WO2020254638A1

WO2020254638A1 - Polymerization process for production of polydisulfide

Info

Publication number: WO2020254638A1
Application number: PCT/EP2020/067207
Authority: WO
Inventors: Sunirmal PAL; Andreas SOMMERFELDT; Kim DAASBJERG; Steen Uttrup PEDERSEN
Original assignee: Aarhus Universitet
Priority date: 2019-06-20
Filing date: 2020-06-19
Publication date: 2020-12-24

Abstract

The present invention relates to the production of polymers synthesized by polymerization of monomers comprising two thiol groups. Said polymerization is performed in the presence of a diaryl or diheteroaryl disulfide to end-cap the polymer chains. The resulting end-capped polydisulfide is easily degradable once 5the end-cap has been removed to trigger the depolymerization. End-capped polydisulfide is thus for use in the manufacturing of recyclable products and application within drug delivery, where a controlled on-demand degradation of the polymer is desirable. In particular, the present invention relates to production of end-capped polymers of dithiothreitol (DTT) which display the distinctive feature of self-immolative depolymerization. Also disclosed are copolymers created from different types of monomers. An important feature of the present invention is that the polymerization may be conducted under non-solvated conditions, without the use of any extensive heating/cooling, and in ambient air.

Description

POLYMERIZATION PROCESS FOR PRODUCTION OF POLYDISULFIDE

Technical field of the invention

The present invention relates to polymers and the manufacture hereof.

Particularly the present invention relates to the production of degradable or self- immolative polymers. In particular, the present invention relates to production of end-capped polydisulfide produced from dithiol monomers and disulfide end capping agents. The polymerization process may be conducted under non- solvated conditions.

Background of the invention

Polymers with the unique ability to spontaneously depolymerize to their monomeric units upon removal of labile end-caps are known as self-immolative polymers (SIPs). These polymers are constructed with thermodynamically unstable backbones and are often produced through anionic polymerizations at low temperatures. The polymers remain stable under ambient conditions while the end-cap is attached. Triggered removal of the end-cap initiates depolymerization through mechanistic pathways that in most cases proceed through anionic intermediates.

The potential applications of SIPs are manifold within e.g. reversible adhesives, point-of-care devices, drug delivery, sensors and recyclable (vanishing) plastics. However, the existing SIPs are yet to find widespread use partly because of the limited availability and purity of the monomers, but also because the

polymerization reaction often leads to small yields of polymer, requires high or low temperatures, and/or a potentially harmful solvent. Furthermore, the depolymerization of many SIPs of the prior art often takes hours to days.

The literature comprises several examples of SIPs, which are not polydisulfides.

WO 2008/053479 discloses poly(carbamate) prepared in solution at elevated temperatures, such as 110 °C in toluene. The aim is to provide SIPs that are designed to depolymerize upon pre-determined cleavage-events or sequence of events. The disclosed method does not involve dithiol as the monomer for polymerization or use of diaryl or diheteroaryl disulfides for providing the end- caps. Also, the polymerization reactions are performed under solvated conditions.

US 8,871,893 discloses methods and preparations of self-immolative

poly(aldehydes) and poly(ethers), especially poly(phthalaldehyde). The

preparation is performed as anionic polymerization in solution at temperatures below -40 °C. The authors mainly focus on developing and screening for different end-caps and linkers that respond to specific stimuli. The described process does not disclose polymers of dithiols and the disclosed end-caps are not installed by reaction with diaryl or diheteroaryl disulfides. In addition, the disclosed

polymerizations are all performed under solvated conditions.

US 2017/0073452 discloses self-immolative poly(glyoxylate). Several end-caps are used on the polymers, and one of them, a carbonate ester, is somewhat similar to dipyridyldisulfide (DPS). Also, a complete degradation of the polymer can be reached within 1 hour when treated with an excess amount of dithiothreitol (DTT). The described process is, however, challenged by the fact that monomers of dithiols are not disclosed and by the fact that no diaryl or diheteroaryl disulfides are used for creating said end-caps. Furthermore, the polymerization reactions are performed under solvated conditions.

The literature also describes polydisulfide polymers. Thus, D. Basak et aL,

Macromolecular rapid communications, 2014, 35, 1340-1344 discloses a

polycondensation route to obtain telechelic poly(l,6-hexanedithiol) that is end- capped with DPS, and a means of generating an ABA-type tri-block copolymer therefrom. The polymerization conditions for producing poly(l,6-hexanedithiol) include the use of acetic acid for catalyzing the reaction, at room temperature, and with dichloromethane as the solvent. Hence Basak et al. do not disclose a non-solvated synthesis of end-capped polydisulfide, and the poly(dilsufides) disclosed are relatively small with a degree of polymerization (DP) of 17-79 (Table 1).

Hence, an improved method to prepare end-capped polydisulfide under ambient conditions and without the use of solvent would be advantageous, and also a large polydisulfide that is able to self-immolate upon removal of the end-cap is desirable. Furthermore, an efficient and/or reliable process conducted at room temperature and without the need of catalyst, solvent, and super dry conditions would be advantageous. Particularly desirable is a scalable polymerization process that do not require any hazardous solvents and can provide polymers with a high degree of polymerization.

Summary of the invention

Thus, an object of the present invention relates to providing a process for production of end-capped polydisulfides under scalable conditions, which does not require extensive heating/cooling of the reaction mixture and may be performed under ambient conditions without rigorous exclusion of oxygen and moisture.

In particular, it is an object of the present invention to provide a process for production of end-capped polydisulfides that solves the above mentioned problems of the prior art, such as the need for the polymerization to be performed in bulk amounts of solvents with rigorous exclusion of air (oxygen) and moisture. The process of the present invention further provides large end-capped polymers that are degradable when the end-cap is removed by exposing the polymer to specific external stimuli.

It is a further object of the present invention to provide end-capped polydisulfides with improved properties including high molecular weight and controllable but facile degradability. A stable high molecular weight polydisulfide which may be degraded when treated with a trigger molecule or composition is a particularly object of the invention.

Thus, one aspect of the invention relates to a process for the manufacture of an end-capped polydisulfide comprising the steps of:

• providing a monomer selected from the group consisting of an optionally substituted C1-C12 alkyl dithiol, and an optionally substituted C6-C14 aryl dithiol, • providing an end-capping agent selected from the group consisting of an optionally substituted diaryl disulfide, and an optionally substituted diheteroaryl disulfide,

• performing a polymerization by mixing said monomer with said end

capping agent to obtain said end-capped polydisulfide,

wherein said polymerization is performed under non-solvated conditions.

A second aspect of the invention relates to a process for the manufacture of an end-capped copolymer comprising at least two different polydisulfides comprising the steps of:

• providing a first monomer selected from the group consisting of an

optionally substituted C1-C12 alkyl dithiol, and an optionally substituted C6- C14 aryl dithiol,

• providing a second monomer selected from the group consisting of an optionally substituted C1-C12 alkyl dithiol, and an optionally substituted C6- C14 aryl dithiol, which is different from the that of the first monomer

• optionally providing one or more further monomers selected from the group consisting of an optionally substituted C1-C12 alkyl dithiol, and an optionally substituted C6-C14 aryl dithiol,

• providing an end-capping agent selected from the group consisting of an optionally substituted diaryl disulfide, and an optionally substituted diheteroaryl disulfide,

• performing a polymerization by mixing said first and second and optionally further monomers with said end-capping agent to obtain said end-capped copolymer comprising at least two polydisulfides,

wherein said polymerization is performed under non-solvated conditions.

The process of the present invention allows for the manufacture of polydisulfide with a high molecular weight or degree of polymerization (DP).

Hence, a third aspect of the invention relates to a polydisulfide of formula (I): wherein

R¹ and R² are independently selected from the group consisting of -H, -OR', - N(R')R", and -N(R')₃ ⁺ or wherein R¹ and R² are fused to form a 5- or 6-membered cyclic ketal or silicon ketal, or wherein R¹ and R² are fused to form an epoxide R' and R" are independently selected from the group consisting of H, -(Ci-C6 alkyl), -CO(Ci-C₆ alkyl), -COO(Ci-C₆ alkyl), -CONH(CI-C6 alkyl), -Si(Ci-Ce alkyl)₃, and -Si(phenyl)2(Ci-C6 alkyl), wherein Ci-C6 alkyl may be substituted with halogen,

R³ is selected from the group consisting of an optionally substituted aryl, an optionally substituted silyl alkyl dithiol, and an optionally substituted heteroaryl, n is an integer selected from 0, 1, 2, 3, and 4,

m is an integer selected from 0, 1, 2, and 3, and

y is an integer between 80 and 2000.

Brief description of the figures

Figure 1 shows a putative reaction scheme of a disulfide exchange mechanism causing poly(DTT) to depolymerize once the end-cap has been removed from the polymer. Especially important is the formation of a 6-membered cyclic disulfide (c-DTT) which is expected to be the driving force for the depolymerization.

Figure 2 shows that the depolymerization of end-capped poly(DTT) is triggered by addition of the base, triethylamine (TEA). Addition of an acid, such as acetic acid (AcOH), does not allow the depolymerization to take place and nor does neutral conditions. However, heating the end-capped poly(DTT) to 60 °C will slowly degrade the polymer. The extent of depolymerization was evaluated by measuring the amount of c-DTT formed during each of the experiments.

Figure 3 shows that depolymerization of end-capped poly(DTT) may be triggered by exposing the polymer to UV light. Figure 4 shows a thermogram obtained for end-capped poly(DTT) using differential scanning calorimetry (DSC). It shows that the value for the glass transition temperature (T_g) is between 20 and 40 °C.

Figure 5 shows that a fast depolymerization of end-capped poly(DTT) can be achieved by using a mixture of DTT and TEA in ambient air and temperature, at which the polymer is completely degraded after only a few minutes. However, the figure also shows that the presence of O2 greatly slows the degradation if there is no base in the mixture, yet performing the depolymerization under nitrogen greatly increases the degradation rate.

Figure 6 shows an example of an end-capped copolymer polymerized from monomers of DTT and 1,4-butanethiol.

Figure 7 shows an NMR spectra of pDTT with a pyridyl end-cap.

Figure 8 shows degradation of solid pDTT in D2O initiated by trimethylamine and DTT over 5 days. The solid polymer visibly disappears. The spectra show the consumption of the added DTT from the loss of peaks at d = 3.71 and 2.68 ppm. At the same time, peaks corresponding to pyridine-2-thiol (7.87, 7.68, 7.55, and 7.08 ppm) and cDTT (3.62, 3.10, and 2.92 ppm) appear.

The present invention will now be described in more detail in the following.

Detailed description of the invention

Definitions

Prior to discussing the present invention in further details, the following terms and conventions will first be defined :

Monomer

In the present context, monomers are compounds that can be used in a

polymerization reaction to form a polymer thereof. Thus, a monomeric compound, is a compound which cannot be regarded as a polymer. Polym eriza tion/polym erisa tion

In the present context, a polymerization is a reaction in which monomers, of the same or different compounds, bond to form a polymer. Copolymer

In the present context, a copolymer is a polymer that was created by

polymerization between at least two different monomeric compounds. For a bipolymer, a ratio may be used to express the numerical relationship between the number of structural units originating from each of the monomers used to create the bipolymer. A 1: 1 copolymer, thus refers to a bipolymer that comprises equal numbers of the two different structural units. The arrangement of the structural units in a copolymer determines whether the polymer is a segregated (i.e. block or graft), regular (i.e. alternating or periodic), or uncontrolled (i.e. statistical or random) copolymer.

Polydisulfide

In the present context, a polydisulfide is a polymer created from monomers of compounds having at least two thiol groups. The polymers are termed "end- capped polydisulfides" if the polymerization was performed in the presence of an end-capping agent thus to install end-caps at the ends of the polymer.

End-capping agent

In the present context, an end-capping agent is a diaryl or diheteroaryl disulfide compound that may at any given time during the polymerization, attach to the growing polydisulfide, instead of a monomer, and thereby change the properties of the polymer. The end-cap thus blocks the developing end(s) of the polydisulfide from depolymerization.

End-cap

In the present context, an end-cap is an aryl or heteroaryl disulfide compound that is terminally attached to the end(s) of the polydisulfide. An end-capped polydisulfide has improved stability, protecting it from depolymerization even above the ceiling temperature. Degradable

In the present context, polydisulfide may be degradable in the sense that it may as long as it is subjected to specific external stimuli depolymerize and split into smaller fragments, preferably the disulfide monomers from which it was initially polymerized.

Self-immola tive polydisulfide

In the present context, a self-immolative polydisulfide is an end-capped polydisulfide with the ability to spontaneously degrade preferably to the disulfide monomers, from which it was initially polymerized, once an end-cap has been removed by subjecting the end-capped polydisulfide to an external stimulus.

Optionally substituted

In the present context, optionally substituted means that a specific compound may have one or more H exchanged with other substituents.

Mixing

In the present context, mixing is the act of manipulating a physical system comprising one or more components thus to obtain a system where the components are essentially randomly distributed. The most common manipulation methods are stirring, blending, grinding, and milling. However, any method applying mechanical work may be used.

Non-soivated conditions

In the present context, a reaction may be performed under non-solvated conditions which imply that the reaction mixture does not comprise any solvent able to dissolve the reactants or products, but without precluding the presence of other liquids in the mixture. Other liquids may include liquid non-solvents, unreacted monomer, end-capping agent, or other liquid reactants or catalyst and other reactants or impurities.

Conditions essentially free of a solvent

In the present context, a reaction performed under conditions essentially free of a solvent refers to conditions where there may be an insignificant amount of a substance able to dissolve the reactants. However, without precluding the possibility that other liquids are present.

Ketal

In the present context, a cyclic ketal refers to a chemical moiety that is obtained when a ketone group has reacted with both hydroxyl groups in a diol, thus to form a ring characterized by comprising a -O-C-O- connection. A silicon ketal (or silyl based ketal) refers to a similar compound, but wherein the characterizing connection is -O-Si-O-.

The present inventors have developed a process which surprisingly allows for facile, scalable, and efficient production of end-capped polydisulfides. The process also produces polymers of considerable size, such as polymers comprising more than 80 repeating monomeric units. The process involves mixing a monomer comprising at least two thiol groups with a diaryl disulfide or diheteroaryl disulfide for end-capping the polymer. The mixing of the monomer and end-capping agent applies a sufficient amount of energy in the form of mechanical work to allow fast polymerization of the monomers. Herein, mechanical work originates from any compressive or shear forces applied by methods such as, but not limited to, grinding, milling, stirring, kneading, and ultra-sonication. Furthermore, the polymerization may advantageously be performed under non-solvated conditions and ambient air.

Thus, a first aspect of the present invention relates to a process for the manufacture of an end-capped polydisulfide comprising the steps of:

• providing a monomer selected from the group consisting of an optionally substituted C1-C12 alkyl dithiol, and an optionally substituted C6-C14 aryl dithiol,

• performing a polymerization by mixing said monomer with said end

capping agent to obtain said end-capped polydisulfide,

wherein said polymerization is performed under non-solvated conditions. The term "non-solvated conditions" means that the monomer and end-capping agent are mixed without adding any solvent, however other liquids that are unable to dissolve the reactants may in principle be present during the

polymerization.

Thus, an alternative aspect of the invention relates to a process for the

manufacture of an end-capped polydisulfide comprising the steps of:

• performing a polymerization by mixing said monomer with said end

capping agent to obtain said end-capped polydisulfide,

wherein said polymerization is performed under conditions essentially free of a solvent.

The term "essentially free of solvent" may preferably refer to less than 5% solvent in the reaction mixture, such as less than 2%, 1%, 0.5%, 0.1% such as less than 0.05% solvent in the reaction mixture. Preferably the process is performed without the presence of solvent. Even more preferably the process is performed with the addition of only monomer and end-capping agent, i.e. with no further additives or solvents. The process is preferably performed in a reaction mixture consisting of monomer, end-capping agent and the resulting product.

The resulting polymer of the present process has the advantage of being stable, but also degradable if subjected to certain specific stimuli. Hence, preferably the end-capped polydisulfide is degradable.

Especially interesting are self-immolative polymers that possess the ability to spontaneously depolymerize once the end-cap has been removed. Thus, in a particularly preferred embodiment the end-capped polydisulfide is a self- immolative polydisulfide. The product of the polymerization reaction is an end-capped polydisulfide which may be further defined as follows. Thus, in one embodiment, the end-capped polydisulfide is a polydisulfide of formula (I):

wherein

R¹ and R² are independently selected from the group consisting of -H, -OR', - N(R')R", and -N(R')₃ ⁺ or wherein R¹ and R² are fused to form a 5- or 6-membered cyclic ketal or silicon ketal, or wherein R¹ and R² are fused to form an epoxide, R' and R" are independently selected from the group consisting of H, -(C1-C6 alkyl), -CO(Ci-Ce alkyl), -COO(Ci-C₆ alkyl), -CONH(Ci-Ce alkyl), -Si(Ci-Ce alkyl)₃, and -Si(phenyl)2(Ci-C6 alkyl), wherein the C1-C6 alkyl may be substituted with halogen,

m is an integer selected from 0, 1, 2, and 3, and

y is an integer between 3 and 2000. In the present context, the chemical moieties with the formulae -CO(Ci-C6 alkyl), -COO(Ci-C6 alkyl), and -CONH(CI-C6 alkyl), are moieties comprising an acyl group represented by -CO.

Halogen may preferably be selected from the group consisting of Cl, Br, and I.

The monomer forms the backbone of the resulting polymer chain and has two terminal thiols (-SH), where the remainder of the monomer may otherwise vary. In one preferred embodiment, the monomer is an optionally substituted Ci-Cio alkyl dithiol, such as an optionally substituted Ci-Cs alkyl dithiol, an optionally substituted C1-C6 alkyl dithiol, such as preferably an optionally substituted C2-C6 alkyl dithiol. The alkyl may be branched or linear, preferably linear. In another embodiment the monomer is an optionally substituted C6-C12 aryl dithiol, such as preferably an optionally substituted C6-C10 aryl dithiol. The aryl part of the monomer may preferably be phenyl or naphtyl.

The alkyl or aryl part of the monomer may comprise various substituents, and thus in one embodiment the monomer is optionally substituted with a moiety selected from the group consisting of C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, amino (-NH2), -CH2NH(CI-CIO alkyl), -CH2N(CI-CIO alkyl)2, aminoalkyl (-NH(Ci-Cio alkyl) or -N(Ci-Cio alkyl)₂), cyano (-CN), CONH2, CONH(Ci-Cio alkyl), CON(Ci-Cio alkyl)2, hydroxyl (-OH), C1-C10 alkyl hydroxyl (-alkyl-OH), C1-C10 alkoxy(-O-alkyl), C1-C10 alkyl carbonyloxy (-O-CO-alkyl), carboxylic acid (-COOH), C1-C10 alkyl esters (-COO-alkyl), C1-C10 alkyl acyl (-CO-alkyl), sulfonic acid (-SO3H), C1-C10 alkyl sulfonate (-S03-alkyl), phosphonic acid (-PO(OH)2), C1-C10 alkyl phosphonate (-P0(0-alkyl)2), phosphinic acid (-P(0)(H)0H), SO2NH2, hydroxamic acid (- CONHOH), C1-C10 alkyl sulfonylureas (-NHC0NHS02(alkyl)), C1-C10

acylsulfonamides (-S02-NHC0-(alkyl), hydroxyl amine (-NHOH), nitro (-NO2), - Si(Ci-C6 alkyl)3, -Si(phenyl)2(Ci-C6 alkyl), ketals, silicon ketals, and halogens.

In yet another embodiment the monomer is a compound of formula (II):

wherein

R¹ and R² are independently selected from the group consisting of -H, -OR', - N(R')R", and -N(R')₃ ⁺ or wherein R¹ and R² are fused to form a 5- or 6-membered cyclic ketal or silicon ketal,

R' and R" are independently selected from the group consisting of H, -(C1-C6 alkyl), -CO(Ci-Ce alkyl), -COO(Ci-Ce alkyl), -CONH(CI-C6 alkyl), -Si(Ci-C6 alkyl)₃, and -Si(phenyl)2(Ci-C6 alkyl),

n is an integer selected from 0, 1, 2, 3, and 4, and

m is an integer selected from 0, 1, 2, and 3.

In a more preferred embodiment R¹ and R² are independently selected from the group consisting of -H, -OR', -N(R')R", and -N(R')3⁺ or wherein R¹ and R² are fused to form a 5- or 6-membered cyclic ketal or silicon ketal, R' and R" are independently selected from the group consisting of H, -(C1-C6 alkyl), -CO(Ci-Ce alkyl), -COO(Ci-Ce alkyl), -CONH(Ci-Ce alkyl), -Si(Ci-Ce alkyl)₃, and -Si(phenyl)2(Ci-C6 alkyl),

n is an integer selected from 1 and 2, and

m is an integer selected from 0 and 1.

In an even more preferred embodiment R¹ and R² are independently selected from the group consisting of -OR', or wherein R¹ and R² are fused to form a 5- or 6- membered cyclic ketal or silicon ketal,

R' is selected from the group consisting of H, -(Ci-C6 alkyl), -Si(Ci-C6 alkyl)₃, and -Si(phenyl)2(Ci-C6 alkyl),

n is 1 and

m is 0. In a particular preferred embodiment the monomer is selected from the group consisting of: ami nobutane- 1,4-dithiol (DTBA), thiothreitol (DTT),

thioerythritol (DTE), and hydroxyl-protected derivatives of DTT and DTE. In the present context, a hydroxyl-protected derivative is the compound that is obtained upon reaction of a molecule having one or more hydroxyl groups in its structure with a hydroxyl protecting agent. Preferred hydroxyl protecting agents may be selected from the group consisting of triethylsilyl ether (TES), tert-butyldimethylsilyl ether (TBS), acetyl ester (Ac), ketal, ferf-butyloxycarbonyl carbonate (boc), benzyl ether (Bn), 4-methoxybenzyl ether (PMB), and benzoyl ester (Bz). The polymerization of the monomers is conducted in the presence of an end capping agent which is partly controlling the extent of polymerization and thus the size of the resulting polymers. The installed end-caps block the developing ends of the polymers and prevent any self-immolative polymers from spontaneously depolymerizing once they have been formed. The end-capping agents may be optionally substituted diaryl disulfides or diheteroaryl disulfides.

In a particular embodiment the end-capping agent is a compound of formula (III):

wherein

R³ is selected from the group consisting of an optionally substituted aryl, and an optionally substituted heteroaryl.

The sulphur atoms of the disulfide end-capping agent are preferably connected to an aromatic group (R³), e.g. an aryl or heteroaryl. Hence, in one embodiment the aryl of the end-capping agent is selected from the group consisting of phenyl and naphthyl. The heteroaryl of the end-capping agent may be selected from the group consisting of pyrrolyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, oxazolyl, isooxazolyl, pyrazolyl, imidazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5- oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridinyl,

pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,4-triazinyl, and 1,3,5-triazinyl. The aryl or heteroaryl may be substituted with substituents other than hydrogen. In one embodiment the optional substituent(s) on the aryl or heteroaryl are independently selected from the group consisting of Ci-Cio alkyl, C2-C10 alkenyl, C2-C10 alkynyl, amino (-NH2), -CH2NH(CI-CIO alkyl), -CH2N(CI-CIO alkyl)2, aminoalkyl (-NH(Ci-Cio alkyl) or -N(Ci-Cio alkyl)2), cyano (-CN), CONH2,

CONH(Ci-Cio alkyl), CON(Ci-Cio alkyl)2, hydroxyl (-OH), C1-C10 alkyl hydroxyl (- alkyl-OH), C1-C10 alkoxy(-O-alkyl), carboxylic acid (-COOH), C1-C10 alkyl esters (- COO-alkyl), C1-C10 alkyl acyl (-CO-alkyl), sulfonic acid (-SO3H), C1-C10 alkyl sulfonate (-SCte-alkyl), phosphonic acid (-PO(OH)2), C1-C10 alkyl phosphonate (- P0(0-alkyl)2), phosphinic acid (-P(0)(H)0H), SO2NH2, hydroxamic acid (- CONHOH), Ci-Cio alkyl sulfonylureas (-NHC0NHS02(alkyl)), Ci-Cio

acylsulfonamides (-S02-NHC0-(alkyl), hydroxyl amine (-NHOH), nitro (-NO2), and halogens. In a particular preferred embodiment the end-capping agent is selected from the group consisting of:

An advantage of the polymerization process is that it can be conducted without rigorous exclusion of e.g. water and oxygen, i.e. without elaborate processes such as degassing the reaction solution and reaction chamber, and/or drying the equipment and atmosphere used during the polymerization process. Thus, in one embodiment the polymerization is performed in an ambient atmosphere, such as ambient air. In another embodiment said polymerization is performed without the exclusion of oxygen. In yet another embodiment said polymerization is performed without the exclusion of water, i.e. without drying.

In one embodiment the mixing may be performed for 0.01-120 minutes, such as 2-60 minutes, 5-30 minutes, such as preferably 8-20 minutes. In another embodiment the temperature of the mixture during polymerization may be between -78 °C and 90 °C, such as -21 °C to 65 °C, 5 °C to 50 °C, 15 °C to 40 °C, 15 °C to 30 °C, such as preferably 18 °C to 25 °C.

Mixing of the monomer and end-capping agent can be done using various methods and the polymerization process is therefore considered to be very flexible and scalable. In one embodiment, mixing of the monomer and end-capping agent is performed by applying mechanical work. In a preferred embodiment the mechanical work is selected from grinding, milling, stirring, kneading, and ultra- sonication.

The amount of end-capping agent present during the polymerization is partly controlling the size of the produced polymers. The molar ratio between monomers and end-capping agent is therefore an important parameter to control. In a further embodiment the ratio between the monomer and the end-capping agent is in the range of 1 : 1.005 to 1: 2, such as 1 : 1.005 to 1 : 1.5, such as preferably 1 : 1.005 to 1 : 1.1.

The process of the present invention facilitates the production of end-capped polydisulfide which has the ability to efficiently degrade into smaller monomeric constituents that may be recycled and used in the production of new polymers or in other applications (SIPs). The produced polydisulfide is thus a stable material under normal circumstances, but degradation or de-polymerization can be triggered by applying specific external stimuli that remove the end-caps from the polymer thereby initiating degradation. In the present context, an external stimulus, is anything that is added, or otherwise applied to an end-capped polymer, or a mixture comprising end-capped polymer. Examples of such external stimuli are, but is not limited to, addition of acids or bases (pH changes), addition of reductants or oxidants (redox changes), addition of nucleophiles, exposure to UV and visible light, radicals, radical initiators (e.g. azobisisobutyronitrile (AIBN) and benzoyl peroxide (BPO)), heat, electrochemically induced redox changes, plasma, and nuclear irradiation.

Hence, in one embodiment, the degradation of the degradable end-capped polydisulfide may be initiated by one or more catalysts and/or UV radiation. In a more preferred embodiment the catalyst comprises a dithiol. In an even more preferred embodiment the catalyst comprises the dithiol monomer of the degradable polydisulfide. In a particularly preferred embodiment the catalyst comprises a base. Preferably, degradation may be triggered by the addition of both a base and a dithiol, such as e.g. the monomer of the degradable

polydisulfide.

In one embodiment the resulting polydisulfide may be further purified by

• dissolving the polydisulfide in a first solvent, optionally selected from

chloroform, dichloromethane, /V,/V,-dimethylformamide and

dimethylsulfoxide, or mixtures thereof

• precipitating the polydisulfide from the first solvent by addition of a second solvent, optionally selected from chloroform, dichloromethane, hexane, pentane, ethyl acetate, ether, acetone, or mixtures thereof

• optionally repeating the above two steps of dissolving and precipitating, and

• optionally drying the polydisulfide.

A particularly preferred embodiment of the invention relates to a process for the manufacture of an end-capped polydisulfide comprising the steps of:

• providing dithiothreitol (DTT) as the monomer,

• providing 2,2'-dipyridyldisulfide as the end-capping agent,

• performing a polymerization by mixing said monomer with said end

capping agent to obtain said end-capped polydisulfide,

wherein said polymerization is performed under non-solvated conditions.

Another particularly preferred embodiment of the invention relates to a process for the manufacture of an end-capped polydisulfide comprising the steps of:

• providing 2-aminobutane-l, 4-dithiol (DTBA) as the monomer,

• providing 2,2'-dipyridyldisulfide as the end-capping agent,

• performing a polymerization by mixing said monomer with said end

capping agent to obtain said end-capped polydisulfide,

wherein said polymerization is performed under non-solvated conditions. Apart from polymers obtained by polymerization of a single monomers, the invention also relates to polymers that are obtained by polymerization of two or more different monomers, to form copolymers thereof.

In some cases certain substituents on the monomer unit are desirable, which are however not suitable for participation in the polymerisation process, typically since they will participate in the process or self-polymerise in undesirable ways. In these cases the monomer unit i.e. the alkyldithiol moiety of the polymer may be modified after polymerisation.

Hence, one embodiment of the present invention is the process for the

manufacture of an end-capped polydisulfide as described above, comprising the additional step of:

• modifying the alkyl dithiol moiety after polymerisation.

For example, placing an epoxide group on the alkyl dithiol group may be advantageous, an thus in one embodiment wherein m is 0, the end-capped polydisulfide is further modified in an additional step, such that R¹ and R² are fused to form an epoxide.

This modification may be obtained where R¹ and R² are hydroxyl, m is 0, and by addition of an epoxidation agent to the polymer selected from the group consisting of l,l-dimethoxy-N,N-dimethylmethanamine, l,l-diethoxy-N,N- dimethylmethanamine, l,l-diphenyloxy-N,N-dimethylmethanamine, 1,1- dibenzyloxy-N,N-dimethylmethanamine, and l,l-diethoxy-N,N- diethylmethanamine.

Other groups may be introduced after polymerisation, to form a polydisulfide wherein R¹ and R² are e.g. hydroxyl and further modified to form a moiety selected from the group consisting of O-acetyl, 0-1-methyl-ethylcarbonyl, and O-

1-bromo-l-methyl-ethylcarbonyl. For the 0-1-bromo-l-methyl-ethylcarbonyl substituent, the modification is achieved by a process comprising the addition of

2-bromo-2-methylpropionyl bromide (BIBB) to the polydisulfide. Furthermore, the end-cap (S-R³) may also be exchanged by another end-cap (S- R^3') after polymerisation. This is also particularly relevant in relation to end-caps which would reduce the yields of the polymerisation process if used therein.

Thus, one embodiment of the present invention is the process for manufacturing an end-capped polydisulfide as decribed above comprising the additional step of:

• exchanging the end-cap (-S-R³) with an alternative end-cap (-S-R³ ) after polymerisation.

The step may be achieved via treatment of the polymer with free thiol, i.e. HS-R^3'. The polymer and free thiol may be dissolved in solvent, such as DMF or DMSO.

R^3' may preferably be selected from the group consisting of 4-aminophenyl, an alkyl silyl derivative, such as ferf-butyldimethylsilyl-thiopropylthio, or tert- butyldimethylsilyl-thiobutylthio.

Thus, a second aspect of the invention relates to a process for the manufacture of an end-capped copolymer comprising at least two different polydisulfides comprising the steps of:

• providing a first monomer selected from the group consisting of an

• providing a second monomer selected from the group consisting of an

optionally substituted C1-C12 alkyl dithiol, and an optionally substituted C6- C14 aryl dithiol, which is different from the that of the first monomer

• optionally providing one or more further monomers selected from the

group consisting of an optionally substituted C1-C12 alkyl dithiol, and an optionally substituted C6-C14 aryl dithiol,

wherein said polymerization is performed under non-solvated conditions. The ratio between the accumulated two or more monomers and the end-capping agent are preferably as described for the first aspect involving a single monomer. The ratio between individual dithiol monomers may be varied according to the desired percentage of each monomer unit in the polymer.

The solvent-free process of the present invention allows for the facile production of larger polymers with a high molecular weight and a high degree of

polymerization as compared to analogous polymerizations in solution. Thus, a third aspect of the invention relates to a polydisulfide of formula (I) :

wherein

R¹ and R² are independently selected from the group consisting of -H, -OR', - N(R')R", and -N(R')₃ ⁺ or wherein R¹ and R² are fused to form a 5- or 6-membered cyclic ketal or silicon ketal, or wherein R¹ and R² are fused to form an epoxide,

R' and R" are independently selected from the group consisting of H, -(C1-C6 alkyl), -CO(Ci-Ce alkyl), -COO(Ci-Ce alkyl), -CONH(Ci-Ce alkyl), -Si(Ci-Ce alkyl)₃, and -Si(phenyl)2(Ci-C6 alkyl), wherein the C1-C6 alkyl may be substituted with halogen

m is an integer selected from 0, 1, 2, and 3, and

y is an integer between 80 and 2000.

R¹, R², R³, R^3', R^' and R^" may preferably be further defined as described for the above aspects. Preferably n is 0 and m is 1. In one preferred embodiment the polydisulfide is the polydisulfide obtained when y is an integer between 90 and 1800, such as between 100 and 1600, such as preferably between 120 and 1400. Alternatively the size of the polymer may be defined by the degree of polymerisation (DP). Hence, the end-capped polydisulfide may preferably have a DP of 5-2000, such as 10-1000, such as 20-1000, 50- 1000, 100-1000, such as 200-1000. It should be noted that embodiments and features described in the context of one of the aspects of the present invention also apply to the other aspects of the invention. Particularly the preferred embodiments of the first aspect also apply to the second and third aspect as well as alternative aspects. All patent and non-patent references cited in the present application, are hereby incorporated by reference in their entirety.

The invention will now be described in further details in the following non-limiting examples.

Examples

Materials

Dithiothreitol (DTT) (95-99% pure)

Triethylamine (TEA) (95-99% pure)

/V,/V,-Dimethylformamide (DMF) (HPLC grade)

Chloroform (HPCL grade)

Hexanes (HPCL grade)

Acetic acid (Glacial)

DMSO-de (99.96 atom% D)

All chemicals were purchased from Sigma-Aldrich and used without further purification.

Certain suitable end-capping agents are illustrated in Table la.

Table la: Non-exhaustive list of end-capping agents that can be used for manufacturing of end-capped polydisulfides.

Certain suitable monomers are illustrated in Table lb.

Table lb: Non-exhaustive list of dithiol monomers that can be used for manufacturing of end-capped polydisulfides. See also Table 3 for additional monomers tested.

Instrumentations

Nuclear magnetic resonance (NMR) :

NMR spectroscopy was recorded on a Bruker 400 MHz spectrometer

Gel permeation chromatography (GPC) :

Gel permeation chromatography was performed using a system comprising a LC-20AD Shimadzu HPLC pump, a Shimadzu RID-10A refractive index detector, and a DAWN HELEOS 8 light scattering detector with a SPD-M20A PDA detector, equipped with a Mz-Gel SDplus Linear column (8 c 300 mm) with 5 pm particles from MZ-Analysentechnik providing an effective molecular weight range of 1 x 10³ - 1 x 10⁶ Da. For solvent was used /V,/V-dimethylformamide (DMF) with 10 mM LiBr.

Differential scanning calorimetry (DSC) :

DSC analysis was performed with a PerkinElmer DSC 8000. The samples (~11 mg) were loaded in Al pans (50 pL with holes) and rapidly cooled down to -25 °C in inert (N2) atmosphere. DSC analysis was performed from -25 to 140 °C with a 5 °C/minute gradient, in N2 atmosphere. Example 1 Solvent free preparation of end-capped oolviDTT )

DTT (1 equiv.) and DPS (1 + z equivalent) are added to a mortar without any pre purification and with the excess parameter z ranging between 0.005 and 0.1. The two components are grinded to a paste using a pestle for 10 minutes or until the entirety has turned into a yellow solid. The heat produced from the grinding is sufficient to melt the materials. This process results in the crude polydisulfide product in very good purity.

To further purify the product, the polymer may be dissolved in DMF and precipitated using a 1/1 (v/v) mixture of chloroform and hexanes to remove any small molecular fragments. The polymer is then separated by centrifugation and the solvent removed by decantation. The polymer is dissolved again in DMF and precipitated using a 1/1 (v/v) mixture of chloroform and hexanes. The last process step is repeated 5 times and followed by drying under vacuum. Five different samples of end-capped poly(DTT) were prepared and data for the samples are provided in Table 2, entries 1-5. The polymers are characterized by properties such as the degree of polymerization (DP), molecular weight of the polymer (M), and the polydispersity index (PDI).

ratio between dithiothreitol and 2,2'-dipyridyldisulfide (n(DTT)/n(DPS)) used in the preparation of the respective polymer samples; Mtheo, MNMR, and MGPC are the theoretically calculated and experimentally obtained (NMR or GPC) values for the molecular weight of the polymer. Experimental values for MNMR were obtained using ^-NMR spectroscopy in d6-DMSO as internal reference (2.50 ppm). The recorded spectra for the produced polymers have peaks in the aromatic region at d = 8.4, 7.8, and 7.2 ppm which pertain to the pyridyl disulfide group (end-cap) at the end of the chain, whereas the one appearing at d = 4.9 ppm is attributed to the main chain hydrogen in - CH(O )-. Integration values for the peaks were used to calculate experimental values for MNMR and DPNMR. See also figure 7 for exemplary ^-NMR. The molecular weight of each of the prepared polymers obtained from NMR and shown in Table 2, ranges from 3000 g/mol to 17100 g/mol. These numbers can be used to calculate DP, which relates to the number of monomeric units in a polymer. The experimental values for the molecular weight, reveal that the molar ratio between DTT and DPS defines the size of the final polymers. Increasingly heavy polymers are thus obtained when using decreasing amounts of end-capping agent, proving that the polymerization stops when the polymers are end-capped. Apart from the data provided in Table 2, the polymers are also characterized by other properties, such as the glass transition temperature (T_g).

Differential scanning calorimetry (DSC) was used to obtain a range for Tg of the produced end-capped poly(DTT). The thermogram for the experiment is depicted in Figure 4 and shows that the value for the glass transition temperature is somewhere in between 20 and 40 °C.

Additional monomers and end-capping agents are tested in equivalent

experiments with satisfactory yields, purity and DP/MW, cf. Table la and Table lb.

Example 2 - Triggered depolvmerization of end-capped polvfDTT )

The depolymerization may be a result of a disulfide exchange reaction happening along the backbone of the polymer as shown in Figure 1. The formation of the thermodynamically stable 6-membered cyclic disulfide (c-DTT) is considered the driving force for the depolymerization.

Stabilities and depolymerization of the end-capped poly(DTT) were investigated NMR. A stock solution of the polymer (entry 2, Table 2) (24 mg) was prepared in DMSO-d6 (1.8 ml_) and equally divided into 3 NMR tubes. Stock solutions were prepared of TEA (0.005 ml_) in DMSO-d6 (0.5 ml_) and acetic acid (0.005 ml_) in DMSO-d6 (0.5 ml_). The TEA solution (0.017 ml_) was added to the polymer solution in one NMR tube, and the acetic acid solution (0.007 ml_) was added to another NMR tube containing the polymer solution. The resulting solutions of polymer were stored at RT and

NMR were taken periodically.

Percentages of formed c-DTT were calculated from integration values of the main chain (-CH(0 H)-) peak at d = 4.91 ppm and peak (-CH(0 H)-) at d = 5.22 ppm of c-DTT.

The results of the stability studies are shown in Figure 2, together with the results obtained from an experiment where a neutral sample was heated to 60 °C. Taken together, the graphs illustrate that the depolymerization of end-capped poly(DTT) can be triggered by adding a base, because of the vast increase in the rate of depolymerization measured in the experiment where TEA is added. Figure 2 also shows that the end-capped poly(DTT) is stable under neutral and acid conditions at ambient temperature and only degrades slowly when heated to 60 °C.

Another possibility for activating the depolymerization is to expose the end- capped poly(DTT) to UV-light. Figure 3, shows the results of an experiment where an NMR tube containing end-capped poly(DTT) and DMSO-d6 was exposed to UV light (365 nm) in 1 minute intervals. It is seen from Figure 3, that the end-capped poly(DTT) depolymerizes quickly under exposure to UV light, but is at a hold when the light is turned off.

Example 3 - Composition for fast depolvmerization of end-capped oolviDTT ) Depolymerization of end-capped poly(DTT) in the presence of monomeric DTT was studied by the following procedure. A stock solution of a polymer (entry 2, Table 2) (30 mg) was prepared in DMSO-d6 (3.5 ml_) in a scintillation vial equipped with a magnetic stir bar. Stock solutions were prepared of TEA (0.005 ml_) in DMSO-d6 (0.05 mL), DTT (5 mg) in DMSO-d6 (0.05 ml_), and DPS (4 eq., 4.0 mg) in DMSO- 06 (0.7 mL). The DPS solution was equally divided into 7 small vials. The TEA solution (0.0064 mL) was then added to the polymer solution together with the DTT solution (0.014 ml). Aliquots were taken periodically and the reaction immediately quenched by adding one of the DPS solutions. The extent of depolymerization of poly(DTT) was determined using

NMR relative integration values for the -OH peak in the linear polymer and the -OH peak of c-(DTT).

Similar experiments were performed under the same conditions as above, but in the absence of TEA, and with and without O2.

The experiments revealed that a fast depolymerization of end-capped poly(DTT) can be achieved by using a mixture of DTT and TEA in ambient air, see Figure 5. The figure also shows that the presence of O2 greatly slows the depolymerization if there is no base in the mixture, yet performing the degradation under N2 increases the rate of depolymerization.

Example 4 - Preparation of copolymers

End-capped copolymers were created from DTT and 1,4-butanedithiol monomers by the method outlined in example 1. The end-capped copolymer obtained by this procedure is a 1 : 1 copolymer (see Figure 6). It is expected that any other compound comprising at least two thiol groups should able to polymerize with DTT monomers, thus to give a copolymer of the two.

DTT (1 equiv.), 1,4-butanedithiol (1 equiv.), and DPS (2 + 2z equivalent) are added to a round bottomed flask without any pre-purification and with the excess parameter z being 0.05. To the three components are added dichloromethane (DCM), 2 ml per gram of monomers, and a drop of acetic acid (AcOH). The mixture was stirred for 3 hours or until a yellow slush was obtained. The reaction mixture is precipitated into diethyl ether. The polymer may be dissolved in chloroform and precipitated using a 1/4 (v/v) mixture of chloroform and hexanes to remove any small molecular fragments. The polymer is then separated by centrifugation and the solvent removed by decantation. The polymer is dissolved again in chloroform and precipitated using a 1/4 (v/v) mixture of chloroform and hexanes. The last process step is repeated 5 times and followed by drying under vacuum. Example 5 - Preparation of end-capped polymers from other monomers

Polymers of other monomers than DTT have also been prepared by the procedure described in example 1. The respective monomer (1 equiv.) and DPS (1.05 equiv.) are added to a round bottomed flask. The two components are stirred using 2 ml per gram of monomer in DCM until the reaction turned into a yellow slush, or 2 hours. The produced polymers are further purified and their yields calculated (Table 3). By dissolving in chloroform and precipitating into diethyl ether. The polymer may be dissolved in chloroform and precipitated in diethyl ether to remove any small molecular fragments. The polymer is then separated by centrifugation and the solvent removed by decantation. The last process step is repeated 5 times and followed by drying under vacuum.

Table 3: Polymers prepared from monomers other than DTT. The molar ratio between monomer and DPS (n(monomer)/n(DPS)) used in the preparation of the respective polymer samples; MNMR is the experimentally obtained values for the molecular weight of the polymer when determined using NMR. Example 6 - preparation of acetylated (Ac) monomer

Synthesis of cDTT DTT (3.022 g, 19.6 mmol, 1 eq.) and Nal (0.0431 g, 0.288 mmol, 0.015 eq.) was dissolved in H2O (55 ml_) by stirring at room temperature in ambient conditions. H2O2 (33 % w/w in water) (1.9 ml_, 20 mmol, 1 eq.) was added and the reaction was left an hour to react. The reaction was quenched with saturated Na2S203 solution (150 ml_) and left a moment before extracted 4 times with ethyl acetate (EtOAc) (4x 125 ml_). The combined organic phases were divided in 3 portions, which were each washed with brine (150 ml_). The washed organic phases were combined and dried over MgSCb. The product was concentrated under reduced pressure to yield a white solid (2.431 g, 16.0 mmol, 81 %). 1H NMR (400 MHz, DMSO-de) H(ppm) 5.22 (2H, d), 3.34 (2H, m) 3.02 (2H, d), 2.73 (2H, dd). 13C NMR(100 MHz, DMSO-de) C(ppm) 73.4, 40.2. IR(ATR) max crrr¹) 3427, 3300, 2874, 1452, 1033, 1006.

Synthesis of cDTT(Ac)2

AC2O (0.97 ml_, 10 mmol, 2.4 equiv.) was mixed with pyridine (1.4 ml_, 17 mmol, 4.1 equiv.) under argon atmosphere and heated to 50 °C. cDTT (0.648 g, 4.26 mmol, 1.0 equiv.) was added little at a time, and the mixture was stirred for an hour. The reaction was quenched with milliQ water and extracted with EtOAc. The combined organic phases was washed with brine, dried over MgS04 and concentrated under reduced pressure yielding a crude product consisting of CDTT(AC)2, acetic acid and pyridine. The crude product was dissolved in EtOAc and washed 3 times with water to remove acetic acid and pyridine and one time with brine. The organic phase was dried over MgS04 concentrated under reduced pressure which yielded clean product (0.664 g, 2.81 mmol, 66.0 %). 1H NMR (400 MHz, CDCb) H(ppm) : 5.01 (2 H, dd), 3.15 (2 H, dd), 3.08-3.03 (2H, m), 2.05 (6 H, s). 13C NMR (101 MHz, CDCb) C(ppm) 169.9, 72.2, 38.4, 21.0.

IR(ATR) max(cm ^_1) 2952(w), 1734(s), 1229(s), 1023(s), 544(w).

Synthesis of DTT(Ac)2

CDTT(AC)2 (0.099 g, 0.419 mmol, 1.00 equiv.) was suspended in 0.1 M phosphate buffer (10 ml_). Tris(2-carboxyethyl)phosphine hydrochloride (TCEP) (0.211 g, 0.736 mmol, 1.76 equiv.) was added and the reaction was stirred for 3 hours and 40 minutes, until all cDTT was dissolved. The water phase was extracted with DCM 8 times. The combined organic phases was washed with brine, dried over MgSCb and concentrated under reduced pressure yielding the monomer (0.067 g, 0.281 mmol, 67 %). 1H NMR (400 MHz, CDCb) H(ppm) : 5.24 (2 H, m), 2.67 (4 H, dd), 2.14 (6 H, s), 1.55 (2 H, t).

13C NMR (101 MHz, CDCb) C(ppm) 170.4, 73.4, 24.7, 20.9. IR(ATR) max crrr¹) 2943(w), 2570(w), 1734(s), 1210(s), 1028(s).

The DTT(Ac)2 monomer is ready for polymerization as described in the preceding examples.

Example 7 - Treatment of already prepared end-capped polvdisulfide for

pDTT

The synthesis of pDTT follows the general procedure of Example 1 :

DPS (0.750 g, 3.40 mmol, 1.05 equiv.) and DTT (0.500 g, 3.32 mmol, 1.00 equiv.) was measured very precisely and mixed in a mortar with a pestle until the compounds turned into a yellow glaze of the bowl. The mixture was left to react ten minutes and dissolved in DMF. The dissolved polymer was precipitated in CHCb/pentane 1 : 1 and centrifuged. The precipitate was dissolved in DMF and precipitated again in CHCb/pentane 1 : 1 three times. Precipitated another two times and dried on vacuum. 1H NMR (400 MHz, DMSO-d6) H(ppm) : 8.45 (1 H, d), 7.86-7.80 (2 H, m), 7.26-7.23 (1 H, m), 4.91 (12 H, s), 3.72 (12 H, s), 2.94-2.89 (12 H, m), 2.80-2.73 (12 H, m). Synthesis of PDTT(AC)2

pDTT pDTT(ac)2 AC2O (0.15 mL, 1.6 mmol) was mixed with pyridine (0.25 ml_, 3.1 mmol) under argon atmosphere and heated to 50 °C while stirring. pDTT (0.100 g) was added and dissolved quicker than 30 minutes. The reaction was left to react for 2 hours. The reaction was quenched with milliQ water and extracted with EtOAc. The combined organic phases were washed with water 3 times, washed with brine, dried with Mg2SC>4 and concentrated under reduced pressure to yield the crude product, which contained cyclic monomer. This byproduct was washed off by washing the polymer in 9 batches of methanol. This resulted in acetylated polymer pDTT(Ac)₂ (0.071 g). 1H NMR (400 MHz, DMSO-de) H(ppm) : 8.48 (1H, d), 7.83 (1H, m), 7.73 (1H, m), 7.26 (1H, m), 5.29 (8H, s), 2.99-2.84 (15H, m), 2.07 (16H, s), 2.05 (5H, s).

Synthesis of pDTT(BrdiMeAc)2

pDTT(BrdiMeAc)₂ pDTT (300 mg, 1.97 mmol, 1 equiv.) was dissolved in dry DMF (1.5 mL) and dry pyridine (1.5 mL) in a test tube equipped with stir bar. The solution was purged with N2 and placed in the ice water bath. 2-Bromo-2-methylpropionyl bromide (BiBB) (907 mg, 3.94 mmol, 2 equiv.) was taken in a syringe and added slowly through the needle. The reaction was carried out for 2 hours at room

temperature. The solvent was washed with water 3 times. The solvent was reduced by rotary evaporator, and product precipitated in pentane, and dried in high vacuum pump, then obtained as a white product. Yield (30-40%).

Example 8 Treatment of already prepared end-capped polvdisulfide to prepare polvdisulfides with alternative end-caps

Substitution of pyridine end-cap bv 4-aminobenzenethiol pDTT

4-aminobenzenethiol was dissolved in 0.2 ml_ DMF and added to a solution of pDTT (30 mg) dissolved in 1 ml_ DMF equipped with a magnetic stir bar. The mixture was left to react for 30 minutes before precipitation into CHC /pentane 1 : 1 v/v resulting in the product as a white powder.

Substitution of end-cap bv mono TBS-protected 1,4-butanedithiol

TBS-protected 1 ,4-butanedithiol

The TBS-protected 1,4-butanedithiol was first prepared by the following

procedure. A mixture of ferf-butyldimethylsilyl chloride (TBSCI) (0.904 g, 6 mmol) and imidazole (0.408 g, 6 mmol) was dissolved in 2 ml_ DMF in a 10 ml_ round bottomed flask equipped with a magnet and argon atmosphere. 1,4-butanedithiol (0.734 g, 6 mmol) was added and the solution heated to 40 °C and stirred overnight. The solution was transferred to a separation funnel using 5 ml_ EtOAc and 5 ml_ demineralized water. Additional 10 ml_ EtOAc and 10 ml_ water was added. The organic phase was washed 3 times with water (10 ml_). The product was purified with column chromatography using 1 : 100 EtOAc/pentane yielding the mono TBS-protected 1,4-butanedithiol (i.e. 4-((tert-butyldimethylsilyl)thio- butane-l-thiol) as a clear oil (0.742 g, 52% yield). 1H NMR (400 MHz, CDC ) H(ppm) : 2.54 (4H, m), 1.73 (4H, m), 1.35 ( 1H, dt), 0.95 (9H, s) 0.25 (6H).

pDTT PDTT20-TBS Substitution of the end-caps in pDTT by the prepared mono TBS-protected 1,4- butanedithiol as depicted in the reaction scheme above, follows the following procedure. The mono TBS-protected 1,4-butanedithiol was dissolved in 0.2 ml_ DMF and added to a solution of pDTT (30 mg) dissolved in 1 ml_ DMF equipped with a magnetic stir bar. The mixture was left to react for 30 minutes before precipitation into CHC /pentane 1 : 1 v/v resulting in PDTT20-TBS as a white powder. 1H NMR (400 MHz, DMSO-de) H(ppm) : 5.23 (1H, s), 4.91 (34H, d), 3.72 (34H, bs), 2.91 (34H, m), 2.78 (34H, m), 0.92 (9H, s), 0.24 (6H, s).

Example 9 - solid state depolvmerisation of pDTT

The depolymerization process is significant if it is carried out in solid state to alleviate the need of using potential harmful organic solvents. To test this possibility, a solid piece of pDTT20 was submerged in D2O. In itself, pDTT20 neither dissolves nor degrades when stored in D2O for 20 days (Figure S8). However, when a piece of pDTT is submerged in D2O containing 2 equiv of Et3l\l and 4 equiv of DTT in a NMR tube under ambient conditions, it visually disappears, as depicted in Figure 8.

References

• WO 2008/053479.

• US 8,871,893.

• US 2017/0073452.

• D. Basak et al., Macromolecular rapid communications, 2014, 35, 1340-

Claims

1. A process for the manufacture of an end-capped polydisulfide comprising the steps of:

· performing a polymerization by mixing said monomer with said end

capping agent to obtain said end-capped polydisulfide,

wherein said polymerization is performed under non-solvated conditions.

2. The process according to claim 1, wherein the end-capped polydisulfide is degradable.

3. The process according to any one of the preceding claims, wherein the end- capped polydisulfide is a self-immolative polydisulfide.

4. The process according to any one of the preceding claims, wherein the end- capped polydisulfide is a polydisulfide of formula (I) :

wherein

R¹ and R² are independently selected from the group consisting of -H, -OR', -

N(R')R", and -N(R')₃ ⁺, or wherein R¹ and R² are fused to form a 5- or 6-membered cyclic ketal or silicon ketal, or wherein R¹ and R² are fused to form an epoxide,

R' and R" are independently selected from the group consisting of H, -(C1-C6 alkyl), -CO(Ci-C₆ alkyl), -COO(Ci-C₆ alkyl), -CONH(CI-C6 alkyl), -Si(Ci-Ce alkyl)₃, and -Si(phenyl)2(Ci-C6 alkyl), wherein C1-C6 alkyl may be substituted with halogen, R³ is selected from the group consisting of an optionally substituted aryl, an optionally substituted silyl alkyl dithiol, and an optionally substituted heteroaryl, n is an integer selected from 0, 1, 2, 3, and 4,

m is an integer selected from 0, 1, 2, and 3, and

y is an integer between 3 and 2000.

5. The process according to any one of the preceding claims, wherein the monomer is optionally substituted with a moiety selected from the group consisting of Ci-Cio alkyl, C2-C10 alkenyl, C2-C10 alkynyl, amino (-NH2), - CH₂NH(CI-CIO alkyl), -CH₂N(CI-CIO alkyl)₂, aminoalkyl (-NH(Ci-Cio alkyl) or -N(Ci- C10 alkyl)₂), cyano (-CN), CONH2, CONH(Ci-Cio alkyl), CON(Ci-Cio alkyl)₂, hydroxyl (-OH), C1-C10 alkyl hydroxyl (-alkyl-OH), C1-C10 alkoxy(-O-alkyl), C1-C10 alkyl carbonyloxy (-O-CO-alkyl), carboxylic acid (-COOH), C1-C10 alkyl esters (- COO-alkyl), C1-C10 alkyl acyl (-CO-alkyl), sulfonic acid (-SO3H), C1-C10 alkyl sulfonate (-SC -alkyl), phosphonic acid (-PO(OH)2), C1-C10 alkyl phosphonate (- PO(0-alkyl)2), phosphinic acid (-P(0)(H)OH), SO2NH2, hydroxamic acid (- CONHOH), C1-C10 alkyl sulfonylureas (-NHCONHS02(alkyl)), C1-C10

acylsulfonamides (-S02-NHCO-(alkyl), hydroxyl amine (-NHOH), nitro (-NO2), - Si(Ci-C6 alkyl)3, -Si(phenyl)2(Ci-C6 alkyl), ketals, silicon ketals, and halogens.

6. The process according to any one of the preceding claims, wherein the monomer is a compound of formula (II) :

wherein

R¹ and R² are independently selected from the group consisting of -H, -OR', - N(R')R", and -N(R')₃ ⁺, or wherein R¹ and R² are fused to form a 5- or 6-membered cyclic ketal or silicon ketal,

R' and R" are independently selected from the group consisting of H, -(C1-C6 alkyl), -CO(Ci-C₆ alkyl), -COO(Ci-C₆ alkyl), -CONH(CI-C6 alkyl), -Si(Ci-Ce alkyl)₃, and -Si(phenyl)2(Ci-C6 alkyl),

n is an integer selected from 0, 1, 2, 3, and 4, and

m is an integer selected from 0, 1, 2, and 3.

7. The process according to any one of the preceding claims, wherein the monomer is selected from the group consisting of 2-aminobutane-l, 4-dithiol (DTBA), dithiothreitol (DTT), dithioerythritol (DTE), and hydroxyl-protected derivatives of DTT and DTE.

8. The process according to any one of the preceding claims, wherein the end capping agent is a compound of formula (III):

wherein

9. The process according any of the preceding claims, wherein the optionally substituted aryl of the end-capping agent is selected from the group consisting of phenyl, and naphthyl.

10. The process according to any one of claims 1 to 8, wherein the heteroaryl is selected from the group consisting of pyrrolyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, oxazolyl, isooxazolyl, pyrazolyl, imidazolyl, 1,2,3-oxadiazolyl, 1,2,4- oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,4-triazinyl, and 1,3,5-triazinyl.

11. The process according to any one of the preceding claims, wherein the optional substituent(s) on the aryl or heteroaryl of the end-capping agent are independently selected from the group consisting of Ci-Cio alkyl, C2-C10 alkenyl, C2-C10 alkynyl, amino (- N H2), -CH2N H (CI-CIO alkyl), -CH2N (CI-CIO alkyl)2, aminoalkyl (-NH(Ci-Cio alkyl) or -N(Ci-Cio alkyl)2), cyano (-CN), CONH2,

CONH(Ci-Cio alkyl), CON(Ci-Cio alkyl)2, hydroxyl (-OH), C1-C10 alkyl hydroxyl (- alkyl-OH), C1-C10 alkoxy(-O-alkyl), carboxylic acid (-COOH), C1-C10 alkyl esters (- COO-alkyl), C1-C10 alkyl acyl (-CO-alkyl), sulfonic acid (-SO3H), C1-C10 alkyl sulfonate (-SCte-alkyl), phosphonic acid (-PO(OH)2), C1-C10 alkyl phosphonate (- P0(0-alkyl)2), phosphinic acid (-P(0)(H)0H), SO2NH2, hydroxamic acid (- CONHOH), C1-C10 alkyl sulfonylureas (-NHCONHS02(alkyl)), C1-C10

acylsulfonamides (-S02-NHC0-(alkyl), hydroxyl amine (-NHOH), nitro (-NO2), and halogens.

12. The process according to any one of the preceding claims, wherein the end capping agent is selected from the group consisting of 2,2'-dipyridyldisulfide (DPS), 5,5'-dithiobis-(2-nitrobenzoic acid) (DTNB), 2,2'-dithiobis(5- aminopyridine) (DTAP), and 2,2'-dithiobis(5-hydroxypyridine) (DTHP).

13. The process according to any one of the preceding claims, wherein the process is performed under conditions essentially free of a solvent.

14. The process according to any one of the preceding claims, comprising the additional step of:

• modifying the alkyl dithiol moiety after polymerisation.

15. The process according to claim 14, wherein m is 0, and wherein the end- capped polydisulfide is further treated in an additional step such that R¹ and R² are fused to form an epoxide.

16. The process according to any one of the preceding claims, comprising the additional step of:

17. The process according to claim 16, wherein R^3' is selected from the group consisting of 4-aminophenyl, ferf-butyldimethylsilyl-thiopropylthio, and tert- butyldimethylsilyl-thiobutylthio.

18. A process for the manufacture of an end-capped co-polymer comprising at least two different polydisulfides comprising the steps of:

• providing a first monomer selected from the group consisting of an

optionally substituted C1-C12 alkyl dithiol, and an optionally substituted C6- C14 aryl dithiol, • providing a second monomer selected from the group consisting of an optionally substituted C1-C12 alkyl dithiol, and an optionally substituted C6- C14 aryl dithiol, which is different from the that of the first monomer

• optionally providing one or more further monomers selected from the

· performing a polymerization by mixing said first and second and optionally further monomers with said end-capping agent to obtain said end-capped copolymer comprising at least two polydisulfides,

wherein said polymerization is performed under non-solvated conditions.

19. A polydisulfide of formula (I):

wherein

R¹ and R² are independently selected from the group consisting of -H, -OR', - N(R')R", and -N(R')3⁺, or wherein R¹ and R² are fused to form a 5- or 6-membered cyclic ketal or silicon ketal, or wherein R¹ and R² are fused to form an epoxide,

R' and R" are independently selected from the group consisting of H, -(C1-C6 alkyl), -CO(Ci-C₆ alkyl), -COO(Ci-C₆ alkyl), -CONH(CI-C6 alkyl), -Si(Ci-Ce alkyl)₃, and -Si(phenyl)2(Ci-C6 alkyl), wherein C1-C6 alkyl may be substituted with halogen,

m is an integer selected from 0, 1, 2, and 3, and

y is an integer between 80 and 2000.