same synthon.
  • a 2 , A 4 , A 6 and A 8 comprise the same synthon, which is different from the A 1 , A 3 , A 5 , A 7 synthon.
  • An aspect of this invention is an amphiphilic module, comprising the chemical structure:
  • X and Y are independently hydrogen, —OC(O)CH ⁇ CH 2 , —NHC(O)CH ⁇ CH 2 ,
  • X can be —C(O)OH, —C(O)OCH 3 , —C(O)Cl or another activated acid and Y is —NH 2 , —OH or —SH.
  • R 1 is selected from the group consisting of —CH 2 —(10C-18C)alkyl, —CH ⁇ CH—(10C-18C)alkyl, —C ⁇ C—(10C-18C)alkyl, —OC(O)-(10C-18C)alkyl, —C(O)O-(10C-18C)alkyl, —NHC(O)-(10C-18C)alkyl, —C(O)NH-(10C-18C)alkyl and —O-(10C-18C)alkyl.
  • R 2 , R 3 , R 4 and R 5 are independently selected from the group consisting of hydrogen, —C(O)(CH 2 ) 2 C(O)OCH 3 , —C(O)CH ⁇ CH 2 ,
  • n1 is 1-50 and n2 is 1-4. At least one of R 2 , R 3 or R 4 must be other than hydrogen.
  • L is selected from the group consisting of —C(O)O—, —C(O)NH—, —CH 2 NH— and —CH ⁇ N—, wherein the oxygen or nitrogen is bonded to either the benzene ring or the cyclohexyl ring.
  • the nitrogen or oxygen of the L group is bonded to the cyclohexyl group in the above amphiphilic module.
  • the nitrogen or oxygen of the L group alternate around the ring.
  • the nitrogen or oxygen of the next L group going around the ring is bonded to the benzene ring.
  • An aspect of this invention is an amphiphilic module comprising the chemical structure:
  • Z is —NZ 1 - or —CZ 2 Z 3 .
  • Z 1 is selected from the group consisting of hydrogen, an amino acid residue and —C(O)CH ⁇ CH 2 .
  • Z 2 is hydrogen and Z 3 is selected from the group consisting of hydrogen, —OH, —NH 2 and —SH.
  • one of Z 2 or Z 3 is selected from the group consisting of hydrogen, —OH, —NH 2 , —SH, —(CH 2 ) z4 OH, —(CH 2 ) z4 NH 2 and —(CH 2 ) z4 SH and the other is selected from the group consisting of —(CH 2 ) z4 OH, —(CH 2 ) z4 NH 2 and —(CH 2 ) z4 SH, wherein Z 4 is 1, 2, 3 or 4.
  • R 1 is selected from the group consisting of CH 2 -(10C-18C)alkyl, —CH ⁇ CH-(10C-18C)alkyl, —C ⁇ C-(10C-18C)alkyl, —OC(O)-(10C-18C)alkyl, —C(O)O-(10C-18C)alkyl, —NHC(O)-(10C-18C)alkyl, —C(O)NH-(10C-18C)alkyl and —O-(10C-18C)alkyl.
  • R 2 , R 3 , R 4 and R 5 are independently selected from the group consisting of hydrogen, —C(O)(CH 2 ) 2 C(O)OCH 3 , —C(O)CH ⁇ CH 2 ,
  • n1 is 1-50 and n2 is 1-4. At least one of R 2 , R 3 or R 4 must be other than hydrogen.
  • L is selected from the group consisting of —C(O)O—, —C(O)NH—, —CH 2 NH— and —CH ⁇ N—, wherein the oxygen or nitrogen is bonded to either the benzene ring or the cyclohexane ring.
  • the nitrogen or oxygen of the L group alternates around the ring.
  • the nitrogen or oxygen of the next L group going around the ring is bonded to the benzene ring.
  • An aspect of this invention is an amphiphilic module, comprising the chemical structure:
  • X and Y are independently hydrogen
  • —OC(O)CH ⁇ CH 2 —NHC(O)CH ⁇ CH 2 , —SH or —NH 2 .
  • X can be —C(O)OH, —C(O)OCH 3 , —C(O)Cl or another activated acid and Y is —NH 2 , —OH or —SH.
  • R 1 is selected from the group consisting of —CH ⁇ CH 2 , —OC(O)CH ⁇ CH 2 and —NHC(O)CH ⁇ CH 2 .
  • R 1 is hydrogen.
  • R 6 is selected from the group consisting of CH 2 -(10C-18C)alkyl, —CH ⁇ CH-(10C-18C)alkyl, —C ⁇ C-(10C-18C)alkyl, —OC(O)-(10C-18C)alkyl, —C(O)O-(10C-18C)alkyl, —NHC(O)-(10C-18C)alkyl, —C(O)NH-(10C-18C)alkyl and —O-(10C-18C)alkyl.
  • R 2 , R 3 , R 4 and R 5 are independently selected from the group consisting of hydrogen, —C(O)(CH 2 ) 2 C(O)OCH 3 , —C(O)CH ⁇ CH 2 ,
  • n1 is 1-50 and n2 is 1-4. At least one of R 2 , R 3 or R 4 must be other than hydrogen.
  • L is selected from the group consisting of —C(O)O—, —C(O)NH—, —CH 2 NH— and —CH ⁇ N—, wherein the oxygen or nitrogen is bonded to either the benzene ring or the bicyclo[2.2.1]heptane ring.
  • the nitrogen or oxygen of the L group is bonded to the bicyclo[2.2.1]heptane ring.
  • the nitrogen or oxygen of the L group alternates around the ring.
  • the nitrogen or oxygen of the next L group going around the ring is bonded to the benzene ring.
  • An aspect of this invention is an amphiphilic module comprising the structure:
  • a 1 -A 6 are the synthons.
  • L 1 -L 6 are the linkers.
  • One or more of R 1 , R 3 , R 5 , R 7 , R 9 and R 11 comprises a lipophilic group, which may be same as, or different from, each other.
  • One or more of R 2 , R 4 , R 6 , R 8 , R 10 and R 12 comprises a hydrophilic group, which may be the same as, or different from, each other.
  • Each R group that is not a lipophilic or a hydrophilic group is independently either absent or comprises a group that confer a selected chemical or physical characteristic or combination thereof on the module.
  • Each A and each L may optionally be bonded to one or more additional substituents that confer selected chemical or physical characteristics or combinations thereof on the module.
  • a 1 , A 3 and A 5 comprise the same synthon.
  • a 2 , A 4 and A 6 in the above amphiphilic module also comprise the same synthon, which is different from the A 1 , A 3 , A 5 synthon.
  • An aspect of this invention is an amphiphilic module comprising the structure:
  • X and Y are both —SH or —NH 2 .
  • X is —C(O)OH, —C(O)OCH 3 , —C(O)Cl or another activated acid and Y is —NH 2 .
  • R 1 is selected from the group consisting of —CH 2 -(10C-18C)alkyl, —CH ⁇ CH-(10C-18C)alkyl, —C ⁇ C-(10C-18C)alkyl, —OC(O)-(10C--18C)alkyl, —C(O)O-(10C-18C)alkyl, —NHC(O)-(10C-18C)alkyl, —C(O)NH-(10C-18C)alkyl and —O-(10C-18C)alkyl.
  • R 2 , R 3 and R 4 are independently selected from the group consisting of hydrogen, —C(O)(CH 2 ) 2 C(O)OCH 3 , —C(O)CH ⁇ CH 2 ,
  • n1 is 1-50 and n2 is 1-4. At least one of R 2 , R 3 or R 4 must be other than hydrogen.
  • L is selected from the group consisting of —C(O)O—, —C(O)NH—, —CH 2 NH— and —CH ⁇ N—, wherein the oxygen or nitrogen is bonded to either the benzene ring or the cyclohexyl ring.
  • the nitrogen or oxygen of the L group is bonded to the cyclohexyl ring.
  • the nitrogen or oxygen of the L group alternates around the ring.
  • the nitrogen or oxygen of the next L group going around the ring is bonded to the benzene ring.
  • An aspect of this invention is an amphiphilic module, comprising the chemical structure:
  • X and Y are independently hydrogen
  • —OC(O)CH ⁇ CH 2 —NHC(O)CH ⁇ CH 2 , —SH or —NH 2 .
  • X is —C(O)OH, —C(O)OCH 3 , —C(O)Cl or another activated acid and Y is —NH 2 , —OH or —SH.
  • R 1 is selected from the group consisting of —CH ⁇ CH 2 , —OC(O)CH ⁇ CH 2 and —NHC(O)CH ⁇ CH 2 .
  • R 1 is hydrogen.
  • R 5 is selected from the group consisting of CH 2 -(10C-18C)alkyl, —CH ⁇ CH-(10C-18C)alkyl, —C ⁇ C-(10C-18C)alkyl, —OC(O)-(10C-18C)alkyl, —C(O)O(10C--18C)alkyl, —NHC(O)-(10C-18C)alkyl, —C(O)NH-(10C-18C)alkyl and —O-(10C-18C)alkyl.
  • R 2 , R 3 and R 4 are independently selected from the group consisting of hydrogen, —C(O)(CH 2 ) 2 C(O)OCH 3 , —CH 2 C(O)CH ⁇ CH 2 ,
  • n1 is 1-50 and n2 is 1-4. At least one of R 2 , R 3 or R 4 must be other than hydrogen.
  • L is selected from the group consisting of —C(O)O—, —C(O)NH—, —CH 2 NH— and —CH ⁇ N—, wherein the oxygen or nitrogen is bonded to either the benzene ring or the bicyclo[2.2.1]heptane ring.
  • the nitrogen or oxygen of the L group is bonded to the bicyclo[2.2.1]heptane ring.
  • the nitrogen or oxygen of the L group alternates around the ring.
  • the nitrogen or oxygen of the next L group going around the ring is bonded to the benzene ring.
  • An aspect of this invention is an amphiphilic module, comprising the chemical structure:
  • X and Y are independently hydrogen
  • —OC(O)CH ⁇ CH 2 —NHC(O)CH ⁇ CH 2 , —SH or —NH 2 .
  • X is —C(O)OH, —C(O)OCH 3 , —C(O)Cl or another activated acid and Y is —NH 2 , —OH or —SH.
  • R 1 is selected from the group consisting of —CH 2 -(10C-18C)alkyl, —CH ⁇ CH-(10C-18C)alkyl, —C ⁇ C-(10C-18C)alkyl, —OC(O)-(10C-18C)alkyl, —C(O)O-(10C-18C)alkyl, —NHC(O)-(10C-18C)alkyl, —C(O)NH-(10C-18C)alkyl and —O-(10C-18C)alkyl.
  • R 2 , R 3 and R 4 are independently selected from the group consisting of hydrogen, —C(O)(CH 2 ) 2 C(O)OCH 3 , —C(O)CH ⁇ CH 2 ,
  • n1 is 1-50 and n2 is 1- 4. At least one of R 2 , R 3 or R 4 must be other than hydrogen.
  • L is selected from the group consisting of —C(O)O—, —C(O)NH—, —CH 2 NH— and —CH ⁇ N—, wherein the nitrogen or oxygen is bonded to either the benzene ring or the cyclohexyl ring.
  • the nitrogen or oxygen of the L group is bonded to the cyclohexyl ring.
  • the nitrogen or oxygen of the L group alternates around the ring.
  • the nitrogen or oxygen of the next L group going around the ring is bonded to the benzene ring.
  • An aspect of this invention is an amphiphilic module, comprising the chemical structure:
  • X and Y are independently hydrogen
  • —OC(O)CH ⁇ CH 2 —NHC(O)CH ⁇ CH 2 , —SH or —NH 2 .
  • X is —C(O)OH, —C(O)OCH 3 , —C(O)Cl or another activated acid and Y is —NH 2 , —OH or —SH.
  • R 1 is selected from the group consisting of —CH ⁇ CH 2 , —OC(O)CH ⁇ CH 2 and —NHC(O)CH ⁇ CH 2 .
  • R 1 is hydrogen.
  • R 5 is selected from the group consisting of CH 2 -(10C-18C)alkyl, —CH ⁇ CH-(10C-18C)alkyl, —C ⁇ C-(10C-18C)alkyl, —OC(O)-(10C-18C)alkyl, —C(O)O-(10C-18C)alkyl, —NHC(O)-(10C-18C)alkyl, —C(O)NH-(10C-18C)alkyl and —O-(10C-18C)alkyl.
  • R 2 , R 3 and R 4 are independently selected from the group consisting of hydrogen, —C(O)(CH 2 ) 2 C(O)OCH 3 , —C(O)CH ⁇ CH 2 ,
  • n1 is 1-50 and n2 is 1-4. At least one of R 2 , R 3 or R 4 must be other than hydrogen.
  • L is selected from the group consisting of —C(O)O—, —C(O)NH—, —CH 2 NH— and —CH ⁇ N—, wherein the oxygen or nitrogen is bonded to either the benzene ring or the bicyclo[2.2.1]heptane ring.
  • the nitrogen or oxygen of the L group is bonded to the bicyclo[2.2.1]heptane ring.
  • the nitrogen or oxygen of the L group alternates around the ring.
  • the nitrogen or oxygen of the next L group going around the ring is bonded to the benzene ring.
  • Another aspect of this invention relates to a method of synthesizing an amphiphilic module.
  • a plurality of a first synthon comprising two functional groups that may be the same or different is provided.
  • a plurality of a second synthon which is different than the first synthon, but also comprising two functional groups that may be the same or different, is also provided.
  • the functional groups of the first synthons are selected such that they can only react with the functional groups of the second synthons.
  • the first and second synthons are then put together in a solvent under conditions that cause the functional groups to react to form an amphiphilic module.
  • the amphiphilic module is then isolated.
  • a reagent or reagents that catalyzes the reaction of the functional groups of the first synthon with the functional groups of the second synthon may be used.
  • a further aspect of this invention relates to an alternative method for preparing an Amphiphilic module.
  • This method comprises placing a first synthon comprising a functional group in a solvent and then adding a second synthon comprising a functional group that reacts with the functional group of the first synthon to form a dimer. Then a third synthon is added.
  • the third synthon may be the same as, or different from, the first synthon and comprises a functional group that reacts with a second functional group of the second synthon to form a trimer.
  • the preceding step is repeated until an n th (n is 1-24) synthon is added.
  • the n th synthon comprises a functional group that reacts with a second functional group of the first synthon to form a ring.
  • a reagent or reagents may be added to catalyze the reaction of a functional group of a synthon with a functional group of the next synthon being added.
  • a reagent may be added that reacts with a functional group of a synthon to form an intermediate, which then reacts with a functional group of the next synthon that is added.
  • An aspect of this invention is a two-dimensional array comprising a plurality of amphiphilic modules wherein each module is bonded to one or more adjacent modules by one or more connectors between each pair of adjacent modules.
  • each connector is independently selected from the group consisting of —O—, —S—, —NR 19 —, —SS—, —(CR 19 R 20 ) m —, —CH(OH)—, —C(OH)R 19 —CH 2 NR 20 —, —C(OH)CH(NHR 19 )—, —CR 19 ⁇ CR 20 —, —C ⁇ C—, —C(O)O—, —C(O)S—, —OC(O)O—, C(O)NR 19 —, —CR 19 ⁇ N—, —CR 19 ⁇ NNH—, —NHC(O)O—, —NHC(O)NR 19 —, —NHCH 2 NH—, —NHC(NH)CH 2 C(NH)NH—, —CH(OH)CH 2 (CO 2 R 19 )—, —CH ⁇ CR 19 C(O)—, —
  • R 19 and R 20 are independently selected from the group consisting of hydrogen, (1C-4C)alkyl and a group that confers a selected chemical or physical characteristic, or a combination thereof.
  • the connector is separated from one or both of the modules by a spacer.
  • the spacer comprises a —(CH 2 ) n — group, wherein n is 1-28, in another aspect of this invention.
  • Table 1 is a list of functional groups that can react to form the presently preferred linkers. The linkers formed are also shown.
  • Table 2 shows the results of quantum mechanical and molecular mechanical computations of the size of the pores formed from selected sets of synthons and linkers.
  • Table 3 shows the results of quantum mechanical and molecular mechanical computations of the size of the pores formed by additional sets of synthons and linkers.
  • Table 4 shows the results of experiments carried to determine what size ion can pass through a selected module of this invention.
  • FIG. 2A hexameric modules are used to exemplify close-packed arrays (FIG. 2A). Certain synthons are shown with functional groups that form connectors (FIGS. 2B and 2C). Certain functional groups, e.g., amino (—NH 2 ) groups are shown forming connectors (FIG. 5). It is understood that other size modules, other synthons and other functional groups could just as easily have been used in the figures.
  • FIGS. 1 A- 1 C show the structure of modules of this invention as determined by energy minimization computation.
  • FIG. 1A shows the structure of a tetramer module, essentially a parallelogram.
  • FIG. 1B shows the structure of a hexamer module, essentially an equilateral triangle.
  • FIG. 1C show the structure of an octamer module, essentially a rhombus.
  • FIG. 2 depicts a close-packed two-dimensional array of hexameric modules.
  • FIG. 2A shows the array without any connectors between modules.
  • FIG. 2B show the array with one connector between each pair of adjacent modules.
  • FIG. 2C shows the array with two connectors between each pair of adjacent modules.
  • FIG. 3 is a graph of a Languir isotherm demonstrating that the modules of this invention do form monomolecular Langmuir films.
  • FIG. 4 depicts some presently preferred connectors and the functional groups and reactants used for their formation.
  • FIG. 4A shows an imidate connector
  • FIG. 4B shows an urea connector
  • FIG. 4C shows a boronic acid amide connector
  • FIG. 4D shows a copolymeric connector formed by the reaction of acrylate functional groups on the synthons with external ethyl acrylate.
  • FIG. 5 depicts some additional presently preferred connectors.
  • FIG. 5A shows connectors formed when two functional groups are bonded to the same synthon in each module.
  • the connector is an aminal.
  • FIG. 5B shows the formation of disulfide connectors from mercaptans.
  • FIG. 5C shows the formation of cyclobutyl connectors by the [2+2] cycloaddition of acrylates on the synthons.
  • FIG. 5D shows a copolymeric connector formed by the reaction of acrylate functional groups isolated from the synthons by seven methylene spacers with external ethyl acrylate.
  • FIG. 6 depicts the preparation of a nanomembrane.
  • the figures are cartoon representations only and are not intended to depict an actual Langmuir-Blodgett trough.
  • FIG. 6A shows amphiphilic modules in chloroform which is floating on a layer of water.
  • FIG. 6B shows the amphiphilic modules on the surface of the water after the chloroform has been evaporated.
  • FIG. 6C shows the amphiphilic modules compressed into a close-packed array.
  • FIG. 6D shows the close-packed array in which connectors have been formed between the amphiphilic modules.
  • an “(nC-mC)alkyl wherein n is 1 to 8 and m is 8 to 28, refers to all alkyl groups comprising n to m carbon atoms.
  • a (1 C-4C)alkyl refers to a methyl (1 carbon atom), ethyl (2 carbon atoms), propyl (3 carbon atoms) or butyl (4 carbon atoms) group. All possible isomers of the indicated alkyl are also included.
  • “propyl” includes isopropy
  • butyl includes n-butyl, isobutyl and tbutyl, etc.
  • amphiphilic refers to a molecule that contains both hydrophilic and lipophilic (or, synonymously, hydrophobic) moieties.
  • Hydrophilic means “water-loving.”
  • the hydrophilic moiety of an amphiphilic molecule has an affinity for and is generally miscible with water. If placed at a water/water-immiscible liquid (or a water/air) interface, the hydrophilic moiety will partition into the water layer.
  • hydrophilic moieties include, without limitation, hydroxyl, methoxy, phenol, carboxylic acids and salts thereof, methyl and ethyl esters of carboxylic acids, amides, amino, cyano, ammonium salts, sulfonium salts, phosphonium salts, polyethyleneglycols, epoxy groups, acrylates, sulfonamides, nitro, —OP(O)(OCH 2 CH 2 N + RR′R′′)O ⁇ , guanidinium, aminate, acrylamide and pyridinium.
  • Lipophilic means “lipid-loving,” which, because lipids are oily, water insoluble compounds, is understood to mean generally “oil-loving.”
  • the lipophilic moiety of an amphiphilic molecule avoids water and has an affinity for and is generally miscible with water-immiscible liquids. Thus, if placed at a water/water immiscible liquid (or a water/air) interface, a lipophilic moiety will partition into the water-immisible liquid layer (or into the air).
  • the most common example of a lipophilic moiety is a long, straight or branched chain hydrocarbon. Presently preferred lipophilic groups consist of at least eight (8) carbon atoms in a branched or straight chain.
  • the total number of carbon atoms in the chain will be 10 or more, still more preferably 12 or more.
  • a straight chain or each branch of a branched chain may comprise any number of carbon atoms over the indicated minimum. However, the straight chain or each branch of a branched chain will comprise a maximum of 28 carbon atoms in a presently preferred embodiment of this invention.
  • Each chain may independently comprise, without limitation, alkenyl, alkynyl, alicyclic or aromatic groups.
  • Each chain may also contain, interspersed among the carbons of the chain, one or more silicon atoms substituted with alkyl, alkenyl, alkynyl, alicyclic or aryl groups. Likewise the carbon atoms of each chain may independently be substituted with one or more fluorine atoms.
  • a “synthon” refers to a molecule that can be connected with other molecules, which may be the same as, or different than, the initial molecule and each other, to create a larger molecule.
  • a “synthon” refers to a multifunctional organic molecule of predominantly one stereochemical configuration. It may also refer to a molecule that is predominantly a single enantiomer.
  • multifunctional is meant that the molecule is substituted with at least two functional groups, which may be the same as, or different than, each other.
  • Connection of synthons of this invention to create larger molecular entities occurs through covalent bonds resulting from reaction of a functional group on one synthon with a functional group on another synthon.
  • a synthon may also be substituted with additional functional groups that do not participate in synthon interconnections but rather impart selected physical or chemical characteristics to the synthon.
  • Presently preferred synthons of this invention are cyclic.
  • a “cyclic” synthon is meant a monocyclic or multicyclic ring system.
  • the monocyclic ring or each ring of a multicyclic system may independently be aryl, heteroaryl, alicyclic or heteroalicyclic.
  • Aryl refers to an all-carbon ring that contains a ⁇ -electron system that is delocalized throughout the ring, that is, the ring is “aromatic.”
  • Heteroaryl refers to an aromatic ring that contains nitrogen, oxygen or sulfur in addition to carbon.
  • Alicyclic refers to an all-carbon ring that, while it may contain one or more double bonds, does not have a fully delocalized ⁇ -electron system.
  • Heteroalicyclic refers to a ring that contains atoms other than carbon and that, likewise, does not have a fully delocalized ⁇ -electron system. Multicyclic ring systems may consist of fused rings, i.e., each ring shares at least one ring atom with another ring or they may simply be connected to one another through one or more covalent bonds.
  • cyclic synthons of this invention include, without limitation, benzene, naphthalene, anthracene, phenylene, phenathracene, pyrene, triphenylene, phenanthrene, pyridine, pyrimidine, pyridazine, biphenyl, bipyridyl, cyclohexane, cyclohexene, decalin, piperidine, pyrrolidine, tetrahydropyran, tetranhydrothiane, 1,3-dioxane, 1,3-dithiane, 1,3-diazane, tetrahydrothiophene, tetrahydrofuran, pyrrole, cyclopentane, triptycene, adamantane, bicyclo[2.2.1]heptane, bicyclo[2.2.1]heptene, bicyclo[2.2.2]octane, bicyclo[2.
  • a “linker” refers to the reaction product of a functional group on one synthon with a functional group on another synthon resulting in a bridge of covalently bonded atoms between synthons.
  • the reaction may involve the direct chemical interaction of a functional group on one synthon with a functional group on another synthon to form the linker.
  • a linker might comprise an ester, which is the reaction product of a hydroxyl group on one synthon with an acid or acid halide on another synthon.
  • Another example is an amide, which would result from the reaction of an amine on one synthon with an acid or acid halide on another synthon.
  • a further example would be the reaction of an aldehyde or ketone on one synthon with an amine on another synthon to form an imine.
  • a linker might comprise the reaction product of a 2+2 cycloaddition of two alkenes, one on each synthon.
  • a linker could also contain one or more atoms provided by a moiety other than the two functional groups. This external moiety is selected so as to react with the functional group on one synthon to form an intermediate that then reacts with a functional group on another synthon to form the covalent bridge of atoms between the synthons.
  • linker is the reaction product of an amino group on one synthon, a methyl ketone on another synthon and formaldehyde as the external molecule. Under either acidic or basic conditions, this combination of moieties will enter into the Mannich reaction.
  • the linker is the reaction product of a functional group directly bonded to one synthon with a functional group directly bonded to another synthon.
  • a presently preferred linker is the imine, —CH ⁇ N—, resulting from the reaction of an aldehyde, —CH ⁇ O, on one synthon with an amine, —NH 2 , on another synthon.
  • Other presently preferred linkers are esters and amides, which are discussed above.
  • the linker may be separated from one or both synthons by a spacer.
  • the spacer can be any chemical entity that forms a bridge of covalently bonded atoms between the synthon and a functional group and that does not interfere with the linker-forming reaction.
  • the simplest example of a spacer is methylene, —CH 2 —; for example, if a methylene spacer were inserted between an aldehyde group and its synthon in the above imine linker-forming reaction, the linker would be —CH 2 CH ⁇ N—.
  • Table 1 A list of presently preferred linker-forming functional groups and the linkers that they form are shown in Table 1.
  • a “module” refers to two or more synthons bonded to one another by linkers.
  • an “amphiphilic module” refers to a module in which one or more of the synthons is substituted with one or more lipophilic moieties and one or more of the synthons is substituted with one or more hydrophilic moieties. The same synthon may, if desired, be substituted with both a lipophilic and a hydrophilic moiety.
  • a presently preferred module comprises a two-dimensional array of three (3) or more synthons in which each synthon is covalently bonded to two other synthons to form a ring of synthons. It is also a presently preferred embodiment of this invention that the ring of synthons, i.e., the amphiphilic module, defines a pore.
  • a “pore” refers to the hole created by the ring of synthons that form a module.
  • a “nanopore” refers to a pore, which is from 0.5 nanometer (nm) to approximately 100 nm in diameter.
  • an “activated acid” refers to a —C(O)R moiety in which the R is readily displaced by a nucleophile to form a covalent bond between the —C(O)— and the nucleophile.
  • activated acids include acid chlorides, acid fluorides, p-nitrophenyl esters, pentafluorophenyl esters and N-hydroxysuccinimide esters.
  • a “reagent” refers to a chemical entity or a physical agent w that interacts with functional groups to cause or facilitate the reaction of the functional groups to form a covalent bond or chain of covalent bonds between the moieties to which the functional groups are bonded.
  • chemical reagents are, without limitation, acids and bases.
  • physical agents are, without limitation, ultraviolet light, ion plasma and temperature changes.
  • the reagent might also itself react with one of the functional groups to form an intermediate chemical entity. The intermediate then reacts with another functional group to create a chain of covalently bonded atoms between the moieties to which the functional groups are attached.
  • An “intermediate” refers to a chemical entity that forms during a reaction but which is not itself isolated, in fact is often not isolable, but which reacts further with other entities in the reaction mixture to give a final product.
  • an “amino acid residue” refers to the chemical entity formed when a compound comprising at least one amino (—NH 2 ) and at least one carboxyl (—C(O)O—) group reacts, through the amino or carboxyl group, with an atom or functional group of a synthon. Whichever of the two groups, is not participating in the linker or connector forming reaction may be blocked with a removable protective group.
  • bond refers, unless otherwise expressly stated, to covalent bonds between the entities which are the subject of the bonding.
  • the phrase “confer selected chemical or physical characteristics or combinations thereof on the module” refers to functional groups that are present on the modules for purposes other than forming linkers, forming connectors, or conferring amphiphilicity on the module.
  • a functional group might be bonded to the module in such a manner that it extends into the pore of the module and is capable of chelating a particular atom or molecule should that atom or molecule attempt to traverse the pore.
  • the functional group might be a charged species, e.g., a carboxylate anion or ammonium group, which could be positioned in or near a pore to trap oppositely-charged species.
  • a functional group that alters electrical conductivity in the region of a pore might be incorporated into a module.
  • the functional group might also be one that varies the hydrophilicity or lipophilicity in the vicinity of a pore.
  • a functional group might also be bonded to the module at locations other than the pore and might be used to modify other chemical or physical characteristics of the module.
  • a functional group might also serve more than one purpose. For example, without limitation, a functional group might initially be part of a moiety that confers hydrophilicity on a module. Once the module has formed a Langmuir film, the functional group might be used to form a connector.
  • a “functional group” or “chemical moiety” refers broadly to any group that is covalently bonded, directly or indirectly, to any of the synthons that comprise the module. By “indirectly” is meant that the functional group can be separated form the synthon's ring structure by one or more spacers.
  • the terms include, but are not limited to, the traditional groups considered “functional” by those skilled in the art, e.g., amino (—NH 2 ), hydroxyl (—OH), cyano (—C ⁇ N), nitro (NO 2 ), carboxyl (—COOH), formyl (—CHO), keto (—CH 2 C(O)CH 2 —), alkenyl (—C ⁇ C—), alkynyl (—C ⁇ C—), halo (F, Cl, Br and I) groups and the like.
  • the term also refers to groups such as aryl, heteroaryl, alicyclic and heteroalicyclic, which may themselves be further substituted with one or more of the preceding groups.
  • An amphiphilic module of the present invention is comprised of three or more synthons covalently bonded to one another to form a ring.
  • the ring of synthons circumscribes an open region or pore.
  • the pore is a nanopore.
  • the last synthon in the chain is then covalently bonded to the first synthon through a linker to form a ring of synthons that encloses an open region, which comprises the nanopore.
  • the synthons are prepared or isolated as essentially single configurational isomers or as essentially pure enantiomers.
  • “essentially” is meant as near to configurational or enantiomeric purity as is practically achievable. In general, this means at least 80%, preferably 90% and most preferably 98+% pure.
  • symmetrical diester S1-1 (for the sake of clarity, compounds will be numbered in relation to the scheme in which they appear; thus “S1-1” refers to the structure 1 in Scheme 1, etc.) to give enantiomerically pure S1-2.
  • S1-2 was subjected to the Curtius reaction and then quenched with benzyl alcohol to give protected amino acid S1-3. Iodolactonization of carboxylic acid S1-4 followed by dehydrohalogenation gives unsaturated lactone S1-6.
  • the isocyanate is quenched with 2-trimethylsilylethanol to give differentially protected tricarbamate S1-11.
  • Reaction with trifluoroacetic acid (TFA) selectively deprotects the 1,3-diamino groups to provide the desired synthon S1-12.
  • Norbornanes (bicycloheptanes) are presently preferred synthons of this invention due, in part, to the relative ease with which stereochemically controlled multifunctionalization can be achieved.
  • Diels-Alder cycloaddition can be used to form norbornanes incorporating various functional groups having specific, predictable stereochemistry.
  • Enantiomerically enhanced products may also be obtained through the use of appropriate reagents, thus limiting the need for chiral separations.
  • a Curtius reaction results in trimethylsilylethyl carbamate norbornene S4-31.
  • Biscarbonylation of the olefin in methanol, followed by a single-step deprotection and dehydration gives the monoanhydride S4-33.
  • Quinidine mediated opening of the anhydride with methanol gives S4-34.
  • Curtius transformation of S4-34 gives the biscarbamate S4-35, which is deprotected with TFA or tetrabutylammonium fluoride (TBAF) to give diamine S4-36.
  • TFA tetrabutylammonium fluoride
  • the next step is to connect them to one another through linkers to form the amphiphilic modules of this invention. This can be accomplished in a concerted or stepwise fashion.
  • a concerted module synthesis requires two synthons, each of which is substituted with at least two functional groups.
  • the groups are selected such that a functional group “A” bonded to one of the synthons can react only with one functional group, “A*” on the other synthon.
  • the other functional group, “B,” on the first synthon can react only with “B*” on the other synthon.
  • a chain of alternating synthons will form until an “A” (or “B”) on the last synthon to be added to the chain encounters an “A*” (or “B*”) on the first synthon, which will result in the creation of a ring of synthons, i.e., a module.
  • Scheme 7 illustrates a concerted module synthesis.
  • 1,2-Diaminocyclohexane, S7-1 is a synthon in which A and B are the same, i.e., amino groups.
  • 2,6-diformyl-4-dodec-1-ynylphenol, S7-2 is a synthon in which A* and B* are the same, i.e., formyl groups.
  • a and B will react with A* and B* to form imine linkers.
  • the hexamer is the product shown below; it is in fact the thermodynamic product.
  • the tetramer and octamer may also be formed depending on the reactions conditions. In fact, by appropriate choice of reaction conditions including, without limitation, synthon concentrations, solvent, reaction temperature and reaction time enhanced yields of various sized rings can be realized.
  • the imine groups of S7-3 can be reduced, e.g. with sodium borohydride, to give amine linkers. If the reaction is carried out using 2,6-di(chlorocarbonyl)-4-dodec-1-ynylphenol instead of 2,6-diformyl-4-dodec-1-ynylphenol, the resulting module will contain amide linkers. Similarly, if 1,2-dihydroxycyclohexane is reacted with 2,6-di(chlorocarbonyl)-4-dodec-1-ynylphenol, the resulting module will contain ester linkers. Many such concerted module syntheses will become apparent to those skilled in the art based on the disclosures herein; all such syntheses are within the scope of this invention.
  • stepwise synthesis of modules is somewhat more versatile.
  • a first synthon is substituted with one protected and one unprotected functional group.
  • protected is meant that a functional group is substituted with a readily removable entity that, while bonded to the functional group, prevents the group from entering into the reactions it normally would.
  • a second synthon is provided that is substituted with an unprotected functional group that will react under appropriate conditions with the unprotected functional group on the first synthon to give a dimer.
  • the second synthon is also substituted with another functional group that is either protected or that will not react under the dimer-forming conditions.
  • the dimer which may be isolated and purified or used directly in the next step, is then contacted with a third synthon, which also carries two functional groups, only one of which is capable or reacting with the remaining functional group of the second synthon. This forms a trimer.
  • the trimer is reacted with a fourth synthon to form a tetramer and so on until the desired number of synthons has been added to the chain.
  • a last synthon to be added to the chain is substituted with a functional group that is capable of reacting only with the second functional group, after it is deprotected, of the first synthon.
  • a ring of synthons, that is, a module of this invention, will thus be formed.
  • the stepwise synthesis is more time consuming and difficult to perform but the choice of synthons is virtually limitless and permits much greater diversity in the structure of the amphiphilic modules.
  • Scheme 8 illustrates a step-wise synthesis of module SC8-1.
  • Deprotection/coupling is repeated, alternating synthons S8-3 and S8-6 until a linear construct with eight residues is obtained.
  • the remaining acid and amine protecting groups on the 8-mer are removed and the oligomer is cyclized using standard procedures (e.g., Caba, J. M., et al., J. Org. Chem., 2001, 66:7568 (PyAOP cyclization) and Tarver, J. E. et al., J. Org. Chem., 2001, 66:7575 (active ester cyclization).
  • the R group may be any functional group that is desired in the target module or it can be a link to a solid support such as a Wang resin.
  • the ring of synthons i.e., the module
  • the pore is a nanopore.
  • the size of the pore will determine the size of molecules that can pass through the module. Of course, size need not be the sole determinant of what will be able to pass through a pore. Ionic, chelating or coordinating moieties, moieties that render the interior of the pore more or less hydrophilic, etc., can be disposed within or proximate to a pore to provide an additional means of control over the nature of molecules that will pass through.
  • Moieties can be placed within pores as part of the synthons initially or they can be added later by various derivatization reactions.
  • module S7-1 could be reacted with ClC(O)(CH 2 ) 2 C(O)OCH 2 CH 3 to convert the phenol groups to succinyl esters.
  • the size of a pore will depend on the nature of the synthons used, the number of synthons in a module and the nature of the linkers.
  • a first approximation to pore size can be obtained using quantum mechanical (QM) and molecular mechanical (MM) computations.
  • modules were assumed to constitute two synthons, “A” and “B,” and all linkers were assumed to be the same. As it turns out, the modules approximate various regular polyhedrons quite well depending on the number of synthons in the module. Thus, when stereochemically defined modules comprised of 4, 6, and 8 synthons were subjected to MM3 energy minimization, the structures shown in FIGS. 1 A-C, which are at, or very near, the thermodynamic energy minimums were obtained. As can be seen, the tetramer essentially describes a parallelogram, the hexamer an equilateral triangle and the octamer a rhombus. For the purposes of QM and MM computations, root mean square deviations in the pore areas were computed over the dynamic runs.
  • each module was first optimized using the MM+force field approach of Allinger (JACS, 1977, 99:8127) and Burkert, et al., (Molecular Mechanics, ACS Monograph 177, 1982). They were then re-optimized using the AM1 Hamiltonian (Dewar, et al., JACS, 1985, 107:3903; Dewar, et al., JACS, 1986, 108:8075; Stewart, J. Comp. Aided Mol. Design, 1990, 4:1). To verify the nature of the potential energy surface in the vicinity of the optimized structures, the associated Hessian matrices were computed using numerical double differencing.
  • Synthon “A” is 2,6-benzenediol while in Table 3, synthon “A” is 2,7-naphthanediol.
  • Synthon B is shown in the left-hand column. Nanopore sizes derived from QM and MM computations for various linkers and module size are shown.
  • the computed nanopore size was tested and confirmed experimentally using a voltage-clamped bilayer procedure.
  • Modules are inserted into a lipid bilayer, for example, the bilayer formed by phosphatidylcholine and phosphatidylethanolamine.
  • a solution containing a test cationic species On one side of the bilayer is placed a solution containing a test cationic species.
  • a solution containing an cationic species known to be able to pass through a pore of the calculated size On the other side is a solution containing an cationic species known to be able to pass through a pore of the calculated size.
  • Anions required for charge neutrality are selected such that they will not pass through pores of the calculated size.
  • CH 3 NH 3 + having a radius of 2.0 ⁇ , passed through the pore while CH 3 CH 2 NH 3 + , with a radius of 2.6 ⁇ , did not.
  • the observed ability of hydrated ions to pass through the pore may be due to partial dehydration of the species at the pore with water molecules and ions passing through single file and then re-coordinating on the other side.
  • the ions may coordinate with atoms of the pore during the process.
  • Modules of the present invention can be arranged in a virtually infinite number of ways. They can be randomly distributed in a plane defined by the plane of the ring of synthons without any means of controlling the location of individual modules. The randomly distributed modules may be connected to one another to form a somewhat more robust array. On the other hand, the modules may be arranged in an ordered array such as, without limitation, a close-packed or a dendridic array. In a presently preferred embodiment of this invention, a two-dimensional close-packed planar array of modules is constructed.
  • the arrays cannot technically be two-dimensional because atoms have volume.
  • functional groups attached to the modules may extend above and below the plane defined by the rings of synthons that comprise the modules that, in turn, comprise the arrays.
  • two-dimensional refers simply to the fact that presently preferred arrays of this invention are one module thick.
  • planar is meant that the modules are disposed in a plane defined by the planes of the synthons comprising the modules.
  • close-packed refers to an array in which, for a given polygonal-shaped module, the edges of the polygon fit together such that voids between the modules are minimized.
  • FIG. 2 shows a two-dimensional planar close-packed array of hexameric (i.e., essentially triangular) modules. In FIG. 2, the circles represent synthons.
  • FIG. 2A the modules are shown in a close-packed array without any means of maintaining the structure.
  • Such arrays can be formed and may have practical application. However, in most instances, to form a robust array that can withstand a variety of external forces and therefore should be more practically useful, it is preferred to connect the modules to one another. This is depicted schematically in FIGS.
  • a “connector,” as used herein, is similar to a linker in that it is the reaction product of a functional group associated with one module with a functional group associated with a second module.
  • the term “associated” is used to signify that a connector functional group may be separated from the synthon to which it is attached by a substantially longer spacer than those used with linkers. That is, whereas functional groups comprising linkers are either bonded directly to synthons or, at most, are separated by a methylene or two, connector functional groups may be substantially remote from the synthon. For example, an acrylate double bond at the end of an 8C hydrophilic group may serve as a connector-forming functional group (see infra).
  • Connectors may be formed using one or more functional group on each module.
  • FIG. 2B one line is shown between adjacent modules indicating a single connector formed by the reaction of one functional group on each module.
  • FIG. 2C it is possible to have more than one connector between the same two modules, as shown in FIG. 2C, wherein two functional groups on each module have reacted to from connectors.
  • the connector functional groups may be bonded to a synthon along an edge of a module (FIG. 2B) or at an apex (triangle/hexamer, FIG. 2C) or at a corner (tetramer, octamer). Of course, any combination of these may also be employed.
  • the apparatus in which Langmuir films are created is called a Langmuir-Blodgett (L-B) trough.
  • L-B Langmuir-Blodgett
  • Langmuir films and L-B troughs are well known in the art.
  • the following is an example of a procedure that can be employed to form a Langmuir film. It is not to be construed as limiting the scope of this invention in any way.
  • the procedure is schematically depicted in FIG. 6.
  • Amphiphilic modules 4 are dissolved in HPLC-grade chloroform at a concentration of approximately 1 mg/ml.
  • the chloroform solution 3 is applied to a water (Millipore Milli-Q) surface 2 in an L-B trough 1 (such as that marketed by KSV, Helsinki, Finland).
  • the chloroform is allowed to evaporate, leaving the amphiphilic modules on the surface of the water with their hydrophilic groups 5 immersed in the water and their lipophilic groups 6 in the air.
  • the temperature in the system is carefully controlled (preferably to within ⁇ 0.2° C. or better).
  • the barriers 10 of the L-B trough are slowly compressed (1-10 mm/min).
  • the surface pressure is monitored using an appropriate technique such as the Wilhelmy plate procedure until a sudden change in surface pressure signifies that the film has collapsed. Pressure is released until the film reforms.
  • a plot of surface pressure as a function of the area of water surface available to each module at a constant temperature, known as the surface pressure/area isotherm, often abbreviated “isotherm,” is an indicator of the monolayer properties of a material, which can confirm that a Langmuir film has in fact formed.
  • An example of an isotherm is shown for an amphiphilic synthon and an amphiphilic module of this invention in FIG. 3. The shape of the isotherm confirms that the module does in fact form a Langmuir film on the surface of the water.
  • a Langmuir film Once a Langmuir film has formed, selected functional groups will, by virtue of their pre-determined locations on the modules and the predictable alignment of the amphiphilic modules in the Langmuir film, be located in the correct relationship to one another to react and form connectors 9.
  • the connector-forming functional groups may have served other purposes prior to being recruited for connector duty.
  • a functional group might be employed as part of a hydrophilic moiety to assist in the formation of a Langmuir film and then, once the film has formed, may be used to form a connector.
  • Other multiple-use functional groups will be envisioned by those skilled in the art based on the disclosures herein and are within the scope of this invention.
  • a connector functional group may, as was the case with linker precursors, be covalently bonded directly to a synthon.
  • the same functional groups shown to form linkers in Table 1 may be used to form connectors in exactly the same way.
  • those that will be used later to form connectors are blocked with protecting groups that prevent their reaction until the protecting group is removed.
  • connector formation may also comprise the reaction of three or more moieties, for example, a functional group on one module, a second functional group on an adjacent module and a third external molecule. An example of this would be the Mannich reaction, discussed above with regard to linkers.
  • the distance between modules as defined by the length of the connectors be such that the holes created between modules in the array by the connectors be smaller in size than the pores within the individual modules.
  • Two functional groups used to form two connectors may be bonded to the same synthon. Such an arrangement is depicted in FIG. 5.
  • FIG. 5A two amino groups are bonded to the same synthon in each module. Reaction with formaldeyde gives the connectors shown, i.e., aminals.
  • FIG. 5B two mercapto (-SH) groups are shown bonded to the same synthon. These can be oxidatively coupled to form sulfides. It is, of course, possible, if desired, to have the amino or mercapto groups on different synthons and still form connectors.
  • FIG. 5C acrylate groups are shown coupled by a 2+2 cycloaddition reaction to form cyclobutane connectors.
  • connector-forming functional groups may be separated from the modules by spacers just as linkers could be.
  • connector functional groups may be separated from the ring of the module by a substantially greater distance than linkers, which usually, but not necessarily, equates to a larger number of spacer groups, particularly if the spacers are small moieties such as methylene (—CH 2 —) groups.
  • linkers usually, but not necessarily, equates to a larger number of spacer groups, particularly if the spacers are small moieties such as methylene (—CH 2 —) groups.
  • acrylate groups which are separated from the body of the module by 7 methylene groups, may have initially been used as hydrophilic groups for the formation of a Langmuir film, are reacted with added acrylate to form a polyacrylate connector.
  • a two-dimensional, close-packed planar array of modules bonded to one another by connectors to form a cohesive one module thick sheet is referred to herein as a nanomembrane.
  • the modules of the present invention each contain a pore.
  • the pores are nanopores, that is, they have a diameter between 0.5 and approximately 100 nm.
  • the simplest application would be one involving size exclusion separations.
  • synthons By appropriate selection of synthons, number of synthons in each module and linkers, pores, and more specifically nanopores, of virtually any size can be created.
  • filters would be useful in such applications as ion separation, gas separation, small molecule separation, water purification, sewage treatment, toxin removal, etc.
  • Physiological uses such as filtration of bacteria, fungi, viruses and the like are also envisioned.
  • S1-1 (15.0 g, 75.7 mmol) was suspended in pH 7 phosphate buffer (950 mL). Pig liver esterase (2909 units) was added, and the mixture stirred at ambient temperature for 72 h with the pH maintained at 7 by addition of 2M NaOH. The reaction mixture was washed with ethyl acetate (200 mL), acidified to pH 2 with 2M HCl, and extracted with ethyl acetate (3 ⁇ 200 mL). The extracts were combined, dried, and evaporated to afford 13.8 g (99%) of S1-2.
  • S1-9 (0.85 g, 2.1 mmol) was suspended in 50:50 MeOH/dichloromethane (5 mL) and cooled to 0° C. under N 2 after which 2M NaOH (2.0 mL) was added and the mixture stirred at ambient temperature for 16 h. The mixture was acidified with 2M HCl upon which a white precipitate formed. The precipitate was collected, washed with water and hexane, and dried to give 0.74 g (90%) of S1-10.
  • S1-11 (2.5 g, 4.9 mmol) was added to TFA (10 mL) and the solution stirred at ambient temperature for 16 h after which the solution was evaporated. The residue was dissolved in water (20 mL), basified to pH 14 with KOH and extracted with dichloromethane (3 ⁇ 50 mL). The extracts were combined, washed with water (20 mL), dried and evaporated to give 1.1 g (85%) of S1-12.
  • Mass Spec calculated for C 26 H 34 O 5 426.24; found 425.4 (M ⁇ 1) and 851.3 (2M ⁇ 1).
  • reaction S5-40 is converted to the corresponding mesylate with methanesulfonyl chloride, sodium azide added to displace the mesylate to give exo-azide, which is followed by reduction with tributyl phosphine to give the free amine, which is protected as the t-Boc derivative to give S5-41.
  • the benzyl ether protecting group is removed by catalytic hydrogenolysis of S5-41 with 10% Pd/C in methanol at room temperature for 6 hours. Filtration of the catalyst and removal of the solvent yields crude S5-42.
  • S6-50 formic acid, and a catalytic amount of p-toluenesulfonic acid is heated at 90° C. overnight. Acetic anhydride is added to the reaction mixture, and it is refluxed for an additional 6 hours. Removal of the solvents and washing with ether affords S6-51.
  • the present invention provides versatile synthons and modules for use in the formation of nanomembranes.
  • Methods for the preparation of the synthons, for the linking together of synthons to form modules, in particular modules in which the ring of synthons define a pore in the resulting module, and for the connection of modules to form nanomembranes are also provided.
  • the nanomembranes are useful, among other things, as filters.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Separation Using Semi-Permeable Membranes (AREA)
  • Pyrrole Compounds (AREA)
  • Solid-Sorbent Or Filter-Aiding Compositions (AREA)
  • Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Silicates, Zeolites, And Molecular Sieves (AREA)
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US10/071,377 US20040034223A1 (en) 2002-02-07 2002-02-07 Amphiphilic molecular modules and constructs based thereon
US10/226,400 US20030199688A1 (en) 2002-02-07 2002-08-23 Macrocyclic module compositions
MXPA04007679A MXPA04007679A (es) 2002-02-07 2003-02-07 Composiciones de nanopelicula y membrana.
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US10/359,894 US7432371B2 (en) 2002-02-07 2003-02-07 Nanofilm and membrane compositions
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US11/199,913 US7767810B2 (en) 2002-02-07 2005-08-08 Macrocyclic modules comprising linked cyclic synthon units for use in the formation of selectively permeable membranes
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US7563890B2 (en) 2009-07-21
KR20050013097A (ko) 2005-02-02
US20030199688A1 (en) 2003-10-23
US20100152438A1 (en) 2010-06-17
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